Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][CH2:9][CH2:10]Cl)=[O:7])[CH2:2][C:3]#[CH:4].[OH-].[K+]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][C:6]1=[O:7])[CH2:2][C:3]#[CH:4]
Reactant: C#CCCNC(=O)NCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CCCN1CCNC1=O
Temperature: 75 °C
Yield: 20.6 %

Procedure:
To a solution of 1-but-3-ynyl-3-(2-chloro-ethyl)-urea (5 g, 28.7 mmol) in THF (100 mL) add tetrabutylammonium bromide (1.82 g, 5.65 mmol) and potassium hydroxide (2.01 g, 35.9 mmol). Heat the resulting suspension at 75° C. for 72 h and allow to cool to room temperature. Dilute the mixture with EtOAc (200 mL), wash with water (2×100 mL) and 1N aqueous HCl (100 mL). Dry the organic phase over MgSO4, filter and concentrate in vacuo to obtain the title compound as a white powder (816 mg, 21%).
Reaction SMILES: C(OC([N:6]1[C:14]([NH2:15])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[C:12]2[Cl:16])=[N:7]1)=O)C>C(OC(OC(OCC)=O)=O)C>[NH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:16])[NH:7][N:6]=1
Reactant: CCOC(=O)n1nc2cccc(Cl)c2c1N
Agent: CCOC(=O)OC(=O)OCC
Product: Nc1n[nH]c2cccc(Cl)c12

Procedure:
Analogously to Example 1, 0.2 mol of 3-amino-4-chloroindazole in 100 ml of pyrocarbonic acid diethyl ester gives 3-amino-4-chloroindazole-2-carboxylic acid ethyl ester (melting point: 109°-111° C; 63% of theory) in 3 hours at 20°-30° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:14])[CH2:11][C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CO[CH:18](OC)[CH2:19][NH2:20]>CCOCC>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:14])[CH2:11][C:12]1[NH:13][CH:18]=[CH:19][N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CN)OC
Reactant: N#CC[C@H](O)COCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: O[C@H](COCc1ccccc1)Cc1ncc[nH]1
Yield: 28.1 %

Procedure:
Using (3S)-4-(benzyloxy)-3-hydroxybutyronitrile (6.51 g), a 5.12 N solution of hydrogen chloride in ether (7.0 ml), and aminoacetaldehyde dimethyl acetal (3.58 g), the same reaction as Reference Example 6 was carried out to yield the titled compound (2.22 g) as a light-brown oily substance.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CS(C)=O>[N:32]([C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1)=[N+:33]=[N-:34]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(N=[N+]=[N-])n2Cc1ccc(Cl)cc1
Temperature: 65 °C

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.28 g, 0.4 mmol, intermediate 14) in DMSO (10 mL) was added sodium azide (65 mg, 1 mmol). The reaction was heated at 65° C. for 2.5 h. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 1.800 min; LCMS MH+-THP 390.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[CH:14]=[CH2:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:27]4[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]4)[C:12]=3[CH:14]=[CH2:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1CNCCN1
Reactant: C=Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CC#N
Product: C=Cc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Yield: 75.2 %

Procedure:
A mixture of 1-cyclopropyl-8-ethenyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.80 g, 2.9 mmol), 2-methylpiperazine (1.9 g, 19 mmol) and acetonitrile (5 mL) was heated at reflux for 22 hours. The mixture was cooled and concentrated. The residue was dissolved in H2O (50 mL), treated with charcoal and filtered through celite. The pH of the filtrate was adjusted to 7, with HCl (3N) and after cooling to 0° C. the precipitate was collected and dried to provide 0.81 g (78%) of the desired product; mp 227°-231° dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.Cl[CH2:15][O:16][CH3:17]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:13])([CH3:12])[CH2:10][O:11][CH2:15][O:16][CH3:17])[CH:4]=1
Reactant: COCCl
Reactant: COc1cccc(C(C)(C)CO)c1
Solvent: C1CCOC1
Product: COCOCC(C)(C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
To a solution of 2-(3-methoxyphenyl)-2-methyl-propan-1-ol (Intermediate 39, 900 mg, 4.99 mmol) in THF (15 mL) sodium hydride 60% dispersion in mineral oil (300 mg, 7.49 mmol) was added and the reaction mixture was stirred for 15 minutes at room temperature. Chloro(methoxy)methane (603.02 mg, 7.49 mmol) was added and the reaction mixture was heated to 55° C. and stirred overnight. The reaction was cooled to 0° C. and quenched with water (10 mL) (added dropwise) and extracted with EtOAc (30 mL). Organics were dried over Na2SO4, filtered and evaporated in vacuo to afford the title compound (525 mg) that was used in the next step without further purification.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[C:13](=O)[NH:12][CH:11]=[CH:10]2.[OH-].[Na+]>>[Cl:3][C:13]1[C:14]2[C:9](=[CH:8][C:7]([NH2:6])=[C:16]([Cl:17])[CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1cc2cc[nH]c(=O)c2cc1Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc2ccnc(Cl)c2cc1Cl
Temperature: 100 °C
Yield: 54.8 %

