Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.CO[C:25](OC)([N:27](C)C)[CH3:26].C[N:33](C)C=O>>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][C:5]2[N:11]=[C:10]3[NH:33][NH:27][C:25]([CH3:26])=[C:9]3[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CN(C)C=O
Reactant: COc1cc2c(cc1Br)C(c1ccccc1Cl)=NCC(=S)N2
Product: COc1cc2c(cc1Br)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1.8 g (0.00455 mole) of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-thione (IId), 2.26 mL of 1,1-dimethoxy-N,N-dimethyl-ethanamine and 20 mL of dimethylformamide was stirred at room temperature for 1.5 hours, then at 110° C. for 5 hours. The mixture was cooled and concentrated under reduced pressure. The crude intermediate, IIId, was stirred with a solution of 0.713 mL of anhydrous hydrazine, 9 mL of methanol and 24 mL of dichloromethane for 26 hours and then partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Chromatography on silica gel, eluting with ethyl acetate yielded 0.690 g of 7-bromo-5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVd). Recrystallization from dichloromethane provided the crystalline 7-bromo-5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVd), mp 210-211° C. MH+/Z=417.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[C:28]([CH2:30][CH3:31])[CH:27]=[CH:26][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH3:24])(=[O:20])=[O:19])=[CH:14][C:13]=1[F:25])C1C=CC=CC=1.O1CCCC1>C(O)C>[CH2:30]([C:28]1[CH:27]=[CH:26][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH3:24])(=[O:20])=[O:19])=[CH:14][C:13]=2[F:25])=[C:9]([OH:8])[CH:29]=1)[CH3:31]
Reactant: CCCNS(=O)(=O)c1ccc(Oc2ccc(CC)cc2OCc2ccccc2)c(F)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CCCNS(=O)(=O)c1ccc(Oc2ccc(CC)cc2O)c(F)c1
Yield: 61.9 %

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for 4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-propyl-benzenesulfonamide (140 mg; 0.32 mmol) and tetrahydrofurane for ethanol (3 mL), the title compound (70 mg; 62%) was obtained as a clear oil, after purification on preparative TLC (dichloromethane)
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[F:47][C:48]([F:58])([F:57])[C:49]1[CH:54]=[C:53]([NH:55][NH2:56])[CH:52]=[CH:51][N:50]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:55]([C:53]3[CH:52]=[CH:51][N:50]=[C:49]([C:48]([F:47])([F:57])[F:58])[CH:54]=3)[N:56]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: NNc1ccnc(C(F)(F)F)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccnc(C(F)(F)F)c2)n1

Procedure:
500 mg (1.16 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 370 mg (1.74 mmol) of 2-trifluoromethylpyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 307 mg (53% of theory) of the title compound is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[O:24][CH:23]=[CH:22][C:20]4=3)[CH:15]=[N:14]2)[CH2:9]1)=O)(C)(C)C.C([O:27][C:28](=[O:30])[CH3:29])C.[ClH:31].[C:32]([O:35]CC)(=[O:34])[CH3:33]>>[C:28]([OH:27])(=[O:30])/[CH:29]=[CH:33]/[C:32]([OH:35])=[O:34].[Cl:31][CH2:11][CH:10]([CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][CH:23]=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[CH2:9][NH2:8]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CC(Cn2ncc3ccc4occc4c32)C1
Reactant: CCOC(C)=O
Product: NCC(CCl)Cn1ncc2ccc3occc3c21
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ethyl acetate (10 ml) solution containing 0.46 g of 1-(1-t-butoxycarbonylazetidin-3-ylmethyl)-1H-furo[2,3-g]indazole was added 4 N hydrochloric acid ethyl acetate solution (3 ml), and the resulting mixture was stirred at room temperature for 4 hours. After evaporation of the solvent under a reduced pressure, the residue was extracted with chloroform and washed with 1 N sodium hydroxide and then the thus obtained organic layer was dried with anhydrous sodium sulfate. After removal of the drying agent, the solvent was evaporated and the residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate =5/1) and then treated with fumaric acid in methanol/ethyl acetate to give 0.19 g of 2-chloromethyl-3-(1H-furo[2,3-g]indazol-1-yl)propylamine fumarate.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=C)[CH:28]=2)[C:5]2=[N:6][O:7][C:8]([C:9]3[O:13][N:12]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:10]=3[C:20]([F:23])([F:22])[F:21])=[C:4]2[CH2:3]1.C[N+]1([O-])CC[O:37]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH3:32][C:2]1([CH3:1])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=[O:37])[CH:28]=2)[C:5]2=[N:6][O:7][C:8]([C:9]3[O:13][N:12]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:10]=3[C:20]([F:21])([F:23])[F:22])=[C:4]2[CH2:3]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)C(C)(C)Cc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2c(noc2-c2onc(-c3ccccc3)c2C(F)(F)F)-c2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 94 %

