Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][O:17]C(=O)C)[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+]>C(Cl)(Cl)Cl.CO.O>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][OH:17])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC1CN(C(C)=O)c2cc(C)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CC(=O)N1CC(CCO)c2c(C)cc(C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
1-Acetyl-3-(2-acetoxyethyl)-4,6-dimethylindoline (2.0 g) was dissolved in a mixture of CHCl3 /MeOH=1/1 (25 ml), and a solution of NaOH (1.5 g) in water (5 ml) was added, which was followed by stirring at room temperature for 1 hr. The solvent was evaporated under reduced pressure. CHCl3 (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=50/1-10/1) to give 1.2 g of 1-acetyl-3-(2-hydroxyethyl)-4,6-dimethylindoline.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:8][C:7](=[O:9])[CH2:6][CH2:5][CH:4]=1>[C].[Pd].C(OCC)(=O)C>[Cl:1][CH2:2][CH:3]1[O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4]1
Reactant: O=C1CCC=C(CCl)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCCC(CCl)O1
Reaction time: 2 h
Yield: 96 %

Procedure:
A mixture of 150 mg (1.024 mmol) of (-)-6-chloromethyldihydropyran-2-one obtained in Example 4, 6 ml of ethyl acetate and 60 mg of 10% palladium-carbon was stirred for 2 hours under hydrogen atmosphere. After completion of the reaction, the catalyst was removed by filtration, and the solvent was distilled off. Afterward, the resultant residue was subjected to column chromatography (an eluent of hexane:ethyl acetate=5:1), thereby obtaining 146 mg (yield 96%) of (-)-6-chloromethyltetrahydropyran-2-one having
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([O:33][CH2:34][O:35][CH3:36])=[C:29]([CH:32]=1)[CH:30]=[O:31]>C1COCC1>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([O:33][CH2:34][O:35][CH3:36])=[C:29]([CH:32]=1)[CH:30]([C:2]1[C:7]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:31]
Reactant: Brc1ncccc1C1OCCO1
Reactant: COCOc1ccc(Br)cc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(Br)cc1C(O)c1ncccc1C1OCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
To a solution of 2-bromo-3-(1,3-dioxolan-2-yl)pyridine (m.p. 35°-40° C.; 3.60 g) synthesized by a known method in THF (60 ml) was added, at -78° C. under argon atmosphere, a 1.6M n-butyl lithium hexane solution (10.8 ml). The mixture was stirred for 15 minutes at the same temperature, to which was then added a solution of 5-bromo-2-methoxymethoxybenzaldehyde (3.83 g) in THF (10 ml). The mixture was stirred for 15 minutes at the same temperature, then stirred for further 20 minutes while warming up to room temperature. The reaction mixture was poured into a saturated aqueous saline solution, which was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 2-(5-bromo-α-hydroxy-2-methoxymethoxybenzyl)-3-(1,3-dioxolan-2-yl)pyridine (4.50 g) (Compound D-2). The physical properties and spectrum data are shown in Table 13 and Table 14.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>O1CCCC1.CN(C)C1C=CN=CC=1>[C:17]([O:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:2][CH3:1])(=[O:19])[CH3:18]
Reactant: CNc1ccccc1CO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CNc1ccccc1COC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (50 mL) of [2-(methylamino)phenyl]methanol (1.37 g: synthesized according to the method described in WO 01/32652) in tetrahydrofuran were added pyridine (1.05 mL), acetic anhydride (1.23 mL) and 4-dimethylaminopyridine (0.18 g), and the mixture was stirred at room temperature for 8 hrs. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed successively with a 5% aqueous copper (II) sulfate solution (50 mL), a saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by flash silica gel column chromatography (eluted with ethyl acetate:hexane=1:5, then 1:3) to give the title compound (0.38 g) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=O)[C:19]2=[O:26].FC1C=C2C(=CC=1)NC(=O)C2=O>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]1[C:20](=[N:11][C:5]3[C:6]([C:7]1=[O:8])=[CH:13][CH:2]=[CH:3][CH:4]=3)[C:19]2=[O:26]
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: COc1ccc2c(c1)C(=O)c1nc3ccccc3c(=O)n1-2
Yield: 24 %

