Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[CH3:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:31][CH:30]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Cc1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-methyl-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=9:1) C24H20N2O3
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.C(OC([N:26]1[CH2:33][CH2:32][CH:31]2[CH:28]([NH:29][CH2:30]2)[CH2:27]1)=O)(C)(C)C.Cl[C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:38]=[C:37]([N:45]([CH3:47])[CH3:46])[N:36]=1.ClC1C=NC2C(=CC=CC=2)N=1>>[C@@H:28]12[N:29]([C:35]3[CH:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[N:38]=[C:37]([N:45]([CH3:47])[CH3:46])[N:36]=3)[CH2:30][C@@H:31]1[CH2:32][CH2:33][NH:26][CH2:27]2
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Reactant: CN(C)c1nc(Cl)cc(C(F)(F)F)n1
Agent: Clc1cnc2ccccc2n1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: CN(C)c1nc(N2C[C@@H]3CCNC[C@@H]32)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, substituting (1R,6S)-(3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester for 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester and (4-chloro-6-trifluoromethyl-pyrimidin-2-yl)-dimethyl-amine for 2-chloro-quinoxaline in Step A. MS (ESI) mass calcd. for C13H18F3N5, 301.31. m/z found 302.1 [M+H]+. 1H NMR (CDCl3): 9.04 (s, 1H), 5.98-5.63 (m, 1H), 4.56 (dd, J=4.9, 3.1, 1H), 3.99 (t, J=7.8, 1H), 3.88-3.70 (m, 2H), 3.68-3.37 (m, 2H), 3.33-3.17 (m, 1H), 3.16-3.00 (m, 6H), 2.95-2.74 (m, 1H), 2.33-1.85 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.Br[CH2:16][C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(#N)CC>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]2[O:11][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:12]=2)=[CH:8][CH:7]=1
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCC#N
Product: CCOC(=O)c1coc(-c2ccc(OCCCCl)cc2)n1
Reaction time: 24 h
Yield: 41 %

Procedure:
A mixture of 4-(3-chloropropoxy)benzamide ax54 (3.55 g, 16.6 mmol, 1 eq) and ethyl bromopyruvate (3.24 g, 16.6 mmol, 1 eq) in propionitrile (60 ml) is heated at reflux. After 24 h, the solvent is evaporated, and the residue is taken up in ethyl acetate and washed two times with an aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane/hexane 90:10) affords 2.12 g of ethyl 2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole-4-carboxylate i33.
Reaction SMILES: [CH3:1][C:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][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:22])[CH2:7][CH2:6]3)[CH:3]=1.[CH3:23]OC(=O)C(OC)=O.C[O-].[Na+].C=O>C1COCC1.CO.C(N(CC)CC)C.C(O)(=O)C>[CH3:1][C:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][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:22])[C:7](=[CH2:23])[CH2:6]3)[CH:3]=1
Reactant: COC(=O)C(=O)OC
Reactant: CC1=C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Agent: C=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: C=C1C[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)C1=O
Reaction time: 2 h

