Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C:14]1[S:15][C:16]([CH:19]=[O:20])=[CH:17][N:18]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[OH:20][CH2:19][C:16]1[S:15][C:14]([NH:13][C:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:12])=[N:18][CH:17]=1
Reactant: O=Cc1cnc(NC(=O)OCc2ccccc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ncc(CO)s1)OCc1ccccc1
Yield: 70.8 %

Procedure:
530 mg (14 mmol) of sodium borohydride were added in small portions to a stirred solution of 7 g (27 mmol) of 2-benzyloxycarbonylamino-5-formyl-1,3-thiazole in 80 ml of methanol at room temperature. The reaction went on for 2 hours. After evaporation of the solvent the residue was purified by chromatography (cyclohexane-ethylacetate) to give 5.05 g (71% yield) of the title compound.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.C([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)C1C=CC=CC=1>C(Cl)Cl>[O:26]=[C:23]1[CH2:24][CH2:25][N:20]([C:7]([Cl:10])=[O:6])[CH2:21][CH2:22]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: O=C1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 251.4 %

Procedure:
A solution of triphosgene (2.84 g, 9.6 mmol) in methylene chloride (100 mL) at 0° C. was treated with a solution of 1-benzyl-piperidin-4-one (6.0 g, 31.7 mmol) in methylene chloride (100 mL). The reaction mixture was allowed to warm to 25° C. and was stirred at 25° C. overnight. At this time, the mixture was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, gradient elution 60/40 ethyl acetate/hexanes) afforded 4-oxo-piperidine-1-carbonyl chloride (3.9 g, 76%) as a brown oil. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(Cl)(=O)C(C)(C)C.[CH2:12]([C@H:27]([NH2:31])[C:28]([OH:30])=[O:29])[CH2:13][C:14]([NH:16][C@H:17]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[CH2:18][SH:19])=[O:15]>CC(C)=O.O.CC(C)=O>[NH2:31][C@H:27]([C:28]([OH:30])=[O:29])[CH2:12][CH2:13][C:14]([NH:16][C@H:17]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[CH2:18][S:19][C:1](=[O:3])[CH3:2])=[O:15]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: CC(=O)Cl
Agent: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)SC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Yield: 85 %

Procedure:
Using in the procedure of Example 1 acetyl chloride, in place of pivaloyl chloride, L-glutathione reduced (15.4 g) provides, after usual work-up, a crude white solid which is dissolved in warm acetone/water (2/1; 40° C.; 300 ml). The obtained solution is further diluted with more acetone (100 ml) and cooled on ice-water bath. After about two hours the white crystalline precipitate is collected, washed with the solvent (40 ml) and dried under vacuum affording γ-L-glutamyl-S-acetyl-L-cysteinyl-glycine (14.8 g yield=85%)
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]([OH:20])[CH2:14][NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.C(=O)(O)[O-].[Na+].[O:34]=[C:35]1[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:41]=2)[NH:36]1>C(Cl)Cl.C(OCC)(=O)C>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:13]([OH:20])[CH2:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[S:44]([C:40]2[CH:41]=[C:42]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:34])[CH2:43]3)(=[O:45])=[O:46])[CH2:2]1
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of (1-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 19 (59 mg, 0.15 mmol) in CH2Cl2 (1.6 ml) was added saturated aqueous sodium bicarbonate (0.4 ml), solid sodium bicarbonate (16 mg, 0.19 mmol), and then 2-oxo-2,3-dihydro-1H-indole-5-sulfonyl chloride 14 (42 mg, 0.18 mmol). The mixture was stirred overnight, diluted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide the title product as a white solid, (79 mg, 90%). TLC: Rf 0.33 (Ethyl acetate). MS m/z 588 (MH)+. 1H NMR (CDCl3) is consistent with the structure.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([F:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([S:12](Cl)(=[O:14])=[O:13])=[N:3]1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].O>C1COCC1>[C:16]([NH:20][S:12]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[F:11])[N:2]([CH3:1])[N:3]=1)(=[O:14])=[O:13])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N
Reactant: Cn1nc(S(=O)(=O)Cl)c2c(F)cccc21
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(S(=O)(=O)NC(C)(C)C)c2c(F)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Further, 13.9 g (56 mmol) of 1-methyl-4-fluoro-1H-indazole-3-sulfonylchloride in 50 ml of THF, was added to 12.9 g (177 mmol) of t-butylamine in 100 ml of THF, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was poured into a large excess amount of water, whereupon the crystals were collected by filtration and dried in air to obtain 15.9 g (yield: 99.6%) of 3-(N-t-butylsulfamoyl)-1-methyl-4-fluoro-1H-indazole (compound represented by the formula [I-d]) (slightly purple crystals).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([CH3:19])[CH:21]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: CCOC(=O)C1(CC(C)C)CCCC1O
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(CC(C)C)CCCC1OC(=O)c1cccc(C)c1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-iso-butyl-cyclopentane carboxylate (5.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (2.85 ml) was slowly added, then 3-methyl-benzoyl chloride (4.68 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 7.77 g of yellow liquid. MS: m/e 333(M++1), 332(M+), 287(M+—OCH2CH3), 258, 213(M+−CH3C6H4CO), 197(M+—CH3C6H4CO2), 119(base), 91, 77.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[CH:26]=O)[CH:15]=[CH2:16]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:26][C:18]1[N:17]([CH2:14][CH:15]=[CH2:16])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCn1c(C=O)nc2ccccc21
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: ClCCl
Product: C=CCn1c(CNCCCCNC(=O)OC(C)(C)C)nc2ccccc21
Yield: 30 %

