Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=O)[CH2:21][CH3:22])[CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[C:11]([O:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][CH2:20][CH2:21][CH3:22])[CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2
Reactant: CCC(=O)N[C@H]1CCC[C@@H](Oc2ccc3[nH]ncc3c2OC)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCN[C@H]1CCC[C@@H](Oc2ccc3[nH]ncc3c2OC)C1
Yield: 42.3 %

Procedure:
Under nitrogen, N-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]propanamide (141 mg, 0.444 mmol) was dissolved in tetrahydrofuran (7 ml), followed by adding thereto lithium aluminum hydride (84 mg, 2.22 mmol), and the resulting mixture was stirred with heating under reflux for about 2 hours. Under ice-cooling, the reaction solution was diluted with tetrahydrofuran, and water (84 μl) was added thereto and stirred, and then a 4N-aqueous sodium hydroxide solution (84 μl) and water (250 μl) were added thereto and stirred. The solid was filtered off and the solvent was distilled off under reduced pressure. The resulting concentration residue was purified by a silica gel column chromatography (eluent: acetonitrile/aqueous ammonia=100/0, 100/2, 100/5) to obtain N-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-N-propylamine (57 mg, yield 42.3%) as colorless tar.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.Cl[C:12]1[C:13]2[N:21]=[N:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:14]=2[N:15]=[C:16]([NH2:18])[N:17]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][N:19]1[C:14]2[N:15]=[C:16]([NH2:18])[N:17]=[C:12]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[C:13]=2[N:21]=[N:20]1
Reactant: c1cscn1
Reactant: Nc1nc(Cl)c2nnn(Cc3ccccc3F)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1nc(-c2nccs2)c2nnn(Cc3ccccc3F)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
A stirred solution of thiazole (0.10 mL, 1.43 mmol) in dry THF (5 mL) at −78° C., under argon was treated with n-BuLi (0.9 mL, 1.6-M in hexanes, 1.43 mmol), stirred for 30 min, treated with a solution of ZnCl2 (1.8 mL, 1-M in Et2O, 1.80 mmol) and allowed to warm gradually to room temperature. The mixture was treated with 7-chloro-3-(2-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (200 mg, 0.714 mmol) and Pd(PPh3)4 (50 mg), refluxed for 2 h and partitioned between saturated NH4Cl (20 mL) and EtOAc (20 mL). The organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; iso-hexane:EtOAc (1:1)] to give the title compound (70 mg, 30%) as a cream solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][N:5]2[C:11]=1[C:12]([NH:14][NH2:15])=[O:13].C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26].O>C(Cl)(Cl)Cl>[Cl:23][CH2:24][C:25]([NH:15][NH:14][C:12]([C:11]1[N:5]2[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]2=[N:3][C:2]=1[CH3:1])=[O:13])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc2nc(C)c(C(=O)NN)n2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc2nc(C)c(C(=O)NNC(=O)CCl)n2c1
Temperature: 25 °C
Yield: 105.6 %

Procedure:
To a mixture of 14.8 g of 2,6-dimethylimidazo[1,2-a]pyridine-3-carbohydrazide and 7.36 g of triethylamine in 300 ml of chloroform with stirring under cooling is added dropwise a solution of 8 g of chloroacetyl chloride in 50 ml of chloroform at 5°-10° C. After the mixture is stirred for 30 minutes, the reaction temperature is raised to room temperature and the resultant mixture is further stirred for 30 minutes. To the reaction mixture is added water and the precipitated crystals are collected by filtration to give 21 g of N'-chloroacetyl-2,6-dimethylimidazo[1,2-a]pyridine-3-carbohydrazide, melting at 290°-291° C. with decomposition.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH:14][C:15]1[CH2:19][CH2:18][C:17](=[O:20])[C:16]=1[CH3:21].Cl.Cl[CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[N:14]([C:15]1[CH2:19][CH2:18][C:17](=[O:20])[C:16]=1[CH3:21])[CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1
Reactant: ClCc1ccncc1
Reactant: COc1ccc(NC2=C(C)C(=O)CC2)cc1OC1Cc2ccccc2C1
Agent: Cl
Product: COc1ccc(N(Cc2ccncc2)C2=C(C)C(=O)CC2)cc1OC1Cc2ccccc2C1
Yield: 38.8 %