Procedure:
6-Methylandrosta-4,6-diene-3,17-dione (IA, U.S. Pat. No. 3,177,966, Example 16, 3.0 g) was dissolved in THF (32 ml) and dimethyloxalate (1.64 g) was added. The mixture was cooled under nitrogen to 0°. Sodium methoxide in methanol (25%, 2.75 ml) was added dropwise. The mixture was stirred approximately 2 hrs. at 0°; then neutralized with acetic acid (0.12 ml). Triethylamine (1.2 ml) and methanol (5.0 ml) were added followed by formaldehyde solution (37%, 1.13 ml). Following addition of all the reactants, the ice bath was removed and the reaction stirred at 20°-25° for 1.5 hrs. Water (50 ml) was added, followed by ethyl acetate and methyl t-butyl ether. These phases were separated and the organic phase was washed twice with saline. The combined aqueous layers were back extracted once with ethyl acetate and the combined organic extracts were dried over sodium sulfate after the addition of some methylene chloride. The mixture was filtered through Celite and the filtrate removed under reduced pressure to give an oil which was chromatographed over silica gel (230-400 mesh, 140 g). The appropriate fractions were pooled and concentrated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:5]=[C:4]([Br:16])[C:3]=1[CH2:17][C:18]#[N:19].[H-].[Na+].[Cl:22][C:23]1[N:24]=[N:25][C:26](Cl)=[CH:27][C:28]=1[CH:29]([CH3:31])[CH3:30].[Cl-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[Cl:22][C:23]1[N:24]=[N:25][C:26]([CH:17]([C:3]2[C:2]([Br:1])=[CH:7][C:6]([CH2:8][O:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)=[CH:5][C:4]=2[Br:16])[C:18]#[N:19])=[CH:27][C:28]=1[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)c1cc(Cl)nnc1Cl
Reactant: N#CCc1c(Br)cc(COC2CCCCO2)cc1Br
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(C#N)c2c(Br)cc(COC3CCCCO3)cc2Br)nnc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
A solution of [2,6-dibromo-4-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-acetonitrile (60) (1.52 g, 3.91 mmol) in N,N-dimethylformamide (9 mL) at 25° C. was treated with sodium hydride (192.8 mg, 4.82 mmol, 60% dispersion in mineral oil). The reaction mixture was stirred at 25° C. for 10 min. At this time, the reaction was treated with a solution of 3,6-dichloro-4-isopropyl-pyridazine (7) (810 mg, 4.24 mmol) in N,N-dimethylformamide (2 mL). The reaction was then heated to 90° C. for 1 h. At this time, the reaction was cooled to 25° C., diluted with water (50 mL), a saturated aqueous sodium chloride solution (50 mL) and a saturated aqueous sodium bicarbonate solution (20 mL). This mixture was extracted with ethyl acetate (200 mL). The organics were washed with a saturated aqueous sodium chloride solution (100 mL), dried with magnesium sulfate, filtered, and concentrated under vacuum. Isco chromatography (120 g, Silica, 2:1 hexanes/ethyl acetate) afforded (6-chloro-5-isopropyl-pyridazin-3-yl)-[2,6-dibromo-4-(tetrahydro-pyran-2-yloxymethyl)-phenyl]-acetonitrile (61) (964 mg, 65%) as an orange viscous oil; LRMS for C21H22Br2ClN3O2 (M+H) at m/z=542. Molecular Weight=543.6894; Exact Mass=540.9767
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=4)[N:15]=3)[CH:11]=2)[C:6]([CH3:34])([CH3:33])[CH2:5]1)(=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>CCO.Cl>[CH3:33][C:6]1([CH3:34])[C:7]2[C:12](=[CH:11][C:10]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=4)[N:15]=3)=[CH:9][CH:8]=2)[NH:4][CH2:5]1
Reactant: COc1cc(Nc2nccc(Nc3ccc4c(c3)N(C(C)=O)CC4(C)C)n2)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(Nc2nccc(Nc3ccc4c(c3)NCC4(C)C)n2)cc(OC)c1OC

Procedure:
A mixture of N4-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-N2-(3,4,5-tris(methoxy)phenyl)-2,4-pyrimidinediamine (Example 114, 170 mg, 0.266 mmol) was dissolved in EtOH (6 mL) and 10 drops conc. HCl were added. The mixture was heated to reflux in a sealed tube for 72 h. The crude mixture was poured into EtOAc (125 mL) and sat NaHCO3 (20 mL). The organics were dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude was purified via medium pressure liquid chromatography using linear gradient starting from 0:100 MeOH/CH2Cl2 ending with 10:90 MeOH/CH2Cl2 as the solvent system to provide the desired product as a purple solid. M+H—422; Calc'd for C23H27N5O3—421.
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][CH:22]2[CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClCCl.[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)(=O)C>[NH:42]([C:43]([N:24]1[CH2:25][CH:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:22]([CH2:21][N:13]([C@@H:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:23]1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Nc2ccccc2)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.4 %

