Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([S:8][C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(Cl)c2cccnc2c1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1cc(SCc2ccccc2)c2cccnc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl mercaptan (6 mL, 50.5 mmol) was added dropwise to a mixture of 5,7-dichloroquinoline (10 g, 50.5 mmol), cesium carbonate (20 g, 60 mmol) and DMF (50 mL) at 0° C. The reaction mixture was allowed to warm to room temperature, stirred for 2 hours and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried with sodium sulfate and concentrated. Purification by column chromatography gave the 5-(benzylthio)-7-chloroquinoline (rf=0.5 in 2:1 hexanes/ethyl acetate) as a crystalline yellow solid. The undesired regioisomer elutes afterwards (rf=0.4 in 2:1 hexanes/ethyl acetate). The reaction is mildly selective for the desired isomer.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([CH:28]1[CH2:31][CH2:30][CH2:29]1)[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:20][S:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:9][CH2:8]1.C[Al](C)C.[CH3:37][NH2:38]>C(Cl)Cl>[CH:28]1([N:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[C:14]4[C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:20][S:19][C:15]=4[N:16]=[CH:17][N:18]=3)[CH2:11][CH2:12]2)[CH2:4][C:3]([NH:38][CH3:37])=[O:2])[CH2:29][CH2:30][CH2:31]1
Reactant: COC(=O)CN(CC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1)C1CCC1
Reactant: CN
Agent: C[Al](C)C
Solvent: ClCCl
Product: CNC(=O)CN(CC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1)C1CCC1
Temperature: 25 °C

Procedure:
The reaction was stirred for min and then allowed to warm to room temperature. After stirring for 30 minutes, methyl-2-[cyclobutyl-[[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-4-piperidyl]methyl]amino]acetate (37 mg, 0.082 mmol) in DCM (0.5 mL) was added dropwise and the reaction stirred for 2 h. A further 123 μL of trimethylaluminium and a further 123 μL of methylamine were added and the reaction stirred overnight at room temperature. The solvents were then evaporated and the residue purified by column chromatography eluting 0 to 5% v/v of 7 M ammonia/methanol in DCM to give 2-[cyclobutyl-[[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-4-piperidyl]methyl]amino]-N-methyl-acetamide as a colourless solid (6 mg). LCMS RT=3.01. M+1=450.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C:18](O)=[O:19])[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1>O1CCOCC1>[CH3:16][O:15][C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([O:8][CH3:7])[CH:14]=1)[CH2:17][CH2:18][OH:19]
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1cc(CCO)cc(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
To a mixture of LiAlH4 (1.05 g) in dioxane (100 ml) was added a solution of 3,5-dimethoxyphenyl acetic acid (5.32 g) in dioxane (20 ml) portionwise at 0° C. The mixture was stirred at room temperature for 0.5 hour and at 50° C. for 2 hours. The mixture was quenched with conc. NH4OH and filtered through Celite. The filtrate was evaporated to yield 3,5-dimethoxyphenethyl alcohol (5.1 g). IR (Neat) 3400, 1600 cm−1; MS (GC-EI) 182 (M+), 151 (M-MeO).
Reaction SMILES: C(OC([P:8]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:12])[O:9]CC)OCC)C.O>Cl>[CH:14]1([CH2:13][PH:8](=[O:9])[OH:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(OCC)P(=O)(CC1CCCCC1)OCC
Agent: Cl
Solvent: O
Product: O=[PH](O)CC1CCCCC1
Temperature: 25 °C

Procedure:
A solution of 38.3 g of ethyl diethoxymethyl(cyclohexylmethyl)phosphinate in 30 ml of concentrated aqueous hydrochloric acid is treated with 30 ml of water and the mixture is heated to reflux for 5 hours. After cooling to room temperature, the mixture is washed with ether/hexane (1:1). A three-phase system is obtained. The lower phase is removed and the water removed in vacuo to give a white crystalline solid. The middle phase is an oil which crystallises on standing. These two are combined to give cyclohexylmethylphosphinic acid which is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([C:47]2[C:48]([CH:53]=O)=[N:49][CH:50]=[CH:51][CH:52]=2)([CH3:46])[CH3:45])=[CH:40][CH:39]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=1)[CH2:53][C:48]1[C:47]([C:44]([C:41]2[CH:40]=[CH:39][C:38]([F:37])=[CH:43][CH:42]=2)([CH3:46])[CH3:45])=[CH:52][CH:51]=[CH:50][N:49]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(c1ccc(F)cc1)c1cccnc1C=O
Reactant: Cc1cc(Cl)cnc1CNCCCCNC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1ncccc1C(C)(C)c1ccc(F)cc1