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 5-methoxyisatin for 5-fluoroisatin gave the title compound in 24% yield: mp 267.6°-269° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.28 (d, 1H) 8.25 (d, 1H) 7.93 (d, 2H) 7.68-7.78 (m, 1H) 7.37-7.46 (m, 2H) 3.88 (s, 3H); MS (M+H)+ 279.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33](O)=[O:34])[CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:33]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:32]=2[N:23]=[CH:24][CH:25]=[CH:26]3)=[O:34])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (4.50 mg, 1.44 mmol) in acetonitrile (30 ml) were added 8-quinolinecarboxylic acid (249 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (413 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (162 mg, 24%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][CH2:11][C@@H:12]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:25])=O)=[CH:19][CH:18]=2)[O:15][C:14]([CH3:27])([CH3:26])[N:13]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(=O)(O)[O-].[Na+]>ClCCl.[Sb](Cl)(Cl)Cl>[F:10][CH2:11][C@@H:12]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH2:25][F:7])=[CH:19][CH:18]=2)[O:15][C:14]([CH3:27])([CH3:26])[N:13]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CS(=O)c1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: Cl[Sb](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(SCF)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A solution of diethylamino sulfurtrifluoride (DAST), (9.34 g, 1.75 eq ) in 10 ml of dichloromethane was added drop wise to the solution of 14 (12.3 g) and antimony (III) chloride (0.23 g, 0.03 eq ) in 150 ml of dichloromethane (anhydrous) at −5° C., and the reaction mixture was warmed up to room temperature overnight. A cold saturated solution of sodium bicarbonate (80 ml) was added and stirred for 30 min and extracted with dichloromethane (100 ml×2). The organic layer was washed with a 10% solution of sodium bicarbonate and with brine (50 ml) and dried over sodium sulfate. After purification, via a column, 10.7 g of the desired product (as a heavy oil) was obtained.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][C:21]=1[O:29][CH3:30].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][C:21]=3[O:29][CH3:30])[CH2:3][CH2:2]2)=[N:8]1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 122.8 %

Procedure:
A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]-ethanone (4.3 g, 20.0 mmol), K2CO3 (3.0 g, 21.8 mmol), acetonitrile (125 ml) and a catalytic amount of KI was heated to reflux and stirred under nitrogen for 24 hours. At this point, an additional amount of K2CO3 (1.0 g, 7.2 mmol) and alkylating agent (0.4 g, 1.7 mmol) was added to the reaction mixture and heating at reflux was resumed for 24 hours. The reaction was cooled to ambient temperature and filtered. The filter cake was washed with acetonitrile and the filtrate was concentrated to afford a dark oil. The oil was extracted with methylene chloride, and the organic extract was washed with water, dried with MgSO4 and concentrated to yield 9.2 g of an oil. Purification by preparative HPLC (Waters Associates Prep LC/System 500 utilizing 2 silica gel columns and 3% methanol/methylene chloride as eluent) provided 3.8 g of a soft, beige gum, which readily solidified. The compound was recrystallized twice from ethanol to give 2.1 g (28%) of 1-[4-[2-[4-(1,2-benzisothiazol-3-yl-1-piperazinyl]ethoxy]-3-methoxyphenyl]ethanone as a beige solid, m.p.=98°-100° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:12]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30](O)=[O:31])[CH2:24][CH2:23]1)=[O:20].ON1C2N=CC=CC=2N=N1.N1C(C)=CC=CC=1C.CCN=C=NCCCN(C)C.Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[CH3:11][O:10][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3][CH2:2][C:30](=[O:31])[CH2:29][CH2:28][N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:19](=[O:20])[NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:23][CH2:24]1
Reactant: CNCCCCC(=O)OC
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)CCCCNCC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