Procedure:
To 20.0 mL (215 mmol) of phosphorous oxychloride, cooled to 0 C, was added 5.00 g (25.7 mmol) of 6-amino-7-chloro-2H-isoquinolin-1-one in portions. The mixture was heated to 100° C. for 3 h then cooled to room temperature and poured over ice. After all of the ice had melted the pH of the mixture was adjusted to slightly alkaline by the slow addition of a 10% aqueous NaOH solution. A yellow solid precipitated from solution and was collected by filtration, washed with water and dried over anhydrous Na2SO4 to provide 3.0 g (55%) of 1,7-dichloro-isoquinolin-6-ylamine. MS calc. for C9H7Cl2N2 [M+H]+: 214.08. Found: 213.23 and 215.23.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[O:27]1[CH2:32][CH2:31][CH:30]([O:33][C:34]([O:36][CH2:37]I)=[O:35])[CH2:29][CH2:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:37][O:36][C:34]([O:33][CH:30]3[CH2:29][CH2:28][O:27][CH2:32][CH2:31]3)=[O:35])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C(OCI)OC1CCOCC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)OC3CCOCC3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 90.7 %

Procedure:
In the same manner as in Example 81, 194 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 136 mg of (tetrahydropyran-4-yl)oxycarbonyloxymethyl iodide.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCC2(CC1)OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
A stirred solution of 14.2 grams (0.090 mole) of 1,4-dioxaspiro[4.5]decan-8-ol and 10.0 grams (0.099 mole) of triethylamine in 100 mL of methylene chloride is cooled to 0° C., and a solution of 7.7 mL (0.099 mole) of methanesulfonyl chloride in 25 mL of methylene chloride is added drop-wise at a rate to maintain the reaction mixture temperature at 0° C. to 5° C. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature. The reaction mixture is then washed with two 75 mL portions of an aqueous 5% sodium bicarbonate solution and then with 75 mL of an aqueous solution saturated with sodium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 8-methylsulfonyloxy-1,4-dioxaspiro[4.5]decane
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([S:14][C:15]1([CH2:25][N+:26]([O-])=O)[CH2:24][CH2:23][C:18]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)C.O>O1CCCC1>[CH2:7]([S:14][C:15]1([CH2:25][NH2:26])[CH2:24][CH2:23][C:18]2([O:19][CH2:20][CH2:21][O:22]2)[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])CC1(SCc2ccccc2)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: NCC1(SCc2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 123.3 %

Procedure:
To a mixture of lithium aluminum hydride (2.63 g) and tetrahydrofuran (50 mL) was added a solution of 8-(benzylthio)-8-(nitromethyl)-1,4-dioxaspiro[4.5]decane (8.96 g) in tetrahydrofuran (80 mL) over 1 hr at room temperature, and the reaction mixture was stirred at room temperature for 30 min. Ethanol (15 mL) and water (10 mL) was successively added, and the resulting inorganic salt was removed by filtration. The filtrate was concentrated, and the residue was dissolved in ethyl acetate. The solution was dried (MgSO4), and concentrated to give 1-[8-(benzylthio)-1,4-dioxaspiro[4.5]dec-8-yl]methanamine (10.02 g) as a crude oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][O:32][CH3:33])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1)=O.[CH3:34][NH2:35].[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:34][NH:35][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][O:32][CH3:33])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: COCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CCOC)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.9 %

Procedure:
To a solution of 5-(3-formylphenyl)-3-(1-{[2-(methyloxy)ethyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (25 mg, 0.053 mmol) in MeOH/CH2Cl2 (1 mL/1 mL) was added methyl amine (0.15 mL, 0.33 mmol). The reaction mixture was stirred at room temperature for 2 hours before NaBH4 (13.2 mg, 0.33 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (10.0 mg, 39%).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][C:7]1([CH3:38])[CH2:12][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=4)[CH:21]=3)=[CH:17][C:9]=2[O:8]1)C.O.[OH-].[Li+].O1CCCC1.O>CO>[N:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:28]=1[CH2:27][O:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][O:18][C:16]1[CH:15]=[CH:14][C:10]2[C:11](=[O:13])[CH2:12][C:7]([CH2:6][CH2:5][C:4]([OH:39])=[O:3])([CH3:38])[O:8][C:9]=2[CH:17]=1
Reactant: CCOC(=O)CCC1(C)CC(=O)c2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(CCC(=O)O)CC(=O)c2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2O1
Yield: 34.5 %