Procedure:
Using General Procedure B: Reaction of {4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester in CH2Cl2 and 3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde with NaBH(OAc)3 gave [4-((5-chloro-3-methyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino)-butyl]-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.26 (m, 4H), 1.44 (s, 9H), 1.64 (s, 6H), 2.13 (s, 3H), 2.31 (t, 2H, J=7.5 Hz), 2.94 (d, 2H, J=6.0 Hz), 3.28 (s, 2H), 3.51 (s, 2H), 5.12 (br s, 1H), 6.90-6.98 (m, 4H), 7.23 (dd, 1H, J=7.5, 3.0 Hz), 7.36 (s, 1H), 7.86 (d, 1H, J=9.0 Hz), 8.25 (d, 1H, J=3.0 Hz), 8.53 (d, 1H, J=3.0 Hz).
Reaction SMILES: [SiH](CC)(CC)CC.B(F)(F)F.[CH3:12][CH2:13][O:14]CC.[O:17]([C@H:25]1[CH2:32][C@H:28]2[O:29][CH2:30][CH2:31][C@@H:27]2[CH2:26]1)[Si](C(C)(C)C)(C)C>C(Cl)Cl>[O:29]1[CH2:30][CH2:31][C@H:27]2[CH2:26][C@H:25]([O:17][C:13](=[O:14])[CH3:12])[CH2:32][C@H:28]12
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CCO[C@@H]2C1
Reactant: CCOCC
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Product: CC(=O)O[C@H]1C[C@@H]2CCO[C@H]2C1
Yield: 58 %

Procedure:
To the bicyclic ether (228 mg, 1.065 mmol) and Et3SiH (370 mg, 3.196 mmol) in CH2Cl2 (5 mL) at room temperature, was added BF3.OEt2 (450 mg, 3.196 mmol) following the same reaction conditions as described in the synthesis of compound 3 to obtain compound 5 (140 mg, 58% three steps) as an oil. 1H NMR (CDCl3, 200 MHz): δ 5 (m, 1H), 4.5 (m, 1H), 3.95 (m, 1H), 3.74 (m, 1H), 2.7 (m, 1H), 2.1 (m, 3H), 2 (s, 3H), 1.5–1.9 (m, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.ClC(O[CH2:31][CH3:32])=O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:31][CH3:32])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2cc(N3CCN(CC)CC3)c(F)cc2c1=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
100 parts by weight of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)-3-quinoline-carboxylic acid were dissolved in 300 parts by volume of anhydrous chloroform, and 33.2 parts by weight of triethylamine were added. A solution of 37.7 parts by weight of ethyl chloroformate in 100 parts by volume of anhydrous chloroform was added dropwise to this mixture at -20° C. in the course of 30 minutes, and the mixture was stirred for a further 30 minutes at -20° C. and was then stirred overnight at room temperature. After extraction with twice 300 parts by volume of water, 400 parts by volume of water were added to the organic phase. The pH was adjusted to 5 with glacial acetic acid (consumption approximately 15 parts by volume), and the chloroform was removed by distillation under a water pump vacuum. The pH of the aqueous solution was adjusted to 8.9 with half-concentrated potassium hydroxide solution (consumption approximately 70 parts by volume), and the mixture was stirred overnight at room temperature. The product was filtered off with suction, washed with 500 parts by volume of water and dried overnight at 70° C. in a vacuum drying cabinet.
Reaction SMILES: [OH:1][CH:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]#[N:19].[H][H]>[Ni].CO>[NH2:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][CH2:13][CH2:12][N:6]1[C@@H:5]([CH2:4][CH2:3][CH:2]([OH:1])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:10][CH2:9][CH2:8][C:7]1=[O:11]
Reactant: N#CCOCCCCN1C(=O)CCC[C@@H]1CCC(O)Cc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: NCCOCCCCN1C(=O)CCC[C@@H]1CCC(O)Cc1ccccc1
Reaction time: 19 h
Yield: 65.6 %