Procedure:
According to the same procedure as in Example 28, using 3-[3-(2-indanyloxy)-4-methoxyanilino]-2-methyl-2-cyclopenten-1-one produced in Example 10 instead of 3-(3-cyclopentyloxy-4-methoxyanilino)-2-cyclopenten-1-one, and using 4-(chloromethyl)pyridine hydrochloride instead of methyl iodide, the title compound (yield 38.8%) was obtained as a brown oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH:8]=O.Cl.[CH3:17][C:18]([CH3:20])=[O:19]>C(O)C.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:17][C:18](=[O:19])[CH3:20])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15]
Reactant: CC(C)=O
Reactant: CCOc1ccc(C=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(C=CC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
10% sodium hydroxide aqueous (40 ml) was added under stirring to a solution of 3-methoxy-4-ethoxybenzaldehyde (9.09 g, 50 mmol) in acetone (25 ml), 95% ethanol (25 ml) and water (200 ml). The reaction mixture was stirred for 24 hr at room temperature, after the reaction completed, the reaction mixture was neutralized with 6N hydrochloric acid to adjust pH=7.0. The precipitated solid was collected by filtrating and washed with water and ethanol successively, dried, and then recrystallized from 95% ethanol to give 7.38 g of a pale yellow solid, mp: 95-97° C., yield: 66.5%.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[CH:22]=[O:23].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C1COCC1.C(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[N:17]=[C:16]2[CH:22]=[O:23]
Reactant: O=Cc1n[nH]c2ccc(Br)cc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1nn(C2CCCCO2)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
p-Toluenesulfonic acid (10 mg, 0.052 mmol) was added to a solution of 5-bromo-indazole-3-carbaldehyde (100 mg, 0.444 mmol) and 3,4-dihydro-2H-pyran (75 mg, 0.891 mmol) in a mixture of THF/CH2Cl2 (1:1, 6 mL). The reaction mixture was stirred for 12 h at room temperature after which the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (20 mL) and poured in water (20 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (20 mL). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography (CH2Cl2) afforded 110 mg, (80% yield) of the title compound as a solid. 1H NMR (400 MHz, CDCl3): δ 10.21 (s, 1H), 8.47 (s, 1H), 7.56 (m, 2H), 5.80 (dd, 1H, J=3.2 and 9.2 Hz), 3.98 (m, 1H), 3.79-3.74 (m, 1H), 2.57-2.49 (m, 1H), 2.20-2.12 (m, 2H), 1.83-1.57 (m, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH2:8]P(OCC)(OCC)=O)=[O:7].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:22]=O>O1CCCC1>[CH2:4]([O:5][C:6](=[O:7])[CH:8]=[CH:22][C:21]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:19]([O:18][CH3:17])[CH:20]=1)[CH3:3]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(OC)c(OC)c1

Procedure:
16.5 g (0.55 mol) of sodium hydride (80%) are stirred in 500 ml of tetrahydrofuran and 123.3 g (0.55 mol) of phosphonoacetic acid triethyl ester are added dropwise to give a clear solution. Then over 15 minutes a solution of 83.1 g (0.50 mol) of 3,4-dimethoxybenzaldehyde in 200 ml of tetrahydrofuran are added. The mixture is then stirred under reflux for 30 minutes. After cooling, the clear solution is separated from the insoluble material which is dissolved in 500 ml of water and extracted twice with 250 ml of toluene. The tetrahydrofuran solution is evaporated to dryness and the residue is dissolved in the toluene extract. This solution is washed three times with water, dried and the solvent evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[NH2:10][C:5]1[CH:6]=[C:7]([F:9])[CH:8]=[C:2]([Cl:1])[C:3]=1[NH2:4]
Reactant: Nc1c(Cl)cc(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(F)cc(Cl)c1N
Temperature: 25 °C

