Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][C:26]1[C:27](=[O:33])[NH:28][N:29]=[C:30]([CH3:32])[CH:31]=1>>[CH3:32][C:30]1[CH:31]=[C:26]([CH2:25][NH:24][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[C:27](=[O:33])[NH:28][N:29]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: Cc1cc(CN)c(=O)[nH]n1
Product: Cc1cc(CNC(=O)c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)c(=O)[nH]n1
Yield: 83 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted using 4-aminomethyl-6-methyl-2H-pyridazin-3-one instead of aminomethyl-isoxazolidin-3-one to the title compound (SiO2, heptane:ethyl acetate:methanol=20:80:0 to 0:90:10, 231 mg, 83%) which was obtained as a white solid. MS: m/e=432.3 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=O.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:23][CH2:24][CH2:25][CH2:26][NH2:27].[BH4-].[Na+]>CO>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:10][C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: NCCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reactant: O=Cc1cc2ccccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(CCCCNCc1cc2ccccc2[nH]1)Cc1nc2ccccc2[nH]1
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
A solution of indole-2-carboxaldehyde (prepared as described for COMPOUND 65) (31 mg, 0.21 mmol) and N1-(1H-benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine (see COMPOUND 17) (51 mg, 0.15 mmol) in MeOH (1.8 mL) was stirred at room temperature under nitrogen for 23 hours. NaBH4 (14 mg, 0.37 mmol) was added, and the reaction stirred for a further 15 minutes before the solvent was evaporated under reduced pressure. The residue was dissolved into CH2Cl2 (25 mL) and was washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic solution was dried (MgSO4), filtered and evaporated under reduced pressure. The yellow residue was purified by flash column chromatography on silica gel (CH2Cl2MeOH/NH4OH, 19:1:0.1) giving COMPOUND 31 as a white solid (37 mg, 0.077 mmol, 53%). 1H NMR (CDCl3) δ 1.35-1.49 (m, 4H), 1.60-1.76 (m, 1H), 1.81-1.96 (m, 1H), 1.96-2.08 (m, 1H), 2.11-2.22 (m, 1H), 2.45 (t, 2H, J=6.5 Hz), 2.50-2.60 (m, 1H), 2.66-2.76 (m, 2H), 2.76-2.90 (m, 1H), 3.83 (s, 2H), 3.93-4.10 (m, 3H), 6.27 (s, 1H), 7.02-7.16 (m, 3H), 7.16-7.24 (m, 2H), 7.32 (d, 1H, J=7.8 Hz), 7.41 (d, 1H, J=7.8 Hz), 7.53 (d, 1H, J=7.8 Hz), 7.55-7.62 (m, 2H), 8.56 (d, 1H, J=3.6 Hz), 9.01 (br. s, 1H). 13C NMR (CDCl3) δ 21.6, 23.8, 26.2, 27.5, 29.6, 47.2, 48.9, 49.8, 50.8, 62.3, 100.6, 111.2, 119.8, 120.4, 121.7, 122.0, 122.6, 128.8, 135.1, 136.5, 137.8, 147.1, 156.9, 157.8. ES-MS m/z 479 (M+H). Anal. Calcd. for C30H34N6.0.5CH2Cl2.0.2C4H10O: C, 70.15; H, 6.96; N, 15.68. Found: C, 70.16; H, 6.97; N, 15.73.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:19]([NH:22][C:23]1[CH:24]=[C:25]2[C:30](=O)[O:29][C:27](=[O:28])[C:26]2=[CH:32][CH:33]=1)(=[O:21])[CH3:20]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:30](=[O:29])[C:25]3[C:26](=[CH:32][CH:33]=[C:23]([NH:22][C:19](=[O:21])[CH3:20])[CH:24]=3)[C:27]2=[O:28])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Reactant: CC(=O)Nc1ccc2c(c1)C(=O)OC2=O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3ccc(NC(C)=O)cc3C2=O)ccc1OC