Procedure:
Raney nickel (5 mg) was added to a solution of {4-[(R)-2-(3-hydroxy-4-phenyl-butyl)-6-oxo-piperidin-1-yl]-butoxy}-acetonitrile (10.5 mg, 0.029 mmol) in MeOH (1.5 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 6.9 mg (65%) of the title compound.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][OH:10])[O:5][CH2:4]2)[CH2:2]1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=1[CH3:22]>CS(C)=O>[CH2:2]1[C:3]2([CH2:8][O:7][CH:6]([CH2:9][O:10][C:14]3[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=3[CH3:22])[O:5][CH2:4]2)[CH2:1]1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: OCC1OCC2(CC2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OCC2OCC3(CC3)CO2)cc[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
The 5,7-dioxaspiro[2.5]oct-6-ylmethanol (1.7 g, 11.8 mmol) obtained by the step (2b) was mixed with sodium hydride, in oil (708 mg, 17.7 mmol as the content was regarded as 60%) and dimethylsulfoxide (20 ml), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (1.86 g, 11.8 mmol) was added and stirred at 50° C. overnight. After dimethylsulfoxide was distilled off, methanol and NH silica gel were added to the residue and methanol was distilled off. The mixture of the reaction mixture and NH silica gel was purified by silica gel column chromatography (NH silica gel: 200 g, elution solvent: ethyl acetate/heptane=1/1 to 4/1→methanol/ethyl acetate=1/9 to 1/4) to obtain the title compound (1.8 g, yield: 57.5%) as a red oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH2:18]([CH:20]([CH2:26][CH3:27])[C:21](=O)[CH2:22][C:23]#[N:24])[CH3:19]>>[Cl:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[F:8])[N:1]=[C:21]([CH:20]([CH2:26][CH3:27])[CH2:18][CH3:19])[C:22]([C:23]#[N:24])=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(CC)C(=O)CC#N
Reactant: Nc1cc(F)c(Cl)cc1C(=O)c1ccccc1
Product: CCC(CC)c1nc2cc(F)c(Cl)cc2c(-c2ccccc2)c1C#N

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-4-fluoro-phenyl)-phenyl-methanone (prepared as described in example 105 step D) and 4-ethyl-3-oxo-hexanenitrile (prepared as described in example 101 step A). Off-white solid. MS (ESI): 353.4 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.CC(C)([O-])C.[K+].[C:12]([C:14]1([C:17]2([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][O:18]2)[CH2:16][CH2:15]1)#[N:13].CN(C=O)C>C(OCC)(=O)C>[C:12]([C:14]1([C:17]([OH:18])([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH2:15][CH2:16]1)#[N:13]
Reactant: N#CC1(C2(CCc3ccccc3)CO2)CC1
Reactant: c1nc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC1(C(O)(CCc2ccccc2)Cn2cncn2)CC1
Yield: 26.6 %

Procedure:
0.8 g (12 mmol) of 1,2,4-triazole, 0.1 g (1 mmol) of potassium tert.-butoxide and 0.8 g (4 mmol) of 2-(1-cyanocyclopropyl)-2-(2-phenylethyl)oxirane (IV-16, Example 34) are heated to 80° C. for 6 h in 10 ml of abs. DMF. The solvent is stripped off in vacuo, and the residue is taken up in ethyl acetate and washed with water. After drying over Na2SO4, the solvent is evaporated in vacuo and the residue is chromatographed on silica gel (CH2Cl3 containing 2% ethanol). 0.3 g (28% of theory) of 2-(1-cyanocyclopropyl)-4-phenyl-1-(1,2,4-triazol- 1-yl)butan-2-ol is obtained in the form of a colorless oil, 1H--NMR (CDCl3):
Reaction SMILES: C([O:5][C:6](=[O:50])[CH:7]([NH:12][C:13](=[O:49])[C:14]1[CH:19]=[C:18]([NH:20][CH2:21][CH3:22])[CH:17]=[CH:16][C:15]=1[S:23][S:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH3:33])=[CH:27][C:26]=1[C:34](=[O:48])[NH:35][CH:36]([C:41]([O:43]C(C)(C)C)=[O:42])[CH:37]([CH3:40])[CH2:38][CH3:39])[CH:8]([CH3:11])[CH2:9][CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([S:23][S:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH3:33])=[CH:27][C:26]=2[C:34]([NH:35][C@H:36]([C:41]([OH:43])=[O:42])[C@H:37]([CH2:38][CH3:39])[CH3:40])=[O:48])=[C:14]([C:13]([NH:12][C@H:7]([C:6]([OH:50])=[O:5])[C@H:8]([CH2:9][CH3:10])[CH3:11])=[O:49])[CH:19]=1)[CH3:22]
Reactant: CCNc1ccc(SSc2ccc(NCC)cc2C(=O)NC(C(=O)OC(C)(C)C)C(C)CC)c(C(=O)NC(C(=O)OC(C)(C)C)C(C)CC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNc1ccc(SSc2ccc(NCC)cc2C(=O)N[C@H](C(=O)O)[C@@H](C)CC)c(C(=O)N[C@H](C(=O)O)[C@@H](C)CC)c1

