Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:3]=1[C:24]([OH:26])=O.Cl.Cl.[NH:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:39][CH2:38][CH2:37][C@H:36]2[CH2:40][OH:41])[CH2:31][CH2:30]1>>[OH:41][CH2:40][C@@H:36]1[CH2:37][CH2:38][CH2:39][N:35]1[CH:32]1[CH2:33][CH2:34][N:29]([C:24]([C:3]2[C:4]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)=[N:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:15])[F:16])[CH:8]=3)[C:2]=2[CH3:1])=[O:26])[CH2:30][CH2:31]1
Reactant: Cc1c(C(=O)O)c(-c2ccncc2)nn1-c1cccc(OC(F)(F)F)c1
Reactant: OC[C@@H]1CCCN1C1CCNCC1
Agent: Cl
Product: Cc1c(C(=O)N2CCC(N3CCC[C@H]3CO)CC2)c(-c2ccncc2)nn1-c1cccc(OC(F)(F)F)c1
Yield: 78 %

Procedure:
In analogy to the procedure described in Example 160E], 5-methyl-3-pyridin-4-yl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid (Example 160D]) and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol dihydrochloride gave the title compound in 78% yield as a light yellow foam. MS: 530.0 (MH+).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH:20]=[O:21])=[CH:14][C:13]=2[F:22])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1OC1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:37]([CH:44]([CH2:47]O)[CH2:45][OH:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH:20]3[O:46][CH2:45][CH:44]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:47][O:21]3)=[CH:14][C:13]=2[F:22])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCCCC(CO)CO
Reactant: CCCCCc1ccc(-c2ccc(CCC=O)cc2F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CO1
Product: CCCCCCCC1COC(CCc2ccc(-c3ccc(CCCCC)cc3)c(F)c2)OC1

Procedure:
6 g of 3-(4'-pentyl-2-fluorobiphenyl-4-yl)-propionaldehyde (obtainable by reaction of 4-(2-fluoro-4'-pentylbiphenylyl)-magnesium bromide with ethylene oxide and subsequent oxidation of the resulting alcohol with pyridinium chlorochromate) and 3.5 g of 2-heptylpropane-1,3-diol are heated with a spatula tip of p-toluenesulfonic acid in 100 ml of toluene, using a water separator, until no further water is foamed. After cooling, the mixture is washed with bicarbonate solution and water until neutral and dried over sodium sulfate and the toluene is distilled off. After customary working-up, 1-(4'-pentyl-2-fluorobiphenyl-4-yl)-2-(5-heptyl-1,3-dioxan-2-yl)-ethane is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=O)[CH2:7][NH:8][C:9](=O)[O:10]CC)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)CCC>[OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[CH2:7][NH:8][C:9](=[O:10])[NH:18][N:19]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)NCC(=O)c1ccc(O)cc1
Solvent: O
Solvent: CCCCO
Product: O=C1NCC(c2ccc(O)cc2)=NN1
Yield: 54 %