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-acetamidoisoindoline-1,3-dione was prepared by the procedure of Example 6 from 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 4-acetamidophthalic anhydride (751 mg, 3.66 mmol). The product was obtained as a yellow solid (330 mg, 20% yield): mp, 215.0-217.0° C.; 1H NMR (DMSO-d6) δ 1.32 (t, J=6.9 Hz, 3H, CH3), 2.12 (s, 3H, CH3), 2.99 (s, 3H, CH3), 3.73 (s, 3H, CH3), 4.00 (q, J=7.0 Hz, 2H, CH2), 4.12 (dd, J=4.5, 14.3 Hz, 1H, CHH), 4.35 (dd, J=10.5, 14.2 Hz, 1H, CHH), 5.76 (dd, J=4.5, 10.5 Hz, 1H, NCH), 6.90-6.98 (m, 2H, Ar), 7.08 (br s, 1H, Ar), 7.83-7.84 (m, 2H, Ar), 8.19 (br s, 1H, Ar), 10.95 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 14.66, 24.22, 41.05, 47.35, 53.07, 55.47, 63.80, 111.74, 112.28, 112.72, 123.34, 124.59, 124.66, 129.74, 132.68, 145.00, 147.85, 148.84, 167.00, 167.28, 169.36; Anal Calcd for C22H24NO7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.13; H, 5.18; N, 5.74.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([CH3:14])[CH:9]1[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])C1C=CC=CC=1>[OH-].[OH-].[Pd+2]>[CH3:14][C@@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC1=CCCN(Cc2ccccc2)C1CNC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Product: C[C@@H]1CCCN[C@H]1CNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of rac-tert-butyl ((1-benzyl-3-methyl-1,2,5,6-tetrahydropyridin-2-yl)methyl)carbamate and Pd(OH)2/C (20% wt, 0.1 eq) was pressurized to 4 bar with H2 and maintained at rt for 5 h. The mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to yield the title compound as a colorless oil. MS (ESI) 229.2 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10](=[NH:14])OCC)=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2].[NH3:21]>C(O)C>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([NH2:14])=[NH:21])=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2]
Reactant: N
Reactant: CCCc1c(OCC(=N)OCC)ccc(C(C)=O)c1O
Solvent: CCO
Product: CCCc1c(OCC(=N)N)ccc(C(C)=O)c1O

Procedure:
Obtained using the procedure described in section b of Example 17, starting with 25.0 g (0.0895 mole) of ethyl 2-(4-acetyl-3-hydroxy-2-propylphenoxy)acetimidate and 7.6 g (0.45 mole) of ammonia in 300 ml of absolute ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=O.[Cl:14]CCCl.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Cl:14][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: ClCCCl
Reactant: COc1ccc2nc[nH]c(=O)c2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2ncnc(Cl)c2c1
Reaction time: 1.11 h
Yield: 75 %

Procedure:
To 0.852 mmoles of 6-methoxy-3H-quinazolin-4-one in 0.4M soln of DCE, add 1.022 mmoles of PCl5. Microwave at 150° C. for 4000 secs. Work-up: The reaction mixture was diluted with CH2Cl2 and washed with water and brine. The organic layer was separated dried over MgSO4, filtered and excess solvent was removed on rotavap to yield the title compound in 75% yield. The compound was used for the next step without further purification. LC-MS: m/z=195 (M++1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[CH:5]/[CH2:6]Br.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.CCOC(C)=O>[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:6]/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:8])([O-:11])=[O:10]
Reactant: COC(=O)/C=C/CBr
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/COc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
Methyl-(2E)-4-bromobut-2-enoate (28.2 g, 0.158 mol) was added dropwise to 2-nitrophenol (20 g, 0.144 mol) and K2CO3 (29.8 g, 21.6 mol) in N,N-dimethylformamide (240 mL) at rt. The resulting mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc (2.0 L) and washed with water (1.0 L), sat. aq. Na2CO3 (1.0 L) and brine (1.0 L). The organic phase was separated, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to afford desired product (27.4 g, 80%) as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][CH3:15])[C:12](=[O:16])[CH2:11][N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:8]=2[CH:24]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[CH2:14]([N:13]1[C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:24][C:8]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:10][CH2:11][C:12]1=[O:16])[CH3:15]
Reactant: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)=O)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)O)ccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
12.7 g (39.2 mmol) of 7-acetyl-1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 240 ml of methanol are treated in the cold while stirring with 743 mg (19.6 mmol) of sodium borohydride. The mixture is subsequently stirred at room temperature for 17 hours, treated with water and then with 2 N sulphuric acid and extracted with methylene chloride. The organic phase is washed with water, dried and evaporated. The residue is chromatographed on 500 g of silica gel using ethyl acetate/toluene (1:1) as the elution agent, and gives, from cyclohexane, 1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-7-(1-hydroxyethyl)-2H-1,4-benzodiazepin-2-one of melting point 55°-57°.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12](O)[C:13]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:14]=2[O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=CC(CC2C=C(C(F)(F)F)C=CC=2O)=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]2[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:14]=2[O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(C(O)c2cc(C(F)(F)F)ccc2OCC(=O)O)cc1
Agent: CCS(=O)(=O)c1ccc(Cc2cc(C(F)(F)F)ccc2O)cc1
Product: CCS(=O)(=O)c1ccc(Cc2cc(C(F)(F)F)ccc2OCC(=O)O)cc1