Procedure:
Using General Procedure B: Reaction of (4-amino-butyl)-carbamic acid tert-butyl ester in CH2Cl2 and 1-allyl-1H-benzimidazole-2-carbaldehyde gave {4-[(1-allyl-1H-benzoimidazol-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a colorless oil (0.10 g, 30%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.54 (s, 4H), 2.71 (m, 2H), 3.11 (m, 2H), 4.04 (s, 2H), 4.87 (d, 2H, J=5.3 Hz), 5.02 (d, 1H, J=17.1 Hz), 5.19 (d, 1H, J=11.0 Hz), 5.98 (m, 1H), 7.30 (m, 3H), 7.73 (m, 1H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[Na].[CH3:12][C:13]1[C:14]([CH2:25][S:26]([C:28]2[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[N:29]=2)=[O:27])=[N:15][CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24]>C(N(CC)CC)C.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([N:29]2[C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[N:32]=[C:28]2[S:26]([CH2:25][C:14]2[C:13]([CH3:12])=[C:18]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=[CH:16][N:15]=2)=[O:27])(=[O:9])=[O:8])[CH:2]=1
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: [Na]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2cccnc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
100 mg of pyridine-3-sulfonyl chloride was added to 191 mg of 2-[[[3-methyl-4-(3-methoxypropoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole sodium salt in a mixture of 0.15 ml of triethylamine and 10 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight. Dichloromethane (20 ml) was added and washed with water, and 0.1M sodium bicarbonate solution. Organic layer was dried over anhydrous magnesium sulfate and evaporated. Residue was dissolved in minimum amounts of acetonitrile and ethyl ether was added for precipitation. Solids was collected and dried to give 127 mg of the titled product.
Reaction SMILES: [N:1]([CH:4]([CH3:10])[CH2:5][CH2:6][C:7](O)=[O:8])=[N+:2]=[N-:3].S(Cl)([Cl:13])=O>>[N:1]([CH:4]([CH3:10])[CH2:5][CH2:6][C:7]([Cl:13])=[O:8])=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: CC(CCC(=O)O)N=[N+]=[N-]
Product: CC(CCC(=O)Cl)N=[N+]=[N-]
Yield: 75.1 %

Procedure:
A mixture of crude 4-azidopentanoic acid (8.0 g, 56 mmol) and thionyl chloride (10 g, 84 mmol) was heated at 40°-45° C. for 1.5 h, followed by evaporation of excess thionylchloride in vacuo. The residual oil was distilled to give 6.8 g (75%) of the title compound, bp 60°-65° C./0.3 mm: 1Hmr (CDCl3) δ: 3.55 (1H, q, J=13 Hz), 3.03 (2H, t, J=13 Hz), 1.9 (2H, t, J=13 Hz and 1.3 ppm (3H, d, J=13 Hz); ir (neat νmax : 2100, 1792 cm-1.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([Br:18])[CH:15]=[CH:16][CH:17]=1>O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([Br:18])[C:15]([N+:1]([O-:4])=[O:2])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(Br)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(Br)c1
Temperature: 50 °C
Yield: 30 %

Procedure:
Nitric acid (70%, 5 mL) was placed in a 25 mL round-bottomed flask. Concentrated sulphuric acid (4 mL) was then added dropwise with stirring. The mixture was kept cool during the addition by immersing the flask in an ice bath. 3-Methoxybromobenzene (4 g, 21.5 mmol) was then introduced dropwise. The reaction mixture was then heated to 50° C. and stirred for 5 h. After cooling, the mixture was poured into 100 mL of cold water and extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with water (50 mL×4) and brine. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 95:5 hexanes:ethyl acetate. The first compound that eluted from the column was 3-methoxy-4-nitrobromobenzene (1.2 g) in 24% yield; 1H NMR (CDCl3) δ3.96(3H, s), 7.17 (1H, dd, J1=8.6, J2=1.9), 7.24 (1H, d, J=1.9), 7.75 (1H, d, J=8.6); 13C NMR δ57.34 117.58, 124.00, 127.41, 129.05, 142.26, 154.02. The second compound eluting from the column was 24 (1.5 g, 30% yield); 43-45° C.; 1H NMR (CDCl3) δ3.89 (3H, s), 6.91 (1H, dd, J1=9.1, J2=2.7), 7.21 (1H, d, J=2.7), 7.98 (1H, d, J=9.1); 13C NMR δ56.68, 114.02, 117.29, 120.61, 128.46, 163.23.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([OH:16])[CH:7]=[C:8]([O:13][CH2:14][CH3:15])[C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[CH:17]([N:20]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1)([CH3:19])[CH3:18].Cl>N1C(C)=CC(C)=CC=1C>[CH:30]1([N:20]([CH:17]([CH3:19])[CH3:18])[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([O:16][C:6]3[CH:7]=[C:8]([O:13][CH2:14][CH3:15])[C:9]([O:10][CH2:11][CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:24][CH:23]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCOc1cc(O)cc(OCC)c1OCC
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOc1cc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc(OCC)c1OCC
Reaction time: 18 h