Procedure:
To a mixture of 5,5-dimethyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 1E, 0.036 g, 0.082 mmol) and NMO in water (0.017 mL, 0.082 mmol) in THF (1.5 mL) at room temperature was added osmium tetroxide in water (0.013 mL, 1.65 μmol). The reaction mixture was stirred at room temperature for 7 hours. A solution of sodium periodate (0.026 g, 0.124 mmol) in water (1 mL) was added via syringe. The resulting cloudy reaction mixture was stirred overnight at room temperature concentrated under reduced pressure, and the residue was diluted with ethyl acetate (30 mL) and washed with water (15 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 5,5-dimethyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.034 g, 0.078 mmol, 94% yield) as a tan solid. The product had an HPLC ret. time=3.51 min. (condition A); LC/MS M+1=439.1.
Reaction SMILES: [CH:1]1([C:4]2[N:31]=[C:7]3[NH:8][C:9](=[O:30])[C:10]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:12][CH2:13][CH3:14])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.Br[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH:1]1([C:4]2[N:31]=[C:7]3[N:8]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[C:9](=[O:30])[C:10]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:12][CH2:13][CH3:14])[N:6]3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C3CC3)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(F)cc2)c2nc(C3CC3)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of 4′-[(2-cyclopropyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 1-(bromomethyl)-4-fluorobenzene (0.17 mL), potassium carbonate (0.34 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.44 g, 70%).
Reaction SMILES: [O:1]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN1C[CH2:38][CH2:37][C:36]1=[O:40]>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([NH:22][C:36](=[O:40])[CH2:37][CH3:38])[CH:23]=[CH:24][CH:25]=2)=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1=O
Reactant: Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 65 %

Procedure:
N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide was prepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and pyridine instead of N,N-diethylethanamine, 1-methylpyrrolidin-2-one, dichloromethane using Method G (65% yield). HPLC: 92%, RT=4.234 min. MS: m/z=411 [M+H]+, RT=3.35 min.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(N)=CC=1.C(#N)CC#N.O.[NH2:35][NH2:36]>>[NH2:15][C:14]1[C:11](=[N:10][NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=2)[C:12]([NH2:13])=[N:36][N:35]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccc(C(F)(F)F)cc1
Agent: Nc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccc(C(F)(F)F)cc1
Temperature: 75 °C
Yield: 50 %

Procedure:
This compound was prepared using 119 mg (0.5 mmol) of 2-[(4-trifluoromethylphenyl)-hydrazono]malononitrile, which was derived from 4-(trifluoromethyl)aniline (126 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. No precipitate had formed after heating at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 67 mg (50%) of the title compound as a greenish brown solid. 1H NMR (ppm, DMSO-d6): 6.03 (br s, 2H), 6.48 (br s, 2H), 7.63 (d, 2H), 7.80 (d, 2H), 10.80 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]([N+:16]#[C-:17])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].[Br:18][C:19]1[S:23][C:22]([CH:24]=O)=[CH:21][CH:20]=1.Cl(O)(=O)(=O)=O>C(Cl)Cl>[Br:18][C:19]1[S:23][C:22]([C:24]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[C:17]=2[NH:16][C:9]([CH3:15])([CH3:8])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:21][CH:20]=1
Reactant: Nc1ccccn1
Reactant: O=Cc1ccc(Br)s1
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CC(C)(C)CC(C)(C)Nc1c(-c2ccc(Br)s2)nc2ccccn12
Temperature: 25 °C
Reaction time: 120 h
Yield: 68 %