Procedure:
The title compound was prepared by the method of example 1 steps (iv) and (v) using the product from step (i). Yield 0.11 g
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[OH:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C(OC1C=C(C=CC=1)C(O)=O)CC>>[CH2:1]([O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCCBr
Agent: CCCOc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOc1ccc(C(=O)O)cc1

Procedure:
The reaction of butyl bromide and ethyl 4-hydroxybenzoate in the presence of potassium carbonate was performed as described for Compound 24 to give 4-butoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.57 (s, COOH); 7.85 (d, J=8.8, 2 arom. H); 6.98 (d, J=8.8, 2 arom. H); 4.02 (t, CH3CH2CH2CH2O); 1.69 (m, CH3CH2CH2CH2O); 1.43 (m, CH3CH2CH2CH2O); 0.92 (t, CH3CH2CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 166.99 (—C═O); 162.29; 131.32 (2 arom. C); 122.77; 114.17 (2 arom. C); 67.45; 30.58; 18.66; 13.63.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[NH2:14][C:3]1[N:4]=[CH:5][C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:24](=[O:26])[CH3:25])[CH2:12][CH2:13]2)=[N:7][C:2]=1[Br:1]
Reactant: Nc1ncc(C2CCNCC2)nc1Br
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(c2cnc(N)c(Br)n2)CC1
Reaction time: 0.5 h

Procedure:
To 3-bromo-5-(piperidin-4-yl)pyrazin-2-amine (50 mg, 0.194 mmol) in DCM (4 mL) in ice bath was added DIEA (0.136 mL, 0.778 mmol) and acetyl chloride (0.017 mL, 0.233 mmol). The reaction mixture was stirred at in ice bath 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed with brine. Dried over sodium sulfate, filtered and evaporated. Proceed for next step. LCMS (m/z): 299.1/301.1 (MH+), 0.508 min. 1H NMR (400 MHz, CD3OD) δ ppm 7.81-7.69 (m, 2 H), 7.62-7.45 (m, 2H), 7.37-7.09 (m, 6H), 6.5 (dd, J=8.61, 2.35 Hz, 1H), 6.50 (dd, J=13.50, 2.15 Hz, 1H), 5.17-5.01 (m, 1H), 4.55 (d, J=13.30 Hz, 1H), 3.94 (d, J=13.69 Hz, 1H), 3.83-3.63 (m, 2H), 2.88 (tt, J=11.84, 3.62 Hz, 1H), 2.67 (td, J=12.91, 2.35 Hz, 1H), 2.03 (s, 3H), 1.96-1.79 (m, 2H), 1.78-1.50 (m, 2H).
Reaction SMILES: C([N:8]([C@@H:16]([C@@H:18]([OH:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:17])CC1C=CC=CC=1)C1C=CC=CC=1.NO>>[NH2:8][C@@H:16]([C@@H:18]([OH:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:17]
Reactant: CCCCCCCCCCCCCCC[C@H](O)[C@@H](C)N(Cc1ccccc1)Cc1ccccc1
Agent: NO
Product: CCCCCCCCCCCCCCC[C@H](O)[C@@H](C)N
Yield: 111.4 %