A mixture of methyl 5-methylaminopentanoate hydrochloride (7.27 g, 40.0 mmol), 3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (13.3 g, 36.0 mmol) and 1-hydroxy-7-azabenzotriazole (5.14 g, 37.8 mmol) in DCM (160 mL) and 2,6-lutidine (12.5 mL, 108 mmol) was stirred at room temperature for 3 h. N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (10.4 g, 54.0 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. A saturated aqueous sodium bicarbonate solution (˜100 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (50 mL) and the organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (30-100% EtOAc in hexanes; then 2-10% MeOH in DCM) to give the title compound (12.38 g, 69% yield) as a light yellow thick oil/white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C1COCC1>[N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:26](=[O:27])[O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cnn(CCN3CCCC3)c2c1)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a mixture of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine (0.220 g, 0.955 mmol) and triethylamine (0.240 mL, 1.72 mmol) in 1 mL of THF at 0 C was slowly added phenyl chloroformate (0.246 ml, 1.72 mmol). The mixture was stirred cold for 1 hours and the formed precipitate collected by filtration with rinsing with ether to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.82 (m, 2 H), 1.97 (m, 2 H), 2.97 (m, 2 H), 3.49 (m, 2 H), 3.69 (m, 2 H), 4.71 (t, J=6.27 Hz, 2 H), 7.19 (m, 1 H), 7.28 (m, 3 H), 7.46 (m, 2 H), 7.74 (m, 1 H), 7.99 (m, 1 H), 8.10 (s, 1 H), 10.51 (s, 1 H); MS (DCI/NH3) m/z 351 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[CH3:15][O:16][CH2:17]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)(Cl)Cl>[CH3:15][O:16][CH2:17][N:9]1[C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13]
Reactant: COCOC
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClC(Cl)Cl
Product: COCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To 0.976 g (5.02 mmol) of 6-nitro-2H-1,4-benzoxazin-3(4H)-one in 100 ml of chloroform was added 2 ml of dimethoxymethane. Phosphorous pentoxide (5 g, 35 mmol) was added portionwise and the reaction mixture was stirred at room temperature for 16 hours. TLC analyses showed the starting material was still present therefore additional dimethoxymethane (2 ml) was added along with several batches of phosphorous pentoxide (2×1.2 g and 2.0 g) and chloroform (50 ml). The reaction was stirred for an additional 16 hours then cautiously quenched with water (50 ml). The reaction mixture was slowly neutralized with 50 ml of 1N NaOH during which time an exotherm occurred. When the reaction mixture had cooled to room temperature, the layers were separated and the aqueous phase was extracted with chloroform (2×50 ml). The combined organic phases were washed with water (2×50 ml), dried over MgSO4 and concentrated to afford the desired product (0.5 g, 42% yield) as a pale yellow solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[CH3:13][C:14]1([CH3:21])[NH:18][C:17](=[S:19])[NH:16][C:15]1=[S:20]>CCO>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:19][C:17]1[N:16]=[C:15]([S:20][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]([CH3:12])[CH3:2])[C:14]([CH3:21])([CH3:13])[N:18]=1
Reactant: CN(C)c1ccccc1CCl
Reactant: CC1(C)NC(=S)NC1=S
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccccc1CSC1=NC(C)(C)C(SCc2ccccc2N(C)C)=N1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Initially, a solution of 9.1 g of 2-dimethylaminobenzylchloride hydrochloride in 50 mL of EtOH was added to a solution of 7 g of 5,5-dimethyl-2,4-dithiohydantoin in 100 mL of ethanol (EtOH). The reaction mixture was stirred for 1.5 hour at the room temperature and concentrated in vacuo. To the residue, there was added 100 mL of chloroform (CHCl3). The residue was then washed with an aqueous solution of potassium carbonate (CaCO3), dried over magnesium sulfate (MgSO4), and concentrated in vacuo. The residue was chromatographed on a column of silica gel (CHCl3). From the earlier fractions, 2,4-bis(2-dimethylaminobenzylthio)-5,5-dimethyl-5H-imidazole was isolated as a syrup. The yield of this compound was 1.1 g with a yield ratio of 5.9%.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([OH:24])=[O:23])[CH2:3]1.Cl.[CH:26](O)([CH3:28])[CH3:27]>>[OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([O:24][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:3]1
Reactant: CC(C)O
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Agent: Cl
Product: CC(C)OC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
A solution of 3α-hydroxy-11-oxo-5α-androstane-17β-carboxylic acid (550 mg.) in dry isopropanol containing 3.7%, by weight, of hydrogen chloride (100 ml.) was refluxed for 61/2 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:11])([CH3:10])[CH3:9])[N:3]=1.Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:19][C:17]1[CH:18]=[C:13]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:11])([CH3:9])[CH3:10])[N:3]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: CC(C)(O)c1nccc(N)n1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccnc(C(C)(C)O)n2)c1=O
