Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.C(Cl)(Cl)[Cl:13].S(Cl)(Cl)(=O)=O.[OH-].[Na+]>O>[Cl:13][C:6]1[S:2][C:3]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:11])[C:4]=2[CH:5]=1
Reactant: NC1CCCc2sccc21
Reactant: ClC(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Product: NC1CCCc2sc(Cl)cc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A sample of 11.4 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-amine hydrochloride is stirred in 150 ml. of chloroform at about 10°C., and 6.1 ml. of sulfuryl chloride is added dropwise. The mixture is stirred for 3.5 hours at room temperature, and then about 20 ml. of 50% sodium hydroxide solution is added gradually to dissolve the suspended solid. The mixture is then poured into water and extracted with chloroform twice. The extracts are dried, evaporated to dryness, and the residue is distilled to give 7.4 grams of 2-chloro-4,5,6,7-tetrahydrobenzo[b]thien-4-amine, boiling point 94°C. to 98°C./0.5 Torr.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].[H][H]>CC(O)C>[CH3:3][O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[OH:11]
Reactant: COC1CCCCC1=O
Reactant: [H][H]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CO[C@@H]1CCCC[C@@H]1O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
In a 100 ml autoclave were charged 3.4 ml of a 0.1M solution of potassium hydroxide (0.34 mmol) in 2-propanol, 4.2 mg (0.02 mmol) of (1R,2R)-diphenylethylenediamine, 1.28 g (10.0 mmol) of 2-methoxycyclohexanone, 9.5 mg (0.005 mmol) of Ru2Cl4 [(R)-DM-BINAP]2NEt3, and 6.5 ml of 2-propanol in a nitrogen atmosphere, and hydrogen was introduced therein to 50 atm. The mixture was stirred at 50° C. for 30 minutes and cooled to room temperature. The disappearance of the starting material was confirmed by gas chromatography. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure to obtain (1S,2R)-2-methoxycyclohexanol. The optical purity of the product was found to be 98% d.e. and 96% e.e. by gas chromatography.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:14]=[N:15][N:16]4[C:21]5[NH:22][CH2:23][CH2:24][C:25](=[O:26])[C:20]=5[C:19]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[N:18][C:17]=34)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:33]1[CH:37]=[N:36][C:35]([C:38](O)=[O:39])=[N:34]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[N:33]1[N:34]=[C:35]([C:38]([N:30]2[CH2:31][CH2:32][CH:27]([C:19]3[C:20]4[C:25](=[O:26])[CH2:24][CH2:23][NH:22][C:21]=4[N:16]4[N:15]=[CH:14][C:13]([C:10]5[CH:11]=[N:12][C:7]([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)=[CH:8][CH:9]=5)=[C:17]4[N:18]=3)[CH2:28][CH2:29]2)=[O:39])[NH:36][CH:37]=1
Reactant: O=C(O)c1nc[nH]n1
Reactant: O=C1CCNc2c1c(C1CCNCC1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCNc2c1c(C1CCN(C(=O)c3nnc[nH]3)CC1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one (70 mg, 0.17 mmoL), 1H-1,2,4-triazole-3-carboxylic acid (20.5 mg, 0.18 mmoL), EDC (63 mg, 0.33 mmoL), HOBt (44.6 mg, 0.33 mmoL) and DIEA (172.2 uL, 0.99 mmoL) in DMF (3 mL) was stirred at room temperature for 2 h. Purification with prep-LC provided 5-(1-(4H-1,2,4-triazole-3-carbonyl)piperidin-4-yl)-3-(6-phenylpyridin-3-yl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6(7H)-one: LCMS tR=3.15 Min (10 min run, UV254nm). Mass calculated for, M+ 519.2, observed LC/MS m/z 519.97 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=[O:37])[CH:26]([N:34]=[C:35]=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C.O.[OH-].[Li+]>ClCCl>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:35]([NH:34][C@H:26]([C:25]([OH:37])=[O:24])[CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:36])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(N)ccc32)cc1