Procedure:
A mixture of 215 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl][(4-phenylpyrrolidin-3-yl)methyl]carbamate and 5 ml of dichloromethane was mixed with 119 mg of phenyl isocyanate and stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate and washed with water and 1 M hydrochloric acid. The organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol)to obtain 270 mg of crude tert-butyl {[1-(anilinocarbonyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a colorless solid. The thus obtained compound was dissolved in 5 ml of ethyl acetate, mixed with 1 ml of 4 M hydrogen chloride/ethyl acetate and stirred overnight at room temperature. The resulting precipitate was collected by filtration to obtain 56 mg of 3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-N,4-diphenylpyrrolidine-1-carboxamide hydrochloride as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of 3,4-difluoronitrobenzene (1.00 mL, 9.03 mmol), imidazole (0.615 g, 9.04 mmol) and K2CO3 (2.50 g, 18.1 mmol) in DMF (10 mL) was stirred at room temperature overnight. Water (20 mL) was added to induce precipitation. The precipitate was collected, dried on vacuum to give 1-(2-fluoro-4-nitrophenyl)-1H-imidazole as a solid (1.81 g). MS 208.2 (M+H)
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[NH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[CH2:31][CH2:32][O:33][CH3:34].[F-].[Cs+]>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24]([O:29][CH2:31][CH2:32][O:33][CH3:34])=[N:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc[nH]c3=O)cc1-2
Reactant: COCCBr
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COCCOc1ncccc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Temperature: 80 °C
Yield: 6 %

Procedure:
To 330 (0.075 g, 0.18 mmol) in DMF (2 mL) was added 1-bromo-2-methoxyethane (0.1 mL, 0.55 mmol) and cesium fluoride (0.084 g, 0.55 mmol). The reaction mixture was allowed to stir and heat at 80° C. for 2 days while monitoring by LCMS. To the reaction mixture was added bromo-2-methoxyethane (1 mL, 7.2 mmol) and cesium fluoride (1.0 g, 6.6 mmol). The reaction mixture was allowed to stir and heat at 80° C. for 2 days before cooling, concentrating under reduced pressure, and diluting with EtOAc. The solution was washed sequentially with water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 478 (5 mg, 6%). 1H NMR (400 MHz, DMSO) δ 8.60 (d, J=2.3, 1H), 8.16 (dd, J=4.9, 1.8, 1H), 8.10 (s, 1H), 7.80 (dd, J=7.4, 1.8, 1H), 7.59 (dd, J=8.4, 2.3, 1H), 7.13 (dd, J=7.7, 5.0, 2H), 5.73 (dt, J=13.1, 6.6, 1H), 4.51-4.38 (m, 4H), 3.70-3.58 (m, 2H), 3.48 (t, J=5.0, 2H), 3.18 (d, J=14.6, 3H), 1.55-1.46 (m, 6H). MS (ESI(+)): m/z 464.1 (M+H)
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[CH:23]=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+]>O1CCOCC1.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]>[Br:24][C:22]1[CH:23]=[C:18]([NH:16][C:13]2[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[N:12]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
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(Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)c1=O
Temperature: 120 °C
Yield: 37.4 %

Procedure:
A mixture of 1-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-pyrazol-3-amine 116b (1.2 g, 5 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.3 g, 5 mmol), XantPhos (300 mg, 0.5 mmol), Pd2(dba)3 (460 mg, 0.5 mmol) and Cs2CO3 (4 g, 2.5 mmol) in dioxane (30 mL) was heated in a sealed tube at 120° C. for 2 h under nitrogen. After reaction the mixture was filtered and the filtrated was evaporated in vacuo to give a yellow solid, which was then washed with ethyl acetate (6 mL×3) to give 163a as a yellow solid (0.80 g, 38%) and used without further purification. MS: (M+H)+ 427.
Reaction SMILES: CO[CH:3]=[C:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.Cl(O)(=O)(=O)=O.Cl.[CH2:18]([O:21][NH2:22])[C:19]#[CH:20]>>[CH2:18]([O:21][N:22]=[CH:3][CH:4]1[CH:9]2[CH2:8][CH2:7][N:6]([CH2:11][CH2:10]2)[CH2:5]1)[C:19]#[CH:20]
Reactant: COC=C1CN2CCC1CC2
Reactant: C#CCON
Agent: Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: C#CCON=CC1CN2CCC1CC2
Yield: 61.9 %

