Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][OH:21])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.O>[CH3:29][S:30]([O:21][CH2:20][C:19]1[C:15]([C:10]2[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[C:13](=[O:14])[O:12][N:11]=2)=[N:16][O:17][N:18]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1onc(-c2nonc2CO)n1-c1ccc(F)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Yield: 82.9 %

Procedure:
4-(3-Chloro-4-fluorophenyl)-3-[4-(hydroxymethyl)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one (250 mg, 0.7996 mmol) was dissolved in anhydrous DCM (8 mL) followed by addition of triethylamine (TEA) (134 μL, 0.96 mmol). Reaction was cooled to 0° C. and methanesulfonyl chloride (68 μL, 0.88 mmol) was added dropwise. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography eluting with 25%-70% EtOAc to yield the desired product (259 mg, 83%). MF═C12H8ClFN4O6S; LCMS calculated for C12H9ClFN4O6S (M+H)+: m/z=390.992.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CC(C)([O-])C.[K+].CC(N(C)C)=O>C(O)(C)(C)C>[CH2:10]([O:24][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Yield: 38.8 %

Procedure:
A mixture of 125.0 g (0.652 mole) of 5-bromo-2-furoic acid, 210.0 g (0.978 mole) of 1-tetradecanol, 183.0 g (1.630 mole) of potassium tert-butoxide and 2500 ml of dimethylacetamide is heated with stirring. The tert-butanol formed in the reaction is allowed to distill off, then the mixture is heated to reflux with stirring for 48 hours. To the cooled mixture is added 6 liters of ice water, and the mixture is acidified with malonic acid. The resulting precipitate is collected, dried and recrystallized twice from methanol to give 82.0 g (29%) of 5-tetradecyloxy-2-furoic acid, M.P. 112°-115° C. (dec.).
Reaction SMILES: C([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[CH:22]4)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])(C)(C)C.C(N)CN>CN(C=O)C.O>[NH:24]1[C:25]2[C:21](=[CH:20][CH:19]=[CH:18][C:17]=2[C:14]2[N:15]=[C:16]3[C:8]([C:6]([NH2:5])=[O:7])=[CH:9][NH:10][C:11]3=[N:12][CH:13]=2)[CH:22]=[CH:23]1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc4cc[nH]c34)nc12
Solvent: NCCN
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c[nH]c2ncc(-c3cccc4cc[nH]c34)nc12
Temperature: 60 °C
Reaction time: 72 h
Yield: 43.5 %

Procedure:
To a stirred solution of N-tert-butyl-2-(1H-indol-7-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (54 mg, 116 μmol) in DMF (3 mL) was added ethylenediamine (350 mg, 393 μL, 5.82 mmol) and the mixture heated at 60° C. After 72 h, the reaction mixture was cooled, diluted with water, and extracted into ethyl acetate. The organic phases were combined and washed with water and brine then dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with ether, then water, diluted with dichloromethane, and finally the solvents removed in vacuo to give N-tert-butyl-2-(2-(1H-indol-7-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (14 mg). MS (M+H)+=334.1; 1H NMR (DMSO-d6) δ: 12.83 (br. s., 1H), 11.46 (br. s., 1H), 9.01 (s, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.52 (br. s., 1H), 7.30 (t, J=7.5 Hz, 1H), 6.69 (br. s., 1H), 1.55 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([CH:33]([CH3:35])[CH3:34])=[C:29]([CH:32]=1)[CH:30]=[O:31]>C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:30]([C:29]3[CH:32]=[C:25]([Br:24])[CH:26]=[CH:27][C:28]=3[CH:33]([CH3:35])[CH3:34])[OH:31])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(Br)cc1C=O
Reactant: Brc1ccc2c(c1)N(Cc1ccccc1)CCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1ccc(Br)cc1C(O)c1ccc2c(c1)N(Cc1ccccc1)CCC2
Reaction time: 0.75 h
Yield: 70.9 %