Procedure:
235 mg (2.5 mmol) of 2-aminopyridine were dissolved together with 0.42 ml (2.5 mmol) of 1,1,3,3-tetramethyl-butylisonitrile and 0.27 ml (2.5 mmol) of 5-bromothiophene-2-carbaldehyde in DCM (5 ml). After addition of perchloric acid (0.25 ml), the mixture was stirred at RT for 5 d. Washing was then performed with a sat. aq. sodium carbonate solution and a sat. aq. common salt solution. The organic phase was dried over magnesium sulfate, filtered and evaporated under a vacuum. After carrying out column chromatography (EA/DIPE/DCM 2:2:1) with the group, 724 mg (1.7 mmol, 71% of theoretical) of [2-(5-bromothiophen-2-yl)-imidazo[1,2-a]pyridin-3-yl]-(1,1,3,3-tetramethyl-butyl)-amine were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][F:17])[C:11](=[O:18])[CH2:10]2)=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl>[CH2:29]([O:28][C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][F:17])[C:11](=[O:18])[CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccc(N2CCN(CCF)C(=O)C2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCN(CCF)C(=O)C2)c(F)c1)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
NMR (CDCl3) δ: 3.28 (t, 2H); 3.58 (t, 2H); 3.61 (br s, 2H); 3.68 (t, 1H); 3.72 (s, 2H); 3.80 (t, 1H); 4.56 (t, 1H); 4.75 (t, 1H); 6.40 (dd, 1H); 6.44 (dd, 1H); 6.78 (t, 1H). 5-Amino-2-(4-{2-fluoroethyl}-3-oxopiperazin-1-yl)fluorobenzene (2.6 g) was dissolved in dry dichloromethane (50 ml) under argon. Pyridine (1.03 ml) was added, and the mixture cooled to -20° C. Benzyl chloroformate (1.6 ml) was added, and the mixture stirred for 10 minutes at -20° C., before allowing the temperature to rise to ambient over 1.5 hours. Solvents were evaporated, the residue dissolved in dichloromethane and washed with sodium bicarbonate solution. After drying (MgSO4) and evaporation of solvent, the residue was chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give 5-benzyloxycarbonylamino-2-(4-{2-fluoroethyl}-3-oxopiperazin-1-yl)fluorobenzene (3.43 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2.[CH3:16][C:17](=O)[C:18](=O)[CH3:19]>O>[Cl:13][C:10]1[CH:9]=[C:8]2[N:7]=[C:6]([OH:14])[C:5]([OH:15])=[N:4][C:3]2=[C:2]2[C:11]=1[N:12]=[C:18]([CH3:19])[C:17]([CH3:16])=[N:1]2
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Reactant: CC(=O)C(C)=O
Solvent: O
Product: Cc1nc2c(Cl)cc3nc(O)c(O)nc3c2nc1C
Temperature: 50 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
A mixture of 0,5 g (2,24 mmol) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline in 10 ml water was at 50° C. added a solution of 0,4 g (4,6 mmol) 2,3-butanedione in 5 ml water. The reaction mixture was stirred at 50° C. for 24 h. After cooling to 25° C., the precipitate was filtered off and washed with water and ethanol to give 0,3 g (50%) 6-chloro-2,3- dihydroxy-8,9-dimethylpyrazino(2,3-f)quinoxaline, m.p>300+ C. NMR (DMSO-d6): 8.47 (lH,s), 2.60 (3H,s), 2.53 (3H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][C:17]3[CH:37]=[CH:36][C:20]([C:21]([CH:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]4)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].C(OCC)(=O)C>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][C:17]3[CH:37]=[CH:36][C:20]([CH:21]([OH:22])[CH:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24]4)=[CH:19][CH:18]=3)=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)c2ccc(NC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(C(O)c2ccc(NC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
tert-Butyl 3-[4-[[(4′-chloro[1,1′-biphenyl]-4-yl)carbonyl]amino]benzoyl]-1-piperidinecarboxylate (506 mg, 0.975 mmol) obtained in Example 127-1) was dissolved in a mixed solution of methanol and tetrahydrofuran (1:1) (10 ml). Sodium borohydride (73.8 mg, 1.95 mmol) was added to the solution under ice-cooling, which was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, which was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. Diisopropyl ether was added to the residue, to give the titled compound (488 mg) as a colorless powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21])[CH:12]=[CH:11]2>O1CCCC1>[ClH:7].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17]1[CH:18]=[C:19]([CH2:20][NH2:21])[CH:22]=[CH:23][CH:24]=1)[CH:12]=[CH:11]2
Reactant: N#Cc1cccc(-n2ccc3cc(Cl)ccc32)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cl