Procedure:
A mixture of 20 g of ethyl N-(p-hydroxyphenacyl)carbamate (prepared as described in Preparation 6), 56 g of 80% hydrazine hydrate and 100 ml of butanol was heated under reflux for 30 hours, whilst stirring. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was washed with ethanol to give 9.25 g of the title compound as crystals, melting at 266°-269° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:13]=[CH:12][C:7]=1[C:8](OC)=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:13]=[CH:12][C:7]=1[CH2:8][OH:9]
Reactant: COCCOc1cccc(C(=O)OC)c1OCCOC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cccc(CO)c1OCCOC
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of methyl 2,3-bis{[2-(methyloxy)ethyl]oxy}benzoate (2.0 g, 7.03 mmol) in dry THF (10 mL) was added dropwise a 1M solution of lithium aluminum hydride in THF (7.0 mL), and the resulting mixture was stirred at rt for 1 h. Then, water (0.27 mL) was added slowly, followed by 15% aqueous sodium hydroxide (0.27 mL), and more water (0.81 mL). The mixture was filtered, the filter cake washed with ethyl acetate, and the combined filtrate was concentrated. Column chromatography on silica (1:1 hexanes/ethyl acetate) gave (2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)methanol (1.13 g, 63% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ6.96 (dd, 1H), 6.86 (m, 2H), 4.60 (d, 1H), 4.33 (m, 2H), 4.24 (t, 1H), 4.13 (m, 2H), 3.75 (m, 2H), 3.70 (m, 2H), 3.43 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:21]2[C@@:16]([CH3:24])([CH:17]3[CH2:23][CH:18]3[C:19](=[O:22])[CH:20]=2)[C@H:15]2[C@H:4]([C@H:5]3[C@:12]([CH3:25])([CH2:13][CH2:14]2)[C@@:8]([OH:26])([C:9](=[O:11])[CH3:10])[CH2:7][CH2:6]3)[CH:3]=1.[CH3:27]N(C)C=O>CI.[Ag]=O>[F:1][C:2]1[C:21]2[C@@:16]([CH3:24])([CH:17]3[CH2:23][CH:18]3[C:19](=[O:22])[CH:20]=2)[C@H:15]2[C@H:4]([C@H:5]3[C@:12]([CH3:25])([CH2:13][CH2:14]2)[C@@:8]([O:26][CH3:27])([C:9](=[O:11])[CH3:10])[CH2:7][CH2:6]3)[CH:3]=1
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=C(F)C4=CC(=O)C5CC5[C@@]4(C)[C@@H]3CC[C@@]21C
Reactant: CN(C)C=O
Agent: O=[Ag]
Solvent: CI
Product: CO[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(F)C4=CC(=O)C5CC5[C@@]4(C)[C@@H]3CC[C@@]21C

Procedure:
A solution of 0.35 g of 6-fluoro-17α-hydroxy-1,2-methylene-9β,10α-pregna-4,6-diene-3,20-dione in 35 ml of dimethylformamide and 17.5 ml of methyliodide is stirred at 20°C for 70 hours in the presence of 3.5 g of silver oxide. Then the solid substance is filtered off and the filtrate is extracted subsequent to decanting in water, from methylene chloride and the resultant extract is evaporated to dryness after having been washed to neutral and subsequent to drying. The residue yields, subsequent to chromatography on silicagel, 6-fluoro-17α-methoxy-1,2-methylene-9β,10α-pregna-4,6-diene-3,20-dione.
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](C)(C)C)=[CH:5][CH:4]=[N:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19](I)[S:20][C:13]=12>CC1C=CC=CC=1C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]=[C:19]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[S:20][C:13]=12
Reactant: Clc1ccnc2cc(I)sc12
Reactant: Cn1nccc1[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: Cn1nccc1-c1cc2nccc(Cl)c2s1