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)] 2-{5-ethylamino-2-[4-ethylamino-2-(1-tert-butoxycarbonyl-2-methyl-butylcarbamoyl)-phenyldisulfanyl]-benzoylamino}-3-methyl-pentanoic acid tert-butyl ester (0.8 g, 1.1 mmol) from Example 45, 10 mL dichloromethane, and 10 mL trifluoroacetic acid. The product was washed with hexane/ether to afford 0.6 of the title compound, mp 97-100° C.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:11])[CH:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21](O)=[O:22])=[N:13]1.C(N(CC)CC)C>ClCCl>[CH3:3][N:4]([CH3:11])[CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][N:13]=2)=[O:22])[CH2:6]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CN(C)C1CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C1CCCN(C(=O)c2n[nH]c3ccccc23)C1
Reaction time: 48 h
Yield: 12.1 %

Procedure:
Dicyclohexycarbodiimide (1.25 g) was added to a stirred solution of 3-dimethylaminopiperidine dihydrochloride (1 g, 5 mmol), indazole3-carboxylic acid (1.05 g, 6 mmol) and triethylamine (1.25 g) in dichloromethane (25 ml). The mixture was stirred for 48 h, filtered and the filtrate extracted with 1M hydrochloric acid. The acid extracts were combined, washed with a little dichloromethane then basified with ammonia solution and back-extracted into chloroform. The extract was dried and evaporated. The residue was chromotographed on silica using methanol-methyl acetate (1:9) as eluent to give the product which was crystallised from a low volume of ethyl acetate to give the product (0.165 g) mp 141-142° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:53][O:54][CH2:55][CH2:56][NH:57][CH3:58]>CN(C)C=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[N:57]([CH2:56][CH2:55][O:54][CH3:53])[CH3:58])=[CH:24][CH:23]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CNCCOC
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C(=O)O)cc4)ccc3O2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COCCN(C)C(=O)c1ccc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)C)CC2)O3)cc1
Reaction time: 12 h

Procedure:
To a mixture of 4-[5-(4-carboxy-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester (41 mg) in N,N-dimethylformamide (1 mL) diethyl-isopropylamine (52 mL) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 32 mg) are added. After 10 min N-(2-methoxyethyl)-methylamine (12 mg) in N,N-dimethylformamide (0.5 mL) is added. The mixture is stirred for 12 h and purified by preparative HPLC (eluent water (+0.1% TFA)/MeOH) to yield the desired product. HPLC (method 12): tR=1.99 min; Mass spectrum (ESI+): m/z=481 [M+H]+.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[NH:11]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:12]1.C([O-])(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[N:17]1([CH2:16][C:13]2[CH:14]=[CH:15][NH:11][C:12]=2[CH:4]=[O:5])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: CN(C)C=O
Reactant: c1cc(CN2CCOCC2)c[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1[nH]ccc1CN1CCOCC1
Reaction time: 0.08 h

Procedure:
To a solution of DMF (66 mmoles) in DCM there is added, dropwise, at 0° C., POCl3. After stirring for 5 minutes, a solution of the compound obtained in Step B (33 mmoles) in DCM (60 ml) is added dropwise. After stiffing for 4 hours at 0° C. and for 30 minutes at reflux, an aqueous solution of sodium acetate (110 mmoles) is added. After a further 30 minutes at reflux, aqueous 2M sodium hydroxide solution is added at ambient temperature until the pH is alkaline (9-10). The solution is stirred for 2 hours at ambient temperature, and then 300 ml of DCM are added. After extracting with DCM, the organic phase is washed with water and with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness. The residue obtained is purified by flash chromatography on silica gel (SiO2; gradient DCM/AcOEt) to yield the title product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.Cl.[NH2:15][OH:16]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]1
Reactant: COCCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: COCCCCN1CCC(=NO)CC1