Procedure:
According to the method of Example 27, from N,N-dibenzylamine 80 (256 mg, 0.55 mmol), aminoalcohol 81was obtained as a white solid (175 mg, 92% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].[H-].[Na+].[CH:20]([N:23]1[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]1)([CH3:22])[CH3:21]>CN(C=O)C.CC(OC)(C)C.O.[OH-].[Na+]>[CH:20]([N:23]1[CH2:28][CH2:27][CH:26]([O:17][C:14]2[CH:15]=[CH:16][C:11]([C:5]3([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)=[CH:12][CH:13]=2)[CH2:25][CH2:24]1)([CH3:22])[CH3:21]
Reactant: CC(C)N1CCC(OS(C)(=O)=O)CC1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)N1CCC(Oc2ccc(C3(CN(C)C)CCOCC3)cc2)CC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (532 mg, 2.26 mmol) in DMF (2 ml) was added to a solution of NaH (100 mg, 2.5 mmol) in DMF (2 ml) at room temperature under N2. The reaction was stirred for 1 hr and a solution of methanesulfonic acid 1-isopropyl-piperidin-4-yl ester (400 mg, 1.81 mmol) in DMF (1.3 ml) was slowly added. The reaction was heated to 75° C. and stirred for 6 hrs. The reaction was allowed to cool to room temperature and diluted with TBME (20 ml), water (10 ml) and 5M NaOH solution (10 ml). The organic layer was washed with 2.5M NaOH (2×20 ml), brine (2×20 ml), dried over MgSO4, filtered and concentrated in vacuo. The crude reaction was purified by column chromatography, eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a white crystalline solid (113 mg, 17%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.87 (d, 2H), 4.27 (m, 1H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.85-2.68 (m, 3H), 2.45-2.32 (m, 2H), 2.40 (s, 2H), 2.14-1.94 (m, 4H), 1.96 (s, 6H), 1.93-1.75 (m, 4H), 1.06 (d, 6H).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([Mg]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1.C(OCC)(=O)C>[C:7]1([C:1]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([OH:6])[CH2:2][CH2:3][CH2:4][OH:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCCO1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCCC(O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
A solution of butyrolactone (10.5 g, 122 mmol) in anhydrous THF (500 mL) was chilled to −78° C. under nitrogen atmosphere. Phenylmagnesium bromide (3M in ether, 100 mL, 300 mmol) was added via syringe at a rate that keeps the reaction temperature below −40° C. After the addition was complete, the reaction was stirred at −78° C. for two hours then the cold bath was removed and the reaction mixture was allowed to warm to room temperature overnight. The solution was then re-cooled to 10° C. on an ice bath before adding 2N aqueous ammonium chloride (200 mL) to quench the reaction. The resulting mixture was diluted with ethyl acetate (1 L) and the organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered. Evaporation of solvent from the filtrate afforded crude 1,1-diphenylbutan-1,4-diol as an oil, which was purified by chromatography on silica gel, eluting with a gradient of 50% to 60% ethyl acetate in hexane. Evaporation of solvents gave a colorless solid that was triturated with hexane and collected by filtration to afford 18.2 g of pure 1,1-diphenylbutan-1,4-diol. MS (EI+): 243 (M+1); 225 (M-H2O+1).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH3:15])=[N:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[CH3:24][Si:25]([C:28]#[C:29][B-](F)(F)F)([CH3:27])[CH3:26].[K+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>[CH3:15][O:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[C:2]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[C:3]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:4]=1
Reactant: C[Si](C)(C)C#C[B-](F)(F)F
Reactant: COc1ccc(-c2nc(OC)c3cc(OC)ccc3c2Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(OC)c3cc(OC)ccc3c2C#C[Si](C)(C)C)cc1
Yield: 93 %

Procedure:
A mixture of the compound 4-bromo-1,7-dimethoxy-3-(4-methoxyphenyl)isoquinoline (compound 26) (187 mg, 0.5 mmol), potassium (trimethylsilyl)ethynyltrifluoroborate (133 mg, 0.65 mmol), palladium diacetate (3.5 mg, 0.015 mmol), RuPhos (14 mg, 0.03 mmol) and potassium carbonate (318 mg, 1.5 mmol) dissolved in 2 mL of a distilled THF/degassed H2O mixture (10/1) is refluxed under argon for 2 hours. The reaction medium is filtered on silica then condensed under vacuum. The crude is purified on a silica column (cyclohexane/dichloromethane, 7/3). 182 mg (93%) of the 1,7-dimethoxy-3-(4-methoxyphenyl)-4-((trimethylsilyl)ethynyl)isoquinoline intermediate is obtained in the form of a brown solid which is used directly in the following stage,
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([C@@H:22]([F:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:25])[CH2:17][CH2:18]1)[C@H:13]1O[C@@H:12]31)(=[O:3])[CH3:2].[ClH:27]>C(O)(=O)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([C@@H:22]([F:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:25])[CH2:17][CH2:18]1)[C:13]([Cl:27])=[CH:12]3)(=[O:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@]12C
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@]12C
Temperature: 0 °C
Reaction time: 24 h