Procedure:
1,2-Diamino-3-chloro-5-fluorobenzene was prepared using an adaptation of the method of Bellamy, et al., (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of 2-chloro-4-fluoro-6-nitroaniline (424 mg, 2.22 mmol) and SnCl2 2H2O (2.50 g, 11.1 mmol) dissolved in 7 mL ethyl acetate and 3 mL absolute ethanol under N2 was heated at 70° C. for 2.5 h. All the starting material had reacted as evidenced by TLC (silica gel, 2:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 20 mL crushed ice. Sufficient solid NaHCO3 was added (foaming!) to bring the pH to 6. The thick yellow white emulsion was then extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a dark brown oil which crystallized on standing to yield 290 mg (82%). 1H NMR (CDCl3) δ3.59 (br s, 4H, 2(NH2)); 6.37 (dd, 1H, H5, J4-5 =2.7, JH-F =9.3); 6.55 (dd, 1H, H4, J4-5 =2.7, JHF =8.4).
Reaction SMILES: [CH:1]1[C:2]([C:10]#[N:11])=[CH:3][C:4](Br)=[C:5](O)[C:6]=1Br.C1C(C#N)=CC(I)=C([OH:19])C=1I>>[OH:19][C:3]1[CH:4]=[CH:5][CH:6]=[CH:1][C:2]=1[C:10]#[N:11]
Reactant: N#Cc1cc(I)c(O)c(I)c1
Reactant: N#Cc1cc(Br)c(O)c(Br)c1
Product: N#Cc1ccccc1O

Procedure:
Bromoxynil and ioxynil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][C:11]([F:35])([F:34])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][CH:22]3[C:30]4[N:29]=[CH:28][C:27]([C:31]#[N:32])=[CH:26][C:25]=4[CH2:24][CH2:23]3)[CH:18]=[CH:17][C:16]=2[F:33])([CH3:14])[N:13]=1)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>>[NH2:7][C:8]1[O:9][CH2:10][C:11]([F:34])([F:35])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][CH:22]3[C:30]4[N:29]=[CH:28][C:27]([C:31]#[N:32])=[CH:26][C:25]=4[CH2:24][CH2:23]3)[CH:18]=[CH:17][C:16]=2[F:33])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(NC3CCc4cc(C#N)cnc43)ccc2F)C(F)(F)CO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: C[C@]1(c2cc(NC3CCc4cc(C#N)cnc43)ccc2F)N=C(N)OCC1(F)F
Yield: 13.7 %

Procedure:
A solution of {(R)-4-[5-((RS)-3-cyano-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-carbamic acid tert-butyl ester (110 mg, 219 μmol) in hydrochloric acid (4M in dioxane; 1.65 ml, 6.58 mmol) was stirred at room temperature and the progress of reaction was followed on TLC. After completion, the mixture was poured into an aqueous saturated solution of sodium bicarbonate, then extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and the solvent removed leaving a yellow solid. The crude material was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The (RS)-7-[3-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenylamino]-6,7-dihydro-5H-[1]pyrindine-3-carbonitrile (12 mg, 14% yield) was obtained as a mixture of epimers and as a yellow solid. MS (ISP): m/z=402.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:4][CH:5]=[N:6][C:7]=1[CH2:8][S+:9]([O-:19])[C:10]1[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[N:18]=1.CCCCCC.C(N(CC)CC)C.CCCCCC.CC(O)C>CC(O)C>[CH3:1][C:2]1[C:7]([CH2:8][S@:9]([C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[N:18]=2)=[O:19])=[N:6][CH:5]=[CH:4][C:3]=1[O:20][CH2:21][C:22]([F:25])([F:23])[F:24]
Reactant: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CC(C)O
Product: Cc1c(OCC(F)(F)F)ccnc1C[S@@](=O)c1nc2ccccc2[nH]1
Yield: 27.2 %