Procedure:
To a solution of 1-benzyl-7-bromo-1,2,3,4-tetrahydro-quinoline (2.50 g, 8.27 mmol) in THF (20 mL) was added 1.6 M n-butyl lithium in hexanes (5.14 mL, 8.27 mmol) at −78° C. The mixture was stirred for 45 min. then transferred to a stirred solution of 5-bromo-2-isopropylbenzaldehyde (1.87 g, 8.27 mmol) in THF (15 mL) at −78° C. After stirring for 30 min, the reaction was quenched by the addition of saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined and washed with water (25 mL) and brine (25 mL), then dried over sodium sulfate, concentrated and purified using neutral alumina column chromatography to furnish (1-benzyl-1,2,3,4-tetrahydro-quinolin-7-yl)-(5-bromo-2-isopropyl-phenyl)-methanol (2.64 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]#[N:14].Br[CH2:16][C:17]1[O:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:16][C:17]3[O:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: CCc1nc2c(Cl)c(C#N)ccc2[nH]1
Product: CCc1nc2c(Cl)c(C#N)ccc2n1Cc1ccc(C(F)(F)F)o1

Procedure:
Synthesized as described in Example 197B from 4-chloro-2-ethyl-1H-benzimidazole-5-carbonitrile and 2-(bromomethyl)-5-(trifluoromethyl)furan: MS (ESI) m/z 354 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12](OC)=[O:13])[N:4]=1.[BH4-].[Na+].Cl>C(O)C>[F:17][C:2]([F:1])([F:16])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([CH2:12][OH:13])[N:4]=1
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1nc(C(F)(F)F)n2c1CNCC2
Reaction time: 12 h
Yield: 82.5 %

Procedure:
Methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (315 mg, 1.26 mmol) was dissolved in 10 mL of ethanol, followed by addition of sodium borohydride (240 mg, 6.33 mmol). After stirring for 12 hours, the reaction mixture was added dropwise with 2 M hydrochloric acid until no gas was generated in the reaction mixture. The reaction mixture was concentrated under reduced pressure to obtain the crude [3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanol 6a (230 mg) as a white solid. The product was used directly in the next reaction without purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.C([O:15][C@H:16]1[C@@H:21]2[C@H:22]([CH3:25])[CH2:23][CH2:24][C@@H:20]2[C:19]([C:26](OC)=O)=[CH:18][O:17]1)(=O)C.[OH-].[Na+]>CCOCC>[OH:15][CH2:16][C@@H:21]1[C@H:22]([CH3:25])[CH2:23][CH2:24][C@@H:20]1[C:19](=[CH2:26])[CH2:18][OH:17]
Reactant: COC(=O)C1=CO[C@@H](OC(C)=O)[C@@H]2[C@H](C)CC[C@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(CO)[C@H]1CC[C@@H](C)[C@H]1CO
Yield: 57.2 %