Reactant: CCOC(=O)C(Cc1ccccc1)N=C=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(Cn2ccc3cc(NC(=O)N[C@@H](Cc4ccccc4)C(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
A mixture of 1-(4-tert-butylbenzyl)-1H-indol-5-amine (0.233 g, 0.84 mmol) and 2-isocyanato-3-phenyl-propionic acid ethyl ester (0.10 g, 0.8 mmol) in 10 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated and dissolved in 2:1:1 THF/MeOH/Water (10 mL). Lithium hydroxide monohydrate (0.30 g, 7.1 mmol) was added and the mixture was stirred at room temperature overnight. Most of the organic solvents were removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid. The solid was collected and purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 minutes: 100% B; Hold 100% B 5 minutes. Flow Rate: 22.5 mL/min) The product was collected based on UV absorption and concentrated to give the title compound as an off-white solid (0.15 g, 40%): MS (ESI) m/z 470; MS (ESI) m/z 468.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1>C1COCC1>[CH2:3]([O:9][C:11]1[C:15]([C:16]2[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCO
Reactant: Cc1ccc(-c2nsnc2Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCOc1nsnc1-c1ccc(C)nc1
Reaction time: 2 h

Procedure:
Sodium hydride (0.72 g, 15 mmol) was dissolved in dry THF (20 ml) and 1-hexanol (1.53 g, 15 mmol) and a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)-6-methylpyridine (1.06 g, 5 mmol) in dry THF (15 ml) was added. The reaction mixture was stirred for 2 h. Afteraddition of water the mixture was extracted with ether, and the ether phasewas dried and evaporated. The residue consisted of the crude title compound, which was used without further purification.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]([CH2:19][C@H:20]3[O:24]C(C)(C)[N:22]([C:27]([O:29][C@@H:30]4[C@H:37]5[C@H:33]([O:34][CH2:35][CH2:36]5)[O:32][CH2:31]4)=[O:28])[C@H:21]3[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=4)=[CH:41][CH:40]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)(C)C.Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:19][C@H:20]([OH:24])[C@@H:21]([NH:22][C:27](=[O:28])[O:29][C@@H:30]3[C@H:37]4[C@H:33]([O:34][CH2:35][CH2:36]4)[O:32][CH2:31]3)[CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=4)=[CH:43][CH:44]=3)(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2ccccn2)cc1)S(=O)(=O)c1ccc2c(c1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)CN(C[C@H](O)[C@H](Cc1ccc(OCc2ccccn2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCCO2
Reaction time: 2 h
Yield: 101.2 %

Procedure:
70 mg of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)(isobutyl)amino]methy}-2,2-dimethyl-4-[4-(2-pyridinylmethoxy)benzyl]-1,3-oxazolidine-3-carboxylate were dissolved in 15 mL of isopropanol and 5 ml of concentrated hydrochloric acid. After 2 h, the reaction was treated with excess 3N sodium hydroxide and extracted with ethyl acetate. Evaporation of the solvent gave 67 mg of the desired product. 1H NMR: 08.3 (6H, dd), 1.4-1.8 (4H, m), 2.6-3.2 (7H, m), 3.6 (2H, m), 3.75 (2H, m), 3.9 (2H, m), 4.25 (4H, bs), 4.95 (1H, d), 5.0 (1H, m), 5.6 (1H, d), 6.9 (2H, d), 6.95 (2H, d), 7.1 (2H, d), 7.2 (2H, m), 7.45 (1H, d), 7.7 (1H, t), 8.58 (1H, d).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>CN(C)C=O>[F:33][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:8]([C:10]2[N:11]([CH2:41][C:42]([F:45])([F:44])[F:43])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCOCC2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC(F)(F)F)N1CCC(N2CCOCC2)CC1