Procedure:
Lansoprazole (racemate) (34.2 g) was dissolved in 2-propanol (1,710 ml) and hexane (1,140 ml) containing triethylamine (0.2%) and fractionated by HPLC (column: CHIRALCEL OD 50 mm dia.×500 mm, temperature: room temperature, mobile phase: hexane/2-propanol=85/15, flow rate: 60 ml/min, detection wavelength: 285 nm, 1 shot: about 300 mg) to isolate the individual optical isomers. Fractions of an optical isomer of shorter retention time were combined and concentrated; the individual lots were combined and dissolved in ethanol (250 ml); after triethylamine (3 ml) was added, the solution was filtered through a 0.45 μm filter. After the filtrate was concentrated, hexane was added, and the filtrate was again evaporated to dryness to yield R(+)-lansoprazole (9.31 g, optical purity 98.3% ee) as an amorphous substance.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[CH:26]=[C:27]([NH:31][C:32](=[N:41][C:42]#[N:43])OOC3C=CC=CC=3)[CH:28]=[C:29]([CH3:30])[C:5]=2[N:4]=1)[CH3:2].[CH3:44][NH:45][CH3:46]>C(O)(C)C>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:13][CH:14]=2)[C:6]2[CH:26]=[C:27]([NH:31][C:32]([N:45]([CH3:46])[CH3:44])=[N:41][C:42]#[N:43])[CH:28]=[C:29]([CH3:30])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CNC
Reactant: CCc1nc2c(C)cc(NC(=NC#N)OOc3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CC(C)O
Product: CCc1nc2c(C)cc(NC(=NC#N)N(C)C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 6d from 4'-[[2-ethyl-4-methyl-6-(2-phenoxy-3-cyano-isoureido)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl and dimethylamine in isopropanol.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(N)cc1OC
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1OC
Yield: 74 %

Procedure:
Prepared from VII and 3,4-dimethoxyaniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 74%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3267, 2839, 2226, 1644, 1610, 1583, 1507, 1460, 1443, 1379, 1308, 1260, 1227, 1201, 1166, 1150, 1129, 1020, 967, 935, 861, 839; 1H NMR (300 MHz, DMSO-d6) δ 8.34 (m, 1H), 7.79 (m, 1H), 7.71 (m, 1H), 6.90 (d, 1H, J=8.1 Hz), 6.54 (m, 2H), 4.26 (s, 6H); HRMS calcd for C18H14N5O2S (M+H+): 364.0868, found 364.0850.
Reaction SMILES: Br[C@H:2]1[C:19]2[C@:14]([CH3:22])([CH:15]3[CH2:21][C@@H:16]3[C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]3)[CH2:3]1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([C@@H:2]1[C:19]2[C@:14]([CH3:22])([CH:15]3[CH2:21][C@@H:16]3[C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]3)[CH2:3]1)=[N+:25]=[N-:26]
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H](Br)C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@H]3[C@@H](C[C@H](N=[N+]=[N-])C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Yield: 70.1 %