Procedure:
8.0 g (0.21 mol) of lithium aluminum hydride was suspended in 100 mι of anhydrous tetrahydrofuran, and 150 mι of an anhydrous tetrahydrofuran solution of methyl (1S, 4aS, 7R, 7aR)-1-acetoxy-7-methyl-1, 4a, 5, 6, 7, 7a-hexahydrocyclopenta[c]pyran-4-carboxylate obtained in Definite Example 52 (14.5 g, 0.057 mol) was added dropwise while being cooled by ice and stirred. The temperature was returned to room temperature and the reaction mixture was stirred for 3 hours. After 300 mι of ether was added, 1N sodium hydroxide solution was further added dropwise. After insoluble matters were filtered by celite, concentration was carried out and the residual substance was purified by chromatography using silica gel. When the solvent of the fraction obtained from ether:ethyl acetate=9:1 eluent was distilled off, and a colorless oily substance was obtained, i.e., 2-[(1S, 2R, 3R)-2-(hydroxymethyl)-3-methylcyclopent-1-yl]-2-propen-1-ol (5.55 g, yield=57.2%). This 2-[(1S, 2R, 3R)-2-(hydroxymethyl)-3-methylcyclopent-1-yl]-2-propen-1-ol had the following physicochemical properties.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[NH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Cl:22][CH2:23][C:24]([N:15]=[S:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: N=S(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N=S(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 19.2 g (0.19 mol) of triethylamine in 50 ml of methylene chloride is added dropwise at room temperature, whilst stirring to a solution of 19 g (0.095 mol) of S,S-diphenylsulphilimine [compare Furukawa et al., Univ. Osaka: Tetrahedron Letters 1972, 1619-1622; Tamura et al., Univ. Osaka: Tetrahedron Letters 1972, 4137-4140] in 120 ml of methylene chloride and subsequently, whilst cooling slightly, a solution of 12.3 g (0.11 mol) of chloroacetyl chloride in 80 ml of methylene chloride is added dropwise. The mixture is stirred overnight at room temperature, the solvent is stripped off in vacuo, the residue is taken up in methylene chloride and the organic phase is washed with water until neutral. The product is then dried over sodium sulphate and the solution is evaporated in vacuo. N-(Chloroacetyl)-S,S-diphenylsulphilimine is obtained as an oily residue and is further processed as the crude product.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][C:11]=2[O:18][CH3:19])[C:5]=1[CH3:20])(=[O:3])[CH3:2].B(Br)(Br)Br.C(Cl)Cl>>[C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[O:18][CH3:19])[C:5]=1[CH3:20])(=[O:3])[CH3:2]
Reactant: COc1ccc(-n2c(C)cc(C(C)=O)c2C)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)ccc1-n1c(C)cc(C(C)=O)c1C

Procedure:
To a solution of 3-acetyl-1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole (2.73 g, 10 mmol) (EXAMPLE 33) in CH2Cl2at rt (75 mL) was added a 1.0M solution of boron tribromide in CH2Cl2 (15 mL, 15 mmol) and the reaction monitored by LC. After complete consumption of the starting material, the reaction was carefully quenched with saturated NaHCO3 and partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography to give 3-acetyl-2,5-dimethyl-1-(4-hydroxy-2-methoxyphenyl)pyrrole as a tan solid: 1H NMR (CDCl3, 500 MHz) δ 6.92 (d, 1H), 6.61 (d, 1H), 6.54 (dd, 1H), 6.32 (s, 1H), 3.72 (s, 3H), 2.44 (s, 3H), 2.26 (s, 3H), 1.93 (s, 3H), 1.69 (br s, 1H); MS (ESI) 260 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:11]([Cl:21])[CH:10]=1)[C:3]([O:5]CC)=[O:4].Cl>C(O)(=O)C>[Cl:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[C:11]([Cl:21])[CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(Cl)Cc1ccc(C2CCCCC2)c(Cl)c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)C(Cl)Cc1ccc(C2CCCCC2)c(Cl)c1

Procedure:
A mixture of 54.8 g. (0.167 moles) of the ethyl α-chloro-β-(3-chloro-4-cyclohexylphenyl)propionate and 160 ml. of glacial acetic acid containing 40 ml. of 37% hydrochloric acid is refluxed for 20 hours. The mixture is concentrated under reduced pressure to give a gummy residue. The latter material is dissolved in 300 ml. of n-hexane, washed with ice-cold water (100 ml. total), dried over sodium sulfate and filtered. The hexane is removed to give α-chloro-β-(3-chloro-4-cyclohexylphenyl)propionic acid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:13](Cl)(=O)[CH3:14]>C(O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:13][CH3:14])=[O:8]
Reactant: CC(=O)Cl
Reactant: COc1ccc(I)cc1C(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(I)ccc1OC

Procedure:
A mixture of 5-iodo-2-methoxybenzoic acid (13.4 g, 48 mmol), acetyl chloride (1 mL) and ethanol (50 mL) was heated 4 hours with stirring at reflux. The mixture was concentrated and the residue was dissolved in diethyl ether. The solution was poured into ice-cold saturated sodium bicarbonate and the organic phase was washed with brine, dried (K2 CO3), filtered and concentrated to give ethyl 5-iodo-2-methoxybenzoate (13.5 g, 44 mmol) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1N(C(CO)CO)C([C@H]1CC[C@H](C)CC1)=O)=[O:4].C=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C(CO)CO
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cccs1
Temperature: 80 °C
Reaction time: 0.23 h