Procedure:
A mixture of 1-methyl-5-trimethylstannanyl-1H-pyrazole 10a (2.1 g, 8.5 mmole), 7-chloro-2-iodo-thieno[3,2-b]pyridine (2.5 g, 8.5 mmole), tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.4 mmole, 5 mol %) in o-xylene (85 ml was degassed, purged with nitrogen and heated to 120°, which gave an orange solution. After 14 hours the black reaction mixture was diluted with toluene (100 ml) and extracted with 1.2 M HCl (3×60 ml). The combined aqueous layers were washed with toluene (100 ml). The organic layers were discarded and the aqueous layer was treated with NaOH to pH 14. The resultant white solid was collected (1.1 g, 52%): TLC (6% methanol-dichloromethane) Rf 0.8; 1H-NMR (DMSO-d6, 400 MHz) δ 8.70 (1H, d, J=5.3 Hz), 8.00 (1H, s), 7.63 (1H,d, J=5.3 Hz), 7.56 (1H, d, J=2.0 Hz), 6.79 (1H, d, J=2.0 Hz), 4.09 (3H, s). ESIMS m/z 250 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@@H:15]3[O:27][C@H:26]([CH3:28])[C@@H:21]([O:22]C(=O)C)[C@H:16]3[O:17]C(=O)C)[C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:29].[OH-].[Li+]>O1CCOCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@@H:15]3[O:27][C@H:26]([CH3:28])[C@@H:21]([OH:22])[C@H:16]3[OH:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:29]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(NC(C)C)nc2c(Cl)c(Cl)ccc21
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Nc1nc2c(Cl)c(Cl)ccc2n1[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
4,5-Dichloro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine (0.82 g, 1.8 mmol) was dissolved in 1,4dioxane (Aldrich, 20 mL). Aqueous lithium hydroxide (5.5 mL, 1.0 M, 5.5 mmol) was added and the mixture was stirred for 30 min. The solution was then diluted with brine (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were dried over magnesium sulfate, filtered, and evaporated. The crude residue was purified on a silica gel column (5×20 cm, 230-400 mesh) with 96:4 dichloromethane-methanol to give the title compound (0.48 g, 1.3 mmol, 72%); MS (AP+): m/z 360 (M+1); 1H NMR (DMSO-d6) δ: 7.11 (d, 1H, Ar—H, J=8.7 Hz), 7.04 (d, 1H, Ar—H, J=8.4 Hz), 6.75 (d, 1H, NH, J=7.5 Hz), 5.70 (d, 1H, H-1′, J=6.3 Hz), 5.27 (d, 1H, OH, J=6.6 Hz), 5.22 (d, 1H, OH, J=4.8 Hz), 4.28-4.35 (m, 1H, CH), 4.05-4.16 (m, 1H, CH), 3.77-3.92 (m, 2H, CH), 1.35 (d, 3H, 5′-CH3, J=6.6 Hz), 1.22 (d, 6H, CH3, J=6.6 Hz).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1COCC1.[CH3:38][NH2:39]>O>[CH3:38][NH:39][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CN
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)NC
Temperature: 80 °C

Procedure:
A mixture of ethyl 12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanoate (4.0 g, 9.1 mmol), THF (5 mL), and methylamine (available as a 40% solution in water, 8 mL) was sealed in a high-pressure vessel and heated at 80° C. overnight. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane. The resulting solution was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 3.8 g of N-methyl-12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[C:8](=[S:12])[NH:7][CH:6]=1)=[O:4].[N:13]([O-])=O.[Na+]>Cl.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]2[N:11]=[N:13][S:12][C:8]2=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c(=S)c(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cnc2snnc2c1
Temperature: -3 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
The amine (i) (1.3 g) was suspended in 0.5 M hydrochloric acid (200 mL) and cooled to −3° C. A solution of sodium nitrite (487 mg) in water (3 mL) was added dropwise over 10 minutes and the mixture was stirred for 2 hours when the solid product was collected and chromatographed on silica gel (chloroform) to afford a solid (0.90 g)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:17][CH2:18][CH3:19])[CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:4][N:3]=1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.CC(C)([O-])C.[K+].O>COCCOC.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-]C1C(Cl)=CC=CN=1)(C)C>[CH2:18]([O:17][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:27][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=2)=[N:3][CH:4]=1)[CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH3:19]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(CC(OCC)c1ccc(Br)nc1)OCC
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-]c1ncccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(CC(OCC)c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)OCC
Temperature: 100 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
2-Bromo-5-(1,3,3-triethoxypropyl)pyridine (328 mg, 0.987 mmol) produced in Example 17 (17B) and 4-trifluoromethylbenzylamine (346 mg, 1.98 mmol) were dissolved in 1,2-dimethoxyethane (10 mL), and potassium tert-butoxide (346 mg, 1.98 mmol) and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (34 mg, 5 mol %) were added thereto, and then, the resulting mixture was stirred under a nitrogen atmosphere at 100° C. for 3 hours. After the reaction solution was cooled to room temperature, water was added thereto, and the organic matter was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 50:50 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (25 mg, yield: 6%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([CH2:31][C:32]2[C:33](=[O:39])[NH:34][C:35](=[S:38])[NH:36][CH:37]=2)=[CH:27][N:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][S:38][C:35]3[NH:36][CH:37]=[C:32]([CH2:31][C:28]4[CH:29]=[N:30][C:25]([O:24][CH3:23])=[N:26][CH:27]=4)[C:33](=[O:39])[N:34]=3)=[CH:10][C:7]=2[C:8]#[N:9])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(F)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1
Yield: 33.2 %