Procedure:
2.6 g of ethyl-3-(7-(3-(quinolin-2-ylmethoxy)benzyloxy)-3,4-dihydro-2-methyl-4-oxo-2H-1-benzopyran-2-yl)propanoate and 1.02 g of lithium hydroxide hydrate are combined in 30 ml of methanol, 30 ml of tetrahydrofuran and 10 ml of water and stirred at room temperature for 3 hours. The solvent is removed by evaporation and the residue diluted with water and washed with ether. The pH of the aqueous portion is adjusted to 5 and the suspension extracted with ethyl acetate. The dried ethyl acetate solution is concentrated and the residue purified by chromatography on silica gel to give 0.85 g of 3-(7-(3-(quinolin-2-ylmethoxy)benzyloxy)-3,4-dihydro-2-methyl-4-oxo-2H-1-benzopyran-2-yl)propanoic acid; m.p. 152°-54° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.CCOC(C)=O.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: Nc1ccccc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of 4-cyanobenzene-1-sulfonyl chloride (200 mg, 0.992 mmol) in pyridine (4960 μL) was added aniline (100 μL, 1.091 mmol) and the reaction mixture stirred overnight at rt. The reaction mixture was diluted with EtOAc and water+0.1N HCl. The phases were separated, the aqueous phase extracted and the combined organic layers washed with 0.1N HCl and brine. After drying over magnesium sulfate, the solution was concentrated under vacuum to yield 4-cyano-N-phenyl-benzenesulfonamide 198 mg (0.652 mmol) of yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH3:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][C:8]1=[O:18].N1C=CC=CC=1.COS([O-])(=O)=O.[CH3:34][S:35][C:36](=[S+]C)[S:37][CH3:38]>O1CCOCC1>[CH3:34][S:35][C:36]([S:37][CH3:38])=[C:9]1[C:8](=[O:18])[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])([CH3:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17]
Reactant: CSC(SC)=[S+]C
Reactant: CC(C)(C)CCCCC1(C)C(=O)C=C(O)c2ccccc21
Agent: COS(=O)(=O)[O-]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CSC(SC)=C1C(=O)c2ccccc2C(C)(CCCCC(C)(C)C)C1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A solution of Example 35G (1.06 g, 3.70 mmol) and pyridine (2.40 mL, 29.6 mmol) in 1,4-dioxane (15 mL) was treated with [bis(methylsulfanyl)methylene](methyl)sulfonium methyl sulfate (3.93 g, 14.8 mmol) and stirred at 100° C. for 1 hour. The mixture was cooled to 25° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane followed by 5%, 10%, and 20% ethyl acetate in hexane to give the title compound (1.45 g, 99%). 1H NMR (300 MHz, CDCl3): δ ppm 0.78 (m, 10 H) 1.01 (m, 5 H) 1.56 (m, 3 H) 1.77 (m, 1 H) 2.23 (m, 1 H) 2.56 (m, 6 H) 7.39 (m, 2 H) 7.56 (m, 1 H) 8.21 (m, 1 H). MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: [N+]([O-])([O-])=[O:2].[NH4+].[Ce].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25]C)[C:17]=3[N:18]=2)=[CH:10][CH:9]=1>C(OCC)(=O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[C:22](=[O:2])[C:21]([O:23][CH3:24])=[CH:20][C:19](=[O:25])[C:17]=3[N:18]=2)=[CH:10][CH:9]=1
Reactant: COc1cc(OC)c2nc(-c3ccc(F)cc3)sc2c1
Reactant: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COC1=CC(=O)c2nc(-c3ccc(F)cc3)sc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
63 ml of a freshly prepared 0.65 M cerium ammonium nitrate solution is added, dropwise, to 3.8 g (13.1 mmol) of 2-(4-fluorophenyl)-4,6-dimethoxy-1,3-benzothiazole in solution in 100 ml of ethyl acetate. The reaction mixture is maintained under stirring at ambient temperature for 3 hours then the aqueous phase is separated and washed with 3 times 75 ml of ethyl acetate. The organic phases are combined, dried over sodium sulphate and the solvents are evaporated off under reduced pressure. The residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane mixture 1:3) in order to provide 0.6 g (16% yield) of expected product.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[CH2:40]([N:44]([CH3:49])[C:45](=O)[CH2:46]Cl)[CH2:41][CH2:42][CH3:43]>>[CH2:40]([N:44]([CH3:49])[CH2:45][CH2:46][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCCCN(C)CCOc1ccc(CCCNc2cc(OC)c(OC)cc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 80.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and N-butyl-2-chloro-N-methylacetamide (8.9 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.6 mg) was obtained.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[CH2:17][CH2:16]2)[CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[CH3:4]>C1COCC1.CO>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:22][CH2:23][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:25][CH2:26]3)[CH2:17][CH2:16]2)[CH:9]=[CH:10][C:11]=1[NH2:12])[CH3:4]
Reactant: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
Sodium borohydride (0.41 g, 10.9 mmol) was added in portions to a stirring suspension of 1-{1-[3-(ethyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (1.50 g, 3.64 mmol) and NiCl2.6H2O (0.26 g, 1.1 mmol) in THF (15 mL) and MeOH (30 mL) at rt. The reaction mixture was allowed to stir at rt overnight and then it was concentrated in vacuo. The residue was taken up in DCM and passed through a bed of celite. The resultant filtrate was then concentrated onto silica gel and purified by flash chromatography to afford 2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.40 g, 30%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.42-6.56 (m, 2H), 6.29 (dd, J=8.4, 2.3 Hz, 1H), 4.21 (br. s., 2H), 3.96 (q, J=6.9 Hz, 2H), 3.37-3.48 (m, 2H), 3.05-3.12 (m, 4H), 2.86 (s, 3H), 2.56-2.63 (m, 4H), 2.26-2.37 (m, 1H), 1.75-1.85 (m, 2H), 1.42-1.61 (m, 2H), 1.31 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11]C=C)[N:6]1[C:14](=[O:27])[CH:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:17]=[CH2:18])=[O:4].CS(C)=O>ClCCl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:1][O:2][C:3]([C@H:5]1[N:6]2[C:14](=[O:27])[C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH:17]=[CH:18][CH2:11][C@H:7]2[CH2:8][CH2:9][CH2:10]1)=[O:4]
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)N1C(CC=C)CCCC1C(=O)OC
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1CCC[C@@H]2CC=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N21
Reaction time: 24 h