Procedure:
The operation is carried out as in Example 1 using 1.75 g of 3-methoxy methylidene quinuclidine, 3.8 cm3 of perchloric acid and 1.22 g of O-2-propynylhydroxylamine hydrochloride (U.S. Pat. No. 3,398,180 (1968)). After the ethyl ether has been evaporated off, the residue is chromatographed on silica (eluant: chloroform-methanol 7-3) then distilled at 190° C. under 0.05 mbar and 1.35 g of expected product is obtained.
Reaction SMILES: Br[C:2](P(=O)(OCC)OCC)([F:4])[F:3].C(=O)=O.CC(C)=O.[I:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=2)[N:23]([CH3:31])[N:22]=1.[OH-].[K+]>CC#N.O.CCOC(C)=O>[F:3][CH:2]([F:4])[O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH3:31])[N:22]=[C:21]2[I:20]
Reactant: Cn1nc(I)c2cc(O)ccc21
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1nc(I)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Yield: 52.4 %

Procedure:
Diethyl bromodifluoromethylphosphonate (9 g, 10.9 mmol) was added in one portion to a cooled (dry ice-acetone bath) solution of 3-iodo-1-methyl-1H-indazol-5-ol (3 g, 37.8 mmol) and KOH (15 g, 267 mmol) in CH3CN (50 mL) and H2O (50 mL) with stirring, the reaction mixture was warmed to room temperature and stirred for 0.5 h, the mixture was diluted with EtOAc (50 mL), The organic layer was washed with H2O (50 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure, the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with petroleum ether/EtOAc=3:1) to give 5-(difluoromethoxy)-3-iodo-1-methyl-1H-indazole (1.85 g, 53%) as a white solid. LCMS: (M+H)+=325; 1H NMR (300 MHz, CDCl3), δ 7.36-7.33 (m, 1H), 7.28-7.23 (m, 1H), 7.19 (s, 1H), 6.53 (t, 1H, J=73.5 Hz), 4.09 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[CH:8]=[CH:7][NH:6][C:5](=O)[C:4]=2[C:3]=1[CH3:12].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:5]1[C:4]2[C:3]([CH3:12])=[C:2]([CH3:1])[NH:10][C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1[nH]c2cc[nH]c(=O)c2c1C
Product: Cc1[nH]c2ccnc(Cl)c2c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 43 %

Procedure:
2,3-dimethyl-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one (6.0 g, 37.0 mmol) prepared in Step 3 was added to phosphorus oxychloride (230 ml). The reaction mixture was refluxed under stirring for 6 hours, cooled to room temperature, and then concentrated under reduced pressure. The resulting residue was dissolved in methanol (200 ml). The obtained solution was alkalized with a saturated ammonia solution in methanol and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate) and recrystallized with ether to give the titled compound as a pale yellow solid. (Yield: 43.0%)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1F.[NH:30]1[CH2:36][CH2:35][CH2:34][C@@H:31]1[CH2:32][OH:33].C(N(C(C)C)CC)(C)C.O>C(#N)C>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([N:30]3[CH2:36][CH2:35][CH2:34][C@@H:31]3[CH2:32][OH:33])[N:11]=2)[C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8]1
Reactant: OC[C@H]1CCCN1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(Cl)c(F)cc2c1=O
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC[C@@H]3CO)ccc2c1=O