Procedure:
The same procedure as E63 from 5-(chloromethyl)-2-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}benzonitrile (198 mg, 0.599 mmol), 5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (150 mg, 0.599 mmol) and K2CO3 (166 mg, 1.199 mmol) in DMF (3 mL), except that the reaction time was prolonged to 1.5 h, to afford the title compound (108 mg, 33.2% yield). LCMS: rt=3.32 min, [M+H+]=544
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29](=[S:31])[NH2:30])[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.CCO.Br[CH2:36][C:37](=O)[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[S:31][CH:36]=[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: CCOC(=O)C(=O)CBr
Reactant: C[C@@H]1CN2c3c(cc4c(C(N)=S)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (2R,4S,4aS)-rel-11-fluoro-2,4-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4′,4a,6′-octahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-8-carbothioamide (Intermediate 575, 54 mg, 0.128 mmol) in mixture of EtOH:DMF (1 mL: 0.5 mL) were added ethyl bromopyruvate (47 mg, 0.24 mmol) and molecular sieves, and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated, the residue was purified by silica gel column chromatography to give product as solid. Yield: 13 mg (20%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:4][CH:3]=1.C1(=O)O[CH2:22][CH2:21][O:20]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][CH2:22][CH2:21][OH:20])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1OCCO1
Reactant: Oc1ccc2nc(Cc3ccc(Cl)cc3)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCOc1ccc2nc(Cc3ccc(Cl)cc3)sc2c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
1.05 g (3.8 mmol) of 2-(4-chlorobenzyl)-6-hydroxy-benzothiazole and 0.67 g (7.6 mmol) of ethylene carbonate are dissolved in 20 ml of dimethylformamide and after the addition of 2.1 g (15.2 mmol) of potassium carbonate the mixture is stirred for 2 hours at 120° C. It is then added to water and extracted with ethyl acetate. After the extracts have been evaporated down the residue is purified by column chromatography on silica gel (eluant: ethyl acetate). Yield: 1.6 g (69% of theory).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[O:18][CH3:19])([CH3:3])[CH3:2].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:32].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:32].[ClH:32].[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][CH2:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])=[C:10]([O:18][CH3:19])[CH:11]=1
Reactant: COc1cc([N+](=O)[O-])ccc1NCCCOC(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COc1cc(N)ccc1NCCCOC(C)C

Procedure:
The N-(3-isopropoxypropyl)-N-(2-methoxy-4-nitrophenyl)amine (11) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[N:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[N+:21]=[N-:22].S(=O)(=O)(O)O>C(Cl)Cl>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH:10][S:29]([C:26]2[CH:25]=[CH:24][C:23]([N:20]=[N+:21]=[N-:22])=[CH:28][CH:27]=2)(=[O:30])=[O:31])=[CH:6][CH:5]=1
Reactant: NCCc1ccc(CCO)cc1
Reactant: [N-]=[N+]=Nc1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1ccc(S(=O)(=O)NCCc2ccc(CCO)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 5.5 g. (33 mmole) 4-(2-hydroxyethyl)-phenethylamine, 100 ml. methylene chloride and 3.4 g. (33 mmole) triethylamine is slowly added dropwise a solution of 7.2 g. (33 mmole) 4-azidobenzenesulphonyl chloride in 50 ml. methylene chloride. Subsequently, the reaction is allowed to continue for 1 hour with ice cooling. The reaction mixture is now shaken out twice with dilute sulphuric acid, then twice with water, dried with anhydrous sodium sulphate and finally evaporated. The residue is recrystallised twice from toluene to give 7.8 g. (64% of theory) of desired product; m.p. 90°-92° C. (recrystallised from toluene).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:4]([OH:5])[C:3]=1[OH:10].[CH3:11]S(C)=O.ClCCl.[OH-].[Na+]>O>[CH3:1][C:2]1[C:3]2[O:10][CH2:11][O:5][C:4]=2[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: Cc1cc(C)c(O)c(O)c1
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c2c(c1)OCO2
Yield: 93 %