Yield: 56 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone (example 170), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a brown oil (56%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[CH:5]=[C:6]([CH3:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1>[Pt].C(O)C>[CH3:20][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:18])[CH3:19])[CH:10]=1)[NH2:21]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(C)C
Agent: [Pt]
Solvent: CCO
Product: COc1ccc(Oc2c(C)cc(N)cc2C)cc1C(C)C

Procedure:
3,5-Dimethyl-4-(3'-isopropyl-4'-methoxyphenoxy)-nitrobenzene (6.0 g) and 600 mg of 10% platinum on carbon in 200 ml ethanol are hydrogenated on a Parr shaker. Catalyst is removed by filtration through Celite and the filtrate is stripped to afford 3,5dimethyl-4-(3'-isopropyl-4'-methoxyphenoxy)-aniline.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][C@H:12]3[NH:23][CH2:22][CH2:21][C@@:18]4([C:19]=2[CH:20]=1)[C@H:13]3[CH2:14][CH2:15][CH2:16][CH2:17]4)(=[O:5])=[O:4].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH2:26]([N:23]1[CH2:22][CH2:21][C@@:18]23[C:19]4[CH:20]=[C:7]([O:6][S:3]([C:2]([F:1])([F:24])[F:25])(=[O:5])=[O:4])[CH:8]=[CH:9][C:10]=4[CH2:11][C@@H:12]1[C@@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: O=S(=O)(Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(Cc1ccccc1)CC3)C(F)(F)F
Reaction time: 5 h
Yield: 84.3 %

Procedure:
To a solution of compound 38 (50 mg, 0.13 mmol) and TEA (74 μL, 0.53 mmol) in dry CH2Cl2 (2 mL) was slowly added benzyl bromide (32 μL, 0.27 mmol) at 0° C. and stirred for 5 h. Solvent was removed under reduced pressure. The crude product was purified on a silica gel column chromatography (90:5 CH2Cl2/MeOH) to give a colorless oil (51 mg, 84% yield): 1H NMR (300 MHz, CDCl3) 1.05˜1.72 (m, 9H); 1.74˜1.85 (m, 1H); 1.90˜1.94 (m, 1H); 1.96˜2.05 (m, 1H); 2.31 (d, J=13.0 Hz, 1H); 2.48˜2.52 (m, 1H); 2.88˜2.91 (m, 1H); 3.12 (d, J=18.6 Hz, 1H); 3.67 (dd, J=13.4 Hz, 2H); 7.03˜7.38 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([OH:22])[N:5]([C:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:6]2=[O:12].CN(CCN(C)C)C.[I:31]I>C1COCC1>[OH:22][CH:4]1[C:3]2[C:7](=[C:8]([I:31])[CH:9]=[C:10]([Cl:11])[C:2]=2[Cl:1])[C:6](=[O:12])[N:5]1[C:13]([CH3:14])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:21]
Reactant: CC(C)(c1ccccc1)N1C(=O)c2ccc(Cl)c(Cl)c2C1O
Reactant: II
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2c(I)cc(Cl)c(Cl)c2C1O
Yield: 63.6 %

Procedure:
In a similar manner to Step 3 of Example 16, 4,5-dichloro-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (400 mg, 1.19 mmol) was dissolved in THF (16 mL), and the solution was treated with TMEDA (0.718 mL, 4.76 mmol), sec-butyl lithium-hexane solution (0.99 mol/L, 4.8 mL, 4.76 mmol) and iodine (453 mg, 1.79 mmol), followed by purification by flash column chromatography (chloroform/methanol=95/5 to 90/10) to obtain 3-hydroxy-4,5-dichloro-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (350 mg, yield 64%).
Reaction SMILES: Cl.O1CCOCC1.[CH3:8][N:9]([CH3:25])[C:10](=[S:24])[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[O:20]COC>CO>[CH3:25][N:9]([CH3:8])[C:10](=[S:24])[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[OH:20]
Reactant: COCOc1c(OC)cccc1SC(=S)N(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cccc(SC(=S)N(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
4 N hydrogen chloride/dioxane solution (50 mL) was added to a methanol (200 mL) solution of the compound (70.49 g) synthesized in the above (2), and stirred at room temperature for 2 hours. The reaction liquid was concentrated and extracted with chloroform. The organic layer was washed with saturated saline, then dried with sodium sulfate, and concentrated to obtain the intended compound (46.65 g, 78%) as a brown solid.