Procedure:
A mixture of 5-bromo-3-[(2-hydroxy-1-hydroxymethyl-ethyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (18 mg, 0.041 mmol), paraformaldehyde (6 mg) and boron trifluoride-diethyl etherate (15 μl, 0.12 mmol) in dry dioxane (0.6 mL) was stirred at 80° C. for 14 min. It was cooled and added to ice and NaHCO3 solution mixture, extracted with ethyl acetate, washed with brine, dried and evaporated. Pure 5-bromo-3-[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester was obtained after chromatography over silica gel (hexane:ethyl acetate-9:1 as eluent) (15 mg; 81%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.[O:14]([C:21]1[N:26]=[C:25]([CH2:27][CH2:28][C:29](OC)=[O:30])[CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCCC1>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:29](=[O:30])[CH2:28][CH2:27][C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:26]=2)[C:12]#[N:13])=[CH:7][CH:6]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: COC(=O)CCc1cccc(Oc2ccccc2)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)C(=O)CCc2cccc(Oc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.6 %

Procedure:
Under a nitrogen atmosphere, 235 mg of sodium hydride (60% oil dispersion) were added to 50 ml of dry tetrahydrofuran, and the mixture was heated to 50° C. to 60° C. A solution of 864 mg of 4-methoxyphenylacetonitrile and 1.51 g of methyl 3-(6-phenoxypyridin-2-yl)propionate in 10 ml of dry tetrahydrofuran were added dropwise thereto over 5 minutes. After dropwise addition, the reaction solution was heated under reflux for 2 hours, cooled with ice, poured into ice water, neutralized to a pH of 7 with aqueous dilute hydrochloric acid and extracted twice with ethyl acetate. The ethyl acetate layers were combined and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue crystallized, so that the crystal was washed with a little diethyl ether, filtered and dried to obtain 0.91 g of the desired 2-(4-methoxyphenyl)-3-oxo-5-(6-phenoxypyridin-2-yl)valeronitrile [corresponding to the compound represented by the foregoing general formula (X) wherein R1 is a methoxy group, R2, R5 and R6 are a hydrogen atom] as a crystal.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Temperature: 10 °C

Procedure:
To a stirred solution of 5-hydroxy-12H-benzo[a]phenothiazine (50 g) in pyridine (115 ml) was added acetic anhydride (48 ml). The reaction was exothermic stirring was continued without cooling for 30 minutes, then the mixture was cooled to 10° C. using an ice bath. The yellow crystalline solid was filtered and washed with ether to afford the title compound (23.4 g). The product was crystallized from ethyl acetate, m.p. 185°-186° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]O)=[CH:6][C:5]([C:13]([NH2:15])=O)=[N:4]1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([C:13]#[N:15])[CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nc(C(N)=O)cc1CCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCn1nc(C#N)cc1CCCCCl
Temperature: 0 °C