Procedure:
A mixture of 6β-bromo-1,2β-methylenandrost-4-ene-3,17-dione (378 mg, 1 mmol), sodium azide (66 mg, 1 mmol) and dimethylformamide (10 ml) is heated from 20° to 100° C. Then the reaction mixture is cooled, poured onto ice water and extracted with ethyl acetate. The organic layer is separated, washed with water, dried and evaporated in vacuo. Purification is achieved by column chromatography over silica gel eluting with benzene/ether to yield pure 6α-azido-1,2β-methylenandrost-4-ene-3,17-dione (238 mg, 70%). Found: C 70.61, H 7.35, N 12.27. C20H25N3O2 requires: C 70.77, H 7.12, N, 12.38.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]([CH2:14][S:15][CH2:16][CH3:17])=[C:12]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO>[Cl:3][C:4]1[C:13]([CH2:14][S:15][CH2:16][CH3:17])=[C:12]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCSCc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSCc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a solution mixture comprising 50 ml of a 10% sodium hydroxide aqueous solution and 150 ml of methanol, 3.9 g of methyl 2-chloro-3-ethylthiomethyl-4-methanesulfonylbenzoate was added, and the mixture was stirred at room temperature for 30 minutes. Methanol was distilled off under reduced pressure, and a dilute hydrochloric acid was added to the residue for acid preparation. The mixture was extracted with ethyl acetate, and the extract was dried. Then, the solvent was distilled off to obtain 3.5 g of the desired product. Melting point: 172°-174° C.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[OH:19].C([O-])([O-])=O.[Na+].[Na+]>O=S(Cl)Cl.N1C=CC=CC=1.O>[OH:19][C:18]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[NH:12][C:9]([C:7]1[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:11]
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Reactant: Nc1cnccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=C(Nc1cnccc1O)c1ccc([N+](=O)[O-])s1
Temperature: 10 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A mixture of 5-nitrothiophene-2-carboxylic acid (5.000 g, 28.9 mmol) in SOCl2 (40 mL) was refluxed for 2 h. The excess SOCl2 was evaporated in vacuo and 3-amino-4-hydroxypyridine (2.65 g, 24.1 mmol) in pyridine (150 mL) was added dropwise. The reaction mixture was stirred at 10° C. overnight. Na2CO3 (1.533 g, 14.5 mmol) in water (100 mL) was added and the resultant mixture was stirred for additional 1 h. The precipitate was collected by filtration, washed with 10% Na2CO3 (120 mL), and dried in vacuo to afford N-(4-hydroxypyridin-3-yl)-5-nitrothiophene-2-carboxamide as a yellow powder (5.87 g, yield: 92%).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[CH:29][C:24]=2[O:23][CH2:22]1.[OH-].[Na+]>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:16][CH2:15][CH2:14][O:13][C:10]4[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=4)=[CH:32][CH:31]=3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: Oc1ccc(-c2ccc3c(c2)OCO3)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccc4c(c3)OCO4)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4-Benzo[1,3]dioxol-5-yl-phenol from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H26O7 [M+NH4]+: 468, [M+Na]+: 473.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[CH:10]=[C:9]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[C:8](=[O:16])[C:7]2[C:17]([CH3:26])=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:6]1=2.[Br:32]N1C(=O)CCC1=O.CC(CC(C)C)C#N.C(OC)(=O)C>O>[Br:32][CH2:26][C:17]1[C:7]2[C:8](=[O:16])[C:9]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:10][N:5]([CH2:4][C:3]3[C:2]([F:1])=[CH:30][CH:29]=[CH:28][C:27]=3[F:31])[C:6]=2[S:19][C:18]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccccc2)sc2c1c(=O)c(C(=O)C(C)C)cn2Cc1c(F)cccc1F
Agent: CC(C)CC(C)C#N
Solvent: COC(C)=O
Solvent: O
Product: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccccc3)c(CBr)c2c1=O
Reaction time: 2 h
Yield: 89.9 %

Procedure:
7-(2,6-Difluorobenzyl)-4,7-dihydro-5-isobutyryl-3-methyl-4-oxo-2-phenylthieno[2,3-b]pyridine (10 g), N-bromosuccinimide (4.86 g), 2,2′-azobis(2,4-dimethylvaleronitrile (0.56 g) and methyl acetate (100 ml) were mixed and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was allowed to cool with stirring over a period of 2 hours, water (50 ml) was added and then the mixture was stirred with cooling on ice for 1.5 hours. The crystal precipitated was recovered by a filtration, washed with an ice-cooled methyl acetate (30 ml) and water (30 ml), dried in vacuo at 40° C. for 6 hours to obtain the title compound (10.61 g, 87.1%).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[CH2:31]([Mg]Br)[CH3:32]>>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH:25]([OH:26])[CH2:31][CH3:32])[CH2:27][CH3:28])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CC[Mg]Br
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)CC)C1=O

Procedure:
The title compound was prepared from (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (Example 91, Step C) and ethylmagnesium bromide as described in Example 149, Step A. The crude material was used in the next step without further purification
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[C:12]#[N:13])=[CH:9][C:8]([O:14][CH3:15])=[CH:7][C:6]=2[O:16][CH3:17].NC(N)=[O:20].OO>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[C:12]([NH2:13])=[O:20])=[CH:9][C:8]([O:14][CH3:15])=[CH:7][C:6]=2[O:16][CH3:17]
Reactant: NC(N)=O
Reactant: COc1cc(OC)c2cnc(C)c(C#N)c2c1
Agent: OO
Product: COc1cc(OC)c2cnc(C)c(C(N)=O)c2c1
Reaction time: 2 h

Procedure:
3-methyl-4-cyano-6,8-dimethoxyisoquinoline (2.28 g, 20 mmol) reported in Tetrahedron Letters, 1968, 44, 1160-1163 is added to a finely powdered urea-hydrogen peroxide adduct (1.88 g, 20 mmol) in a glass tube, and the reaction mixture is placed in an oil bath at 85° C. for 2 hours. After completion of the reaction, the reaction mixture is extracted with ethyl acetate and the combined extracts are washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford the title compound.