Reaction SMILES: [C:1]([C@H:4]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:5]12[CH2:6]C(O)=O)[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:26])[CH2:19][CH2:20]1)[N:15](C(C)(C)C)[CH2:14]3)(O)=[O:2].N1C=CC=CC=1.S(Cl)(Cl)=O.[CH2:41]([Mg]Br)[CH:42]([CH3:44])[CH3:43]>C1(C)C=CC=CC=1.CN(C)C=O>[O:2]=[C:1]([C@H:4]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:5]12[CH3:6])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:26])[CH2:19][CH2:20]1)[NH:15][CH2:14]3)[CH2:41][CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)C[Mg]Br
Reactant: CC(C)(C)N1C[C@H]2[C@@H]3CC[C@H](C(=O)O)[C@@]3(CC(=O)O)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)CC(=O)[C@H]1CC[C@H]2[C@@H]3CNC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Alternatively, a solution of 17β-carboxy-6-t-butylcarboxy-6-azaandrost-4-en-3-one (260 mg, 0.62 mmol), example 3, Part F, is dissolved in toluene (10 mL) and treated with pyridine (3 eq) and catalytic dimethylformamide, cooled to 0° C., and thionyl chloride added (80 μL, 1.10 mmol). The reaction is then allowed to warm to room temperature and is stirred for 1 hr. The solids are then removed by filtration, the solution concentrated, the resulting crude acid chloride dissolved in THF (6 mL), CuL added (120 mg, 0.62 mmol), cooled to -78° C. and treated with isobutylmagnesium bromide (2.0M in diethyl ether, 0.5 mL, 1 mmol). The reaction is allowed to warm to room temperature, stirred for 30 min and is worked up as in Part C above to give 17β-(1-oxo-3-methylbutyl)-6-azaandrost-4-en-3-one.
Reaction SMILES: B(F)(F)F.[CH3:5][C:6]([S:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([OH:23])=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:14]=1)([CH3:11])[CH2:7]C(=O)C.[C:28]([C:32]1[CH:37]=[C:36]([SH:38])[CH:35]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]=1[OH:43])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[CH3:5][C:6]([S:12][C:13]1[CH:14]=[C:15]([C:24]([CH3:27])([CH3:25])[CH3:26])[C:16]([OH:23])=[C:17]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:18]=1)([CH3:11])[CH2:7][C:6]([S:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:21])([CH3:20])[CH3:22])[C:16]([OH:23])=[C:15]([C:24]([CH3:25])([CH3:27])[CH3:26])[CH:14]=1)([S:38][C:36]1[CH:35]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]([OH:43])=[C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:37]=1)[CH3:5]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(=O)CC(C)(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: CC(C)(CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
0.11 Grams of BF3 -etherate is added to a solution of 2.70 grams of the product from (a) and 4.14 grams of 2,6-di-tert-butyl-4-mercaptophenol dissolved in 30 ml of toluene. The mixture is heated at 55°-65° C. for nine hours and 105°-110° C. for three additional hours. The toluene solution is washed with water and dried over sodium sulfate. The residue, isolated by evaporation of the solvent by distillation in vacuum, is purified by passing a solution in 70:30 heptane:toluene through a flash chromatographic column using silica gel. The isolated residue solidifies on cooling, and melts at 93°-115° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([O:18]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24]4[C:29]([C:30](=[O:39])[C:31]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([OH:18])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(F)c(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.1 %

Procedure:
To a solution of Example 82 (0.075 g, 0.142 mmoles) in dichloromethane (15 ml), BBr3 (1M in dichloromethane, 1 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N Hal solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as pale green solid (0.040 g, 55% yield). MP: 241-244° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.15(s,1H), 8.05(s, 1H), 8.05(dd, J=8.6,1.5 Hz, 1H), 7.86(m, 1H), 7.68(d, J=8.4 Hz, 1H),7.53(t, J=7.4 Hz, 1H), 7.28(m,2H), 7.20(dd, J=8.5,1.9 Hz, 1H), 7.05(m,4H),6.04(q, J=7.1 Hz, 1H),1.88(d, J=7.1 Hz, 3H). Mass: 511.94(M+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]([NH:25][CH2:26][C:27]1[O:28][C:29]([CH3:32])=[N:30][N:31]=1)([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:22]([N:25]([CH2:26][C:27]1[O:28][C:29]([CH3:32])=[N:30][N:31]=1)[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:24])([CH3:23])[CH3:21]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: Cc1nnc(CNC(C)(C)C)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(CN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C(C)(C)C)o1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2-methyl-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)propan-2-amine in the presence of TBTU and DIEA to obtain the title compound as yellow solid; MS (EI): m/e=436.4 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:6]2[O:10][CH2:9][C:8](=[O:11])[C:7]=2[CH:12]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[CH:28]1>CO.N1CCCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:9]2\[O:10][C:6]3[C:5]([CH2:13][N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=3[C:8]\2=[O:11])=[CH:28]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c2c(c1)C(=O)CO2
Solvent: C1CCNCC1
Solvent: CO
Product: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c2c(c1)C(=O)/C(=C/c1c[nH]c3ccccc13)O2
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A solution of tert-butyl 4-((5-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl)piperazine-1-carboxylate (0.024 g, 0.066 mmol) in methanol (2.0 mL) was added with 1H-indole-3-carboxaldehyde (0.011 g, 0.073 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-5-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.027 g, 84%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:21]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:11]([CH:8]1[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]1)[CH2:12][CH2:13][CH2:14]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)CCCN2C1CCC2(CC1)OCCO2
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(c1)CCCN2C1CCC2(CC1)OCCO2
Reaction time: 3.5 h
Yield: 91.9 %

Procedure:
A solution of compound 3 (0.19 g, 0.695 mmol) in dry DMF (3 mL) was treated with N-bromosuccinimide (0.124 g, 0.695 mmol) in DMF (2 mL) at 0° C. over a period of 10 minutes. The reaction was stirred at the same temperature for 3.5 h. The reaction was diluted with water (50 mL) and the product was extracted into ethyl acetate (2×20 mL). The combined ethyl acetate layer was washed with water (2×20 mL), brine (15 mL) and dried (Na2SO4). Solvent was evaporated and the crude mixture was purified by column chromatography on silica gel (ethyl acetate:hexanes, 1:9) to obtain compound 4 (0.225 g, 92%) as a syrup. 1H NMR (CDCl3) δ 7.16-7.05 (m, 2H), 6.60-6.52 (m, 1H), 3.96 (s, 4H), 3.64-3.55 (m, 1H), 3.20 (t, 2H, J=5.7 Hz), 2.69 (t, 2H, J=6.0 Hz), 1.91-1.54 (m, 10H); ESI-MS (m/z, %): 352, 354 (MH+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[N:4][C:5]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH2:24].[OH-].[Na+]>Br>[NH2:1][C:2]1[C:3]([C:22]([NH2:23])=[O:24])=[N:4][C:5]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: O
Reactant: COc1ccc(-c2nc(C#N)c(N)nc2-c2ccccc2)cn1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2nc(C(N)=O)c(N)nc2-c2ccccc2)cn1
Temperature: 27.5 °C
Reaction time: 3 h

Procedure:
3-Amino-6-(6-methoxy-3-pyridyl)-5-phenyl-2-pyrazinecarbonitrile (100 mg) was dissolved in 30% hydrogen bromide solution in ACOH (1 ml). The solution was stirred at 25-30° C. for 3 hours. To the solution was added water. The pH of the aqueous mixture was adjusted to 6-7 with 12% aq. NaOH. The crystals were precipitated. The suspension was stirred at 25-30° C. for 3 hours, and stood for 10 hours in refrigerator. The crystals was collected by filtration and dried in vacuo, to give 3-amino-6-(6-methoxy-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide (92.5 mg).