Temperature: 100 °C
Yield: 29.5 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 264a (300 mg, 2.0 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (800 mg, 3.0 mmol), Pd2(dba)3 (182 mg, 0.20 mmol), XantPhos (231 mg, 0.40 mmol), Cs2CO3 (1.30 g, 4.0 mmol), and 1,4-dioxane (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 15 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol (40:1) and further purified by reverse-phase Combiflash to afford 264b as white solid (200 mg, 30%). MS-ESI: [M+H]+ 339.0
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[O-].[Na+].CO.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH2:24][C:25](Cl)=[N:26]O>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH2:24][C:25]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][N:26]=1
Reactant: ON=C(Cl)Cc1c(Cl)cccc1Cl
Reactant: COC(=O)CC(=O)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(Cc2c(Cl)cccc2Cl)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A solution of methyl isobutyrylacetate (1.93 g, 13.4 mmol) in tetrahydrofuran (2.7 mL) was stirred at 0° C. as 0.5 N sodium methoxide in methanol solution (27 mL, 13.5 mmol) was added. A solution of 2-(2,6-dichlorophenyl)-N-hydroxyethanimidoyl chloride (2.60 g, 11.18 mmol) in tetrahydrofuran (8.7 mL) was added and the solution was allowed to warm to room temperature and stir overnight. The mixture was concentrated then partitioned between water and ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0%-30% ethyl acetate in hexane) to provide the title compound (1.10 g, 30%). 1H NMR (DMSO-d6): 7.48 (d, J=8 Hz, 2H), 7.34 (t, J=8 Hz, 1H), 4.42 (s, 2H), 3.84 (s, 3H), 3.68 (septet, J=7 Hz, 1H), 1.24 (d, J=7 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][NH:11][NH2:12]>C(O)C>[CH3:10][NH:11][N:12]=[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)[NH2:9]
Reactant: CNN
Reactant: Cc1cccc(C#N)n1
Solvent: CCO
Product: CNN=C(N)c1cccc(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
6-Methylpyridine-2-carbonitrile (45.3 g, 0.384 mol) and methylhydrazine (94 mL, 5.30 mol) were mixed with ethanol (200 mL). The mixture was stirred at room temperature overnight, and then an additional portion (18 mL, 1.00 mol) of methylhydrazine was added, and the mixture was stirred for a further 16 h. The mixture was then evaporated to give 58.0 g of crude N′,6-dimethylpyridine-2-carbohydrazonamide (˜92% yield), which was used for the next stage of the synthesis without additional purification.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[CH:42]1([CH2:47][C:48](Cl)=[O:49])[CH2:46][CH2:45][CH2:44][CH2:43]1>C(#N)C.CO>[CH:42]1([CH2:47][C:48]([N:29]2[CH2:28][CH2:27][CH:26]([C:19]3[CH:18]=[C:17]4[C:22]([CH2:23][CH:24]([CH3:25])[N:15]([C:13]5[CH:14]=[C:9]([N:6]6[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]6)[N:10]=[C:11]([NH2:32])[N:12]=5)[CH2:16]4)=[CH:21][CH:20]=3)[CH2:31][CH2:30]2)=[O:49])[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC1Cc2ccc(C3CCN(C(=O)CC4CCCC4)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-Methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine HCl salt (21.1 mg) in acetonitrile (0.50 mL) was treated with N,N-diisopropylethylamine (0.070 mL, 0.40 mmol). To the solution was added cyclopentylacetyl chloride (10.0 mg). The mixture was stirred at r.t. for 2 h. The mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=532.3.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[CH3:31])[C:17]([F:23])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CS(C)=O>[N:32]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[CH3:31])[C:17]([F:23])=[CH:18][CH:19]=2)[O:14]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(F)c(-c4ccc(Cl)cc4C)c3O2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(Cl)ccc1-c1c(F)ccc2c1O[C@@H](CN=[N+]=[N-])CC2
Yield: 83 %

Procedure:
Treatment of ((2R)-8-(4-chloro-2-methylphenyl)-7-fluorochroman-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.09 mmol) with sodium azide (0.43 g, 6.54 mmol) in DMSO (15 mL) according to the procedure described for Example 69, Step 9 provided 0.30 g (83%) of (2R)-2-(azidomethyl)-8-(4-chloro-2-methylphenyl)-7-fluorochroman as a colorless oil.