Procedure:
3,5-Dimethylcatechol (13.8 g) in a vigorously stirred mixture of dimethylsulphoxide (150 ml), dichloromethane (10 g) and sodium hydroxide (8.3 g) under nitrogen atmosphere was heated over an oil bath (120°-130° C.) for 2 hours. The mixture was poured into water (600 ml) and extracted (×4) with ether. The ethereal solution was dried and evaporated to afford 3,5-dimethyl-l,2-(methylenedioxy)benzene (14.0 g, 93%) as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:18])=[CH:13][O:14][C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[C:25]1([CH2:31]CC(Cl)=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.CCOCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:18])=[CH:13][O:14][C:15](=[O:17])[CH2:16][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(=O)OC=C(C)Cc1ccc(C(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=COC(=O)CCc1ccccc1)Cc1ccc(C(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 83.5 %

Procedure:
A solution of 65.8 g acetic acid 3-(4-tert-butyl-phenyl)-2-methyl-propenyl ester in 200 ml of THF was cooled to −70° C. A solution of 42.3 g potassium-tert-butoxide in 200 ml of THF was added at −70° C. during 20 min. and the resulting reaction mixture was stirred for 90 min. at the same temperature. 53.5 g 3-phenyl-propionyl chloride was dropped in and the reaction mixture was stirred for another 3 hours at −70° C. Then the reaction mixture was diluted with ether, washed with saturated NaHCO3 and brine. The organic phase was dried, filtered and evaporated to dryness. The residue was thin-layer distilled to yield 75.0 g of a yellow oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1B(O)O)(=[O:4])=[O:3].Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=2)=[C:18]([F:29])[C:17]=1[O:30][CH3:31]>>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[C:17]([O:30][CH3:31])[C:18]=2[F:29])=[N:23][CH:24]=1
Reactant: COc1c(Br)ccc(-c2cnc(N)cn2)c1F
Reactant: CS(=O)(=O)Nc1ccccc1B(O)O
Product: COc1c(-c2ccccc2NS(C)(=O)=O)ccc(-c2cnc(N)cn2)c1F

Procedure:
The title compound was prepared by a method analogous to Example 461 using (2-(methylsulfonamido)phenyl)boronic acid and 5-(4-bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine. MS (ESI): mass calcd. for C18H17FN4O3S, 388.10; m/z found, 389.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.59 (dd, J=2.3, 1.6, 1H), 8.12 (d, J=1.5, 1H), 7.75 (dd, J=8.2, 7.2, 1H), 7.69 (d, J=8.0, 1H), 7.46 (m, 1H), 7.37-7.32 (m, 2H), 7.15 (dd, J=8.2, 1.5, 1H), 7.10 (s, 1H), 4.77 (s, 2H), 3.73 (d, J=1.1, 3H), 2.58 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:12]([OH:14])=O)[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]=1[O:17][CH3:18].[ClH:19].Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:19].[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:12]([N:30]3[CH2:29][CH2:28][N:27]([CH2:26][C:25]4[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:23]([O:22][CH3:21])[CH:24]=4)[CH2:32][CH2:31]3)=[O:14])[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]=1[O:17][CH3:18]
Reactant: COc1ccc2c(c1OC)CCCC(C(=O)O)=C2
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(C(=O)C3=Cc4ccc(OC)c(OC)c4CCC3)CC2)cc(OC)c1OC
Yield: 42.7 %

Procedure:
Using a mixture of 3,4-dimethoxy6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (0.6 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1.3 g), triethylamine (1.5 g), N,N-dimethylformamide (20 ml) and diethyl phosphorocyanidate (0.6 ml), an amidation as that described in Example 6 is carried out. The product is purified by silica gel column chromatography (hexane:acetone=1:1), and converted to the hydrochloride in a mixture of ethyl acetate and ethyl ether to yield 1-(3,4-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.55 g) as colorless crystals, m.p. 225°-229° C. (decomp.).