Procedure:
6-Allyl-1-(2-tert-butoxycarbonylamino-pent-4-enoyl)-piperidine-2-carboxylic acid methyl ester, 40, (1.0 g, 2.6 mmol) is dissolved in dichloromethane (100 mL). Grubbs catalyst (0.5 g, 0.61 mmol) is added and the mixture is heated at reflux for 24 hours. The reaction is cooled and dimethylsulfoxide (2 mL) is added. After 24 hours, the solution is concentrated to a oil, which is purified over silica (ethyl acetate/hexanes) to afford 680 mg of the desired product. 1H NMR (CDCl3) δ 6.02 (d, J=6.6 Hz,1H), 5.61 (m, 1H), 5.21 (m, 1H), 4.93 (ddd, J=6.6, 6.2, 6.2 Hz, 1H), 4.54 (m, 1H), 3.71 (s, 3H), 2.95 (ddd, J=16.2, 5.9, 5.9 Hz, 1H), 2.63 (ddd, J=17.6, 12.0, 5.5 Hz,1H), 2.42 (ddd, J=16.2, 5.8, 5.1 Hz, 1H), 2.34–2.16 (m, 2H), 1.90–1.58 (m, 5H), 1.48 (s, 9H); 13C NMR δ 173.0, 172.5, 155.6, 129.2, 125.0, 79.9, 52.4, 52.0, 51.2, 50.8, 36.6, 34.5, 30.1, 28.8(3C), 26.4, 16.0.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([CH2:25][O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH2:23][N:22]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][CH:20]2[CH2:42][OH:43])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([CH2:25][O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH2:23][N:22]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:21][CH:20]2[CH:42]=[O:43])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(COCCN2CCOCC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(C=O)C(c2ccc(OCCCOCc3ccccc3)cc2)C(COCCN2CCOCC2)C1

Procedure:
In an analogous manner to that described in Example 74(f), from tert-butyl (3RS,4RS,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(2-morpholin4-yl-ethoxymethyl)-piperidine-1-carboxylate by oxidation with dimethyl sulphoxide/oxalyl chloride in methylene chloride there was obtained tert-butyl (3RS,4SR,5SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-formyl-5-(2-morpholin-4-yl-ethoxymethyl)-piperidine-1-carboxylate as a yellow oil; MS: 597 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[CH:14][C:13]=1[F:23])=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[F:23][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([N:18]2[N:19]=[CH:20][CH:21]=[N:22]2)[C:12]=1[C:10]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1)=[O:11]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 464 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.80-6.75 (m, 8H), 5.00-2.70 (m, 5H), 2.00-0.65 (m, 8H).