Product: NCc1cccc(-n2ccc3cc(Cl)ccc32)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a stirred mixture of 1.67 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran (THF), kept at 0°-5° C. under nitrogen, was added dropwise a solution of 5.60 g (0.022 mole) of 3-(5-chloro-1-indolyl)benzonitrile of Example 6a in 150 ml of THF. The mixture was stirred 1 hour more at 0° C., 1 hour at room temperature, and then refluxed for 5 hours. After cooling to 0° C., the reaction was quenched by slow and cautious addition of a solution of 25 ml of water in 25 ml of THF. The resulting mixture was stirred 1 hour at room temperature before filtering to remove the inorganic salts. The filtrate was concentrated to an oily residue which was partitioned between 250 ml of dichloromethane and 250 ml of water. The organic phase was separated and extracted twice more with water before drying over Na2SO4 and concentrating to an oil (5.8 g). This was dissolved in 20 ml of absolute ethanol and the stirred solution treated with 100 ml of ethereal hydrogen chloride. The salt was collected and found to weigh 5.2 g (81% overall yield) m.p. 195° C.-sinter, 220°-228° C. melting. Recrystallization from boiling ethanol (charcoal) furnished 2.4 g (37% yield) of 3-(5-chloro-1-indolyl)benzenemethanamine hydrochloride, m.p. 230°-233° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(O)=O.[C:16]([OH:22])(=[O:21])[CH2:17]C(O)=O.C([O-])=O.[NH4+:26].Cl>O>[NH2:26][CH:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])[CH2:17][C:16]([OH:22])=[O:21]
Reactant: [NH4+]
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C[O-]
Solvent: O
Solvent: O=CO
Product: NC(CC(=O)O)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
4-Fluoro-2-nitrobenzaldehyde (16.91 g, 0.10 mol), formic acid (15.2 mL, 0.40 mol) and malonic acid (13.52 g, 0.13 mol) were stirred at 45° C. for half an hour, and then ammonium formate (15.76 g, 0.25 mol) was added thereto. The reaction temperature was raised to 70° C. and stirred for 1 hour, and then stirred at 9° C. for another 4 hours. Then concentrated hydrochloric acid (38 mL) was added and stirred maintaining this temperature for another 1 hour. It was cooled, water (20 mL) was added, and extracted with ethyl acetate (2×25 mL). The organic phase was discarded, the aqueous phase was adjusted to pH≈4.2 with 50% potassium hydroxide solution. A solid precipitated, pumping filtered, dried in vacuum to obtain a yellow solid 16.71 g, at a yield of 73.2%.
Reaction SMILES: [NH2:1][C@H:2]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH2:3][OH:4].Cl.CCN(C(C)C)C(C)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:5]1([C@@H:2]2[CH2:3][O:4][C:22](=[O:24])[NH:1]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@@H](CO)C1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1N[C@H](C2CCCCC2)CO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-2-Amino-2-cyclohexyl-ethanol.HCl salt (1.0 g, 5.57 mmol, 1.0 equiv) in CH2Cl2 (30.0 mL) at 0° C. was added DIPEA (1.94 mL, 11.1 mmol, 2.0 equiv) followed by triphosgene (4.95 g, 16.7 mmol, 3.0 equiv) and the resulting solution was stirred at room temperature for 12 hours. The solution was then concentrated and the residue was diluted with EtOAc. The solution was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, (EtOAc 100%) to give product 520 mg.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(Cl)s1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
53.6 g of 5-chlorothiophene-2-carboxylic acid (commercially available) are suspended in 344 g of toluene and heated to 80° C. At this temperature, 47.2 g of thionyl chloride are added dropwise over a period of 20 minutes, then the mixture is stirred at from 75 to 80° C. for 30 minutes and then at reflux temperature for two hours until completion of gas evolution. After cooling, the reaction mixture is concentrated to a volume of approx. 200 ml at from 30 to 35° C. and a pressure of from 40 to 48 mbar. The thus obtained solution of the acid chloride in toluene is reacted directly in the next stage.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([N:13]([CH3:23])[C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25].N12CCCN=C1CCCCC2>C1C=CC=CC=1>[C:24]([NH:28][C:29]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([N:13]([CH3:23])[C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N=C=O
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(CO)CC[C@H]4[C@@H]3CC[C@@H]12
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(COC(=O)NC(C)(C)C)CC[C@H]4[C@@H]3CC[C@@H]12
Reaction time: 48 h

Procedure:
To a stirred solution of 17-(hydroxymethyl)-4-methyl-5α-4-azaandrostan-3-one (0.048 g, 0.15 mM) in dried benzene (5 mL) was added at room temperature t-butylisocyanate (0.03 mL, 0.23mM) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.023 mL, 0.15 mM). After stirring for two days, the volatiles were removed in vacuo and the residue flash chromatographed on silica gel using ethyl acetate as eluant to give the title compound as a white solid. MS M+1 calculated for C25H42N2O3, mw=418.55; observed m/e 419.