Procedure:
500 mg. of 17β-acetoxy-6α,7α-epoxy-11β-fluoro-4-androsten-3-one is introduced at room temperature into 25 ml. of glacial acetic acid saturated with gaseous hydrogen chloride. After 24 hours, the solution is poured into ice/water. The thus-precipitated product is vacuum-filtered, taken up in methylene chloride, washed with water, and dried. After recrystallization of the crude product from acetone/hexane, 210 mg. of 17β-acetoxy-6-chloro-11β-fluoro-4,6-androstadien-3-one is obtained. UV: ε283 = 20,300.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:26])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][Si](C)(C)C)=[CH:16][CH:15]=2)[N:13]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:26])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1
Reactant: C[Si](C)(C)C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 223.7 %

Procedure:
To a solution of 5-(2-chloro-6-fluorophenyl)-2-{4-[(trimethylsilyl)ethynyl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.200 g, 0.570 mmol) in DCM was added TBAF (0.362 g, 1.11 mmol). The reaction mass was stirred at RT for 2-3 h. The reaction mass was quenched in water and filtered through celite bed and concentrated. The obtained crude product was purified with column chromatography on silica gel eluting with 2.0% MeOH:DCM to afford 0.400 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 4.21 (s, 1H), 7.50 (t, J=9.3 Hz, 1H), 7.58 (d, J=8.4 Hz, 3H), 7.67-7.71 (m, 1H), 7.96 (d, J=8.1 Hz, 2H), 12.69 (br s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1csc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c12
Product: Cc1csc2nc(-n3cccn3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:11][NH:12][CH3:13]>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([N:12]([CH3:13])[CH3:11])=[N:6][CH:7]=1
Reactant: CNC
Reactant: COc1nc(Cl)ncc1Br
Solvent: C1CCOC1
Product: COc1nc(N(C)C)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (3 g, 13.4 mmol) and dimethylamine (2 M in THF, 33.6 mL, 67.1 mmol) in THF (20 mL) was stirred for 18 h at rt and concentrated. The residue was purified by flash chromatography (hexane/EtOAc, 9:1) to afford 2.95 g of the title compound. tR: 1.04 min (LC-MS 2); ESI-MS: 232.0/234.0 [M+H]+ (LC-MS 2); Rf: 0.34 (hexane/EtOAc 9:1).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.CC(C)=O.C(=O)=O.[CH2:20]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[C:26]([C:35]#[N:36])=[CH:25]1)[CH2:21][CH2:22][CH3:23].B(OC)(OC)OC.I[C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=1>C1COCC1.CN(C=O)C>[NH2:49][C:48]1[CH:50]=[CH:51][C:45]([C:25]2[N:24]([CH2:20][CH2:21][CH2:22][CH3:23])[C:32]3[C:27]([C:26]=2[C:35]#[N:36])=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)=[CH:46][CH:47]=1
Reactant: Nc1ccc(I)cc1
Reactant: CCCCn1cc(C#N)c2ccc(OC)cc21
Agent: COB(OC)OC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CCCCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 86 %

Procedure:
To a solution of (i-Pr)2NH (1.35 mL, 9.65 mmol) in THF (30 mL) cooled to −78° C. is added n-BuLi (3.7 mL, 2.5M in hexanes, 9.21 mmol) in one portion. The acetone/dry ice bath is exchanged for ice/water bath and the solution is stirred further for 40 min. The solution is cooled to −78° C. and solution of 1-butyl-6-methoxy-1H-indole-3-carbonitrile, prepared as in example 1A (2.0 g, 8.77 mmol) in THF (10 mL) is added dropwise. This solution is stirred for 15 min at −78° C., following by 20 min at −20° C. Trimethyl borate (1.0 mL, 8.77 mmol) is added, the reaction mixture is stirred for 15 min at −20° C. after which the cooling bath is removed and this solution is stirred further at room temperature for 1 h. A solution of K3PO4 is added (11.7 mL, 3M aqueous solution, 35.1 mmol) followed by a solution of 4-iodoaniline (2.5 g, 11.40 mmol) and PdCl2dppf catalyst (640 mg, 0.88 mmol) in DMF (40 mL, plus a 5 mL rinse). The reaction mixture is stirred overnight (ca. 18 h) and then water (80 mL) is added and the product is extracted with EtOAc (3×50 mL). The combined organic fractions are dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified via flush chromatography on silica gel (5→60% EtOAc/Hexanes as eluant) to afford the desired 2-(4-aminophenyl)-1-butyl-6-methoxy-1H-indole-3-carbonitrile as a tan solid (2.4 g, 86% yield).