Procedure:
A modification of the method described in Part E of Examples 1-4 was used to treat 1-ethyl-5-(4-hydroxybutyl)-1H-pyrazole-3-carboxamide (18.2 g, 86.1 mmol) with phosphorous oxychloride (60 mL). The reaction was heated for three hours before cooling to 0° C. and pouring into ice water. The mixture was adjusted to pH 12 with the addition of 2 N aqueous sodium carbonate and extracted with chloroform. The combined extracts were passed through a layer of silica gel (eluting first with chloroform and then with 1:1 hexane/ethyl acetate to provide 10.8 g of 5-(4-chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile as a dark oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f35) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([N+:21]([O-])=O)[CH:12]=3)[N:10]=2)[CH:7]=1.CC(O)=O>[Fe].C(O)C.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[C:13]([CH:12]=3)[NH2:21])[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2cn3cc(Cl)ncc3n2)ccc1C(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2cn3cc(Cl)ncc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Iron (0.726 g) is added to a mixture of 6-chloro-2-[3-nitro-4-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrazine (0.891 g), HOAc (1.19 mL), and EtOH—H2O (10 mL, 4:1). The mixture is stirred at 80° C. for 2 hours, cooled, concentrated and taken up into sat. aqueous NaHCO3 and extracted with EtOAc and CH2Cl2. Organic layer is dried and concentrated to give the title compound (813 mg), which is used without further purification. LCMS m/z=313.4 [M+H]+, tR=2.29 min.
Reaction SMILES: N[CH2:2][C:3]1([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][CH2:4]1.N([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]2[CH2:6][CH2:5][CH2:4][C:3](=[O:15])[CH2:2][C:12]=2[CH:11]=1
Reactant: COc1ccc2c(c1)C(O)(CN)CCC2
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)CC(=O)CCC2
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of 1-aminomethyl-7-methoxy-1,2,3,4-tetrahydro-1-naphthalenol (27.50 g) in 10% aqueous acetic acid solution (250 ml) was added dropwise a solution of sodium nitrite (10.07 g) in water (61 ml) at 8° C.~9° C. The reaction mixture was stirred for 2 hours at the same temperature. The resulting precipitates were collected by filtration. The precipitates were dissolved in ethyl acetate. The solution was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel, n-hexane:ethyl acetate:chloroform=5:1:3) to give 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-one (19.39 g) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]([C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]([C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:12]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:10])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C)(C)c1cc(N)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
To a mixture of the compound (100 mg) obtained in Example 565, nickel (II) chloride hexahydrate (123 mg) and methanol (6 ml), sodium borohydride (39 mg) was added. The reaction mixture was stirred at room temperature for 10 min; then, 2 N HCl was added and a saturated aqueous sodium bicarbonate solution and chloroform were also added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:2) to give 87 mg of the titled compound (yield, 94%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]([CH:18]([CH3:20])[CH3:19])[C@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[OH:17].C([O-])([O-])=O.[K+].[K+]>ClCCl.O>[Cl:1][CH2:2][C:3]([O:17][C@@H:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:8]1[N:7]([CH3:6])[CH:18]([CH3:20])[CH3:19])=[O:4]
Reactant: CC(C)N(C)[C@H]1c2ccccc2C[C@H]1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)N(C)[C@H]1c2ccccc2C[C@H]1OC(=O)CCl
Temperature: 35 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
2.00 grams (17.5 mmol) of chloroacetyl chloride was added drop by drop, in 5 minutes, to a solution of 3.00 grams (14.6 mmol) of (1S,2R)-N-methyl,N-i-propyl-1-amino-2-indanol in 40 ml of dichloromethane at room temperature. The temperature increased to 35° C. The reaction was stirred for 15 hours at room temperature. This was followed by the addition of 50 ml of a 5% K2CO3 solution in water and extraction. The basic water layer was once again extracted using 30 ml of dichloromethane. After the collected organic layers had been washed with water, dried using Na2SO4 and evaporated, 3.96 grams (85%) of product was isolated as a yellow oil. 1H NMR (200 MHz, CDCl3): 1.05 (2*d, 6H), 2.09 (s, 3H), 2.96 (dd, J=8.6 and 3.5 Hz +septet, 2H), 3.14 (dd, J=8.6 and 3.5 Hz, 1H), 3.99 (s, 2H), 4.47 (d, J=3,1 Hz, 1H), 5.47 (dt, J=3,1 and 3.5 Hz, 1H) and 7.10-7.25 (m, 4H). 13C NMR (50.31 MHz, CDCl3): 20.59 (q), 33.00 (q), 37.06 (t), 41.10 (t), 53.61 (d), 66.08 (d), 78.47 (d), 124.84 (d), 125.81 (d), 126.62 (d), 127.61 (d), 138.96 (s), 140.46 (s) and 166.85 (s).