Procedure:
A mixture of EXAMPLE 1B (2.96 g), (R)-prolinol (850 μL) and diisopropylethylamine (4 mL) in acetonitrile (70 mL) at 25° C. was stirred for 3 days, treated with water, and filtered.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:25]([O:42][C@@H:43]1[CH2:60][CH2:59][C@@:58]2([CH3:61])[C@@H:45]([CH2:46][CH2:47][C@@H:48]3[C@@H:57]2[CH2:56][CH2:55][C@@:53]2([CH3:54])[C@H:49]3[CH2:50][CH2:51][C@@H:52]2[CH:62]=O)[CH2:44]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]([Br:5])=[CH:62][C@H:52]1[CH2:51][CH2:50][C@H:49]2[C@H:48]3[C@H:57]([CH2:56][CH2:55][C@:53]12[CH3:54])[C@:58]1([CH3:61])[C@H:45]([CH2:44][C@H:43]([O:42][Si:25]([C:38]([CH3:39])([CH3:41])[CH3:40])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:60][CH2:59]1)[CH2:46][CH2:47]3
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C=C(Br)Br)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of tetrabromomethane (1.99 g, 6 mmol) in anhydrous methylene chloride (31 mL) was added at 0° C., triphenylphosphine (3.14 g, 6 mmol) and the resulting mixture is stirred for 10 min. Subsequently, a solution of 3α-(t-butyidiphenylsilyloxy)-5α-androstan-17β-carboxaldehyde (540 mg, 1 mmol) in methylene chloride (6 mL) was added and the mixture was stirred at 0° C. for an additional 10 min. The reaction mixture was diluted with ethyl acetate and the organic layer is washed with water, saturated aqueous NaCl solution and was dried with anhydrous Na2SO4. The solvent was evaporated in vacuo and the residue was purified with flash column chromatography using petroleum ether/ether 95/5 as eluent afforded the desired compound named.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4](=[CH:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2)[CH2:5][C:6]([OH:8])=[O:7]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:20])[CH:4]([CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(=Cc1cc(C)c2[nH]ncc2c1)CC(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(CC(=O)O)Cc1cc(C)c2[nH]ncc2c1
Yield: 100 %

Procedure:
A suspension of 2-(7-methyl-1H-indazol-5-ylmethylene)-succinic acid 1-methyl ester (0.4440 g, 1.62 mmol) and 10% Pd/C (0.04 g) in ethyl acetate (15 mL) and methanol (5 mL) was hydrogenated in a Parr apparatus overnight at 50 psi. The reaction mixture was filtered through a pad of celite and the filtrate evaporated to give the desired product as a yellow solid (100%). Mass spec.: 277 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][CH2:8][N+:9]([O-:27])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][N+]1=C(c2ccccc2)c2cc(Cl)ccc2CCC1

Procedure:
A solution of 1.4 g (5.5 mmole) of 8-chloro-4,5-dihydro-1-phenyl-3H-2-benzazepine and 1.4 g (7 mmole) of 85% m-chloroperbenzoic acid in 50 ml of methylene chloride was stirred at room temperature for 18 hr. The reaction mixture was washed with dilute aqueous sodium hydroxide and the organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue was crystallized from ether to give a colorless solid, mp 120°-125° C. Recrystallization from ether gave colorless prisms, mp 142°-143° C.
Reaction SMILES: C(O)(=O)C.[N:5]1([CH2:10][CH:11]2[C:20]3[C:15](=[C:16]([O:21]C)[CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][NH:12]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.[BrH:23]>>[BrH:23].[BrH:23].[N:5]1([CH2:10][CH:11]2[C:20]3[C:15](=[C:16]([OH:21])[CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][NH:12]2)[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1cccc2c1CCNC2CN1CCCC1
Agent: Br
Solvent: CC(=O)O
Product: Oc1cccc2c1CCNC2CN1CCCC1

Procedure:
0.66 g (2.15 mmoles) of (+)-1-(pyrrolidin-1-yl)methyl-5-methoxy-1,2,3,4-tetrahydroisoquinoline acetate were heated two hours at 130° C. with 7 ml of 47% HBr solution.