Procedure:
1-(4-Methoxybutyl)-4-piperidone oxime is prepared from 1-(4-methoxybutyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[N+:7]([O-:9])[CH:8]=1.[N+:11]([O-])([OH:13])=[O:12]>>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH3:10])=[N+:7]([O-:9])[CH:8]=1
Reactant: COc1ccc(C)[n+]([O-])c1
Reactant: O=[N+]([O-])O
Product: COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
21.2 g of 5-methoxy-2-methylpyridine 1-oxide are metered into 35 ml of 65% strength nitric acid, warmed to 60° C., in a manner such that the temperature of the reaction mixture does not rise above 80° C. The mixture is stirred at 80° C. for 1 hour, a further 13 ml of 100% strength nitric acid are added to bring the reaction to completion and the mixture is stirred at 60°-70° C. for a further 2 hours. For working up, the mixture is poured onto 300 g of ice. The yellow precipitate which has separated out is filtered off over a suction filter, washed with water and dried. The dry solid is boiled up with 200 ml of methylene chloride, filtered off and dried. Further TLC-pure product is isolated by concentration of the filtrate. 22.3 g (87% of theory) of 5-methoxy-2-methyl-4-nitropyridine 1-oxide of m.p. 201°-202° C. are obtained; yellow crystals.
Reaction SMILES: [O-]CC.[Na+].C([O:7][C:8](=O)[CH2:9][C:10]([N:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[NH2:22])[CH3:13])=[O:11])C>C(O)C>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][C:15]2[NH:22][C:8](=[O:7])[CH2:9][C:10](=[O:11])[N:12]([CH3:13])[C:14]=2[CH:19]=1
Reactant: CCOC(=O)CC(=O)N(C)c1cc(OC)ccc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)N(C)C(=O)CC(=O)N2
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 80.1 %

Procedure:
Sodium ethoxide (204 mg) was added to an ethanol solution (15 ml) of N-(2-amino-5-methoxyphenyl)-N-methylmalonamic acid ethyl ester (266 mg). The mixture was stirred at 65° C. for 2.5 hours. The reaction liquid was cooled to room temperature, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0→10:1). The purified product was condensed to dryness under reduced pressure to give the title compound (176.3 mg) as a white powder.
Reaction SMILES: Cl[C:2]1[C:12](Cl)=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[C:3]=1[N+:14]([O-])=O.C(=O)([O-])[O-].[K+].[K+].[H][H]>CO.[C].[Pd]>[NH2:14][C:3]1[C:4]2[O:8][C:7]([F:10])([F:9])[O:6][C:5]=2[CH:11]=[CH:12][CH:2]=1
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)cc2c1OC(F)(F)O2
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1cccc2c1OC(F)(F)O2

Procedure:
68 g (250 mmol) of 5,6-dichloro-4-nitro-2,2-difluoro-benzo(1.3)dioxole, 69 g (500 mmol) of potassium carbonate and 5 g of palladium-carbon (10% strength) are stirred at 50° C. and a hydrogen pressure of 90 bar in 500 ml of methanol in an autoclave for 20 hours. The reaction mixture is filtered, the filtrate is mixed with 500 ml of water and extracted thoroughly with ether, the extract is dried over sodium sulphate and the ether is removed in a rotary evaporator. By distillation, 35 g (81% of theory) of 4-amino-2,2-difluoro-benzo(1.3)dioxole are obtained having a boiling point of 84° to 86° C./16 mm and a refractive index of nD21 : 1.4995.
Reaction SMILES: O.Cl.[F:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([O:11][CH3:12])[CH:5]=1.Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl>ClC1C=CC=CC=1>[F:3][C:4]1[CH:10]=[CH:9][C:7]([N:8]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: COc1cc(F)ccc1N
Reactant: ClCCNCCCl
Agent: Cl
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc(F)ccc1N1CCNCC1
Temperature: 20 °C
Yield: 25 %

Procedure:
9 ml of chlorobenzene and H2O were distilled from a solution of 1.14 g of p-TosOH (6.03×10−3 moles) in 200 ml of chlorobenzene. The solution was cooled to 20° C. and then 1.19 g of 4-fluor-2-methoxyaniline hydrochloride (6.7×10−3 moles) and 1.31 g of bis (2-chloroethyl)amine hydrochloride (7.36×10−3 moles) were added. The reaction was held under reflux for 72 hours after which the solvent was removed and the residue was extracted with 5 ml of NaOH 2N and 30 ml of toluene. The organic phase was washed with H2O, was dried with Na2SO4 and the toluene was removed. The product was purified by silica column using dichloromethane/MeOH (9:1) as mobile phase. An oil was obtained. Yield: 25%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12](=[CH2:14])[CH3:13].OS(O)(=O)=O>ClCCl>[C:12]([O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)([CH3:14])([CH3:13])[CH3:11]
Reactant: C=C(C)C
Reactant: CC(=O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)c1cccc(OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 3'-hydroxyacetophenone (22.64 g), isobutylene (300 mL) and concentrated H2SO4 (1 mL) in dry dichloromethane (310 mL) was stirred in a sealed pressure vessel at room temperature for 3 days. After the reaction vessel was vented, the organic phase was washed (10% NaOH, water and brine), dried and evaporated to an oil (25.95 g) which was purified by chromatography, eluting with dichloromethane:ethyl acetate, to give 3'-tert-butoxyacetophenone (22.62 g); TLC: Rf =0.55, ethyl acetate:dichloromethane (3:97); MS: m/z=193(M+1).