Procedure:
A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-triethoxyphenol (777 mg, 4.0 mmol) and p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (1.30 g, 4.0 mmol) in 2,4,6-collidine (20 ml) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[CH:8][CH:7]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].CO>C1(C)C=CC=CC=1>[CH3:16][N:14]([CH:13]=[C:7]([C:6](=[O:10])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9])[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: c1csc(-c2ccno2)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: CN(C)C=C(C#N)C(=O)c1cccs1
Yield: 87.3 %

Procedure:
A mixture of 5-(2-thienyl)isoxazole (4.3 kg) and dimethylformamide dimethylacetal (6.1 kg; Lancaster) in toluene (12 L; Barton) is heated at reflux. As methanol forms it is removed by distillation. Solid forms from the reaction mixture. The reaction mixture is cooled and diluted with methyl-t-butyl ether (8 L; Van Waters). The precipitate is collected by filtration and washed with methyl-t-butyl ether (4 L). The solid is slurried with acetone (10 L; Batron) and hexanes (10 L; Mallinckrodt), then filtered and washed with hexanes (4 L). After drying in vacuo there is obtained 5.124 kg of α-[(dimethylamino)methylene]-β-oxo-2-thiophenepropane-nitrile (87% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:37])[CH2:11][N:12]([CH2:19][C:20]1[CH:36]=[CH:35][C:23]([O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28]C(C)(C)C)=[O:27])=[CH:22][CH:21]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:37])[CH2:11][N:12]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][C:25]([CH3:34])([CH3:33])[C:26]([OH:28])=[O:27])=[CH:35][CH:36]=1)[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(NC(=O)CN(Cc2ccc(OC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)CN(Cc2ccc(OC(C)(C)C(=O)O)cc2)Cc2ccco2)c(C)c1
Yield: 82 %

Procedure:
7.09 g (14.00 mmol) of the compound from Example 3-1 and 35 ml of trifluoroacetic acid are stirred at room temperature in 35 ml of dichloromethane for 2 hours. The solvent is distilled off and the residue is then dissolved in ethyl acetate, washed with water, 20 percent strength sodium acetate solution and saturated sodium chloride solution and then dried over magnesium sulphate. The solvent is removed and the residue is then purified by flash chromatography on silica gel (dichloromethane→dichloromethane/ethyl acetate 5:1→2:1→1:1): The gives the target compound in a yield of 82%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH:16]=[CH:17][C:18](=[O:22])[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C:8](=[O:10])[CH3:9])[CH2:6][CH2:5]1.[CH3:25][Mg]Br.[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH:16]=[CH:17][C:18](=[O:22])[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C:8]([CH3:25])([OH:10])[CH3:9])[CH2:6][CH2:5]1
Reactant: C[Mg]Br
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H]1C[C@H]2NC(=O)C=C[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)(C)O)CC[C@H]3[C@H]12
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a solution of 20 mg (0.06 mmol) 7β-methyl-5α-4-azapregn-1-ene-3,20-dione in 4 ml dry tetrahydrofuran at -40° C. under N2 was added 10 eq methylmagnesium bromide (0.6 mmol) in ether. The reaction was stirred and allowed to warm to RT over 18 hours. Aqueous ammonium chloride (5 ml) was added and the solvents were evaporated. The residue was partitioned between methylene chloride and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The product was purified via HPLC on a 19×300 mm 8 micron silica column using 5% isopropanol/hexane at 20 ml/min to yield 16 mg (0.046 mmol, 77% yield) of the title compound.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[NH:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[C:19]3/[C:20](=[O:28])[NH:21][C:22]4[C:27]/3=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:15][CH:16]=2)[CH:11]=[N:10]1>CN(C=O)C>[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([C@H:18]3[C@@:19]4([C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:21][C:20]4=[O:28])[CH2:2]3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]ncc2c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
To a solution of trimethylsulfoxonium iodide (33 mg, 0.15 mmol) in anhydrous DMF (1 mL) was added sodium hydride (60% dispersion in oil) (16 mg, 0.4 mmol) at 0° C. The mixture was stirred for 15 min after which time (E)-3-((1H-indazol-5-yl)methylene)indolin-2-one (26 mg, 0.1 mmol) was added. The solution was stirred overnight at rt. The reaction was quenched with sat. NH4Cl solution (2 mL), extracted with EtOAc (50 mL), dried over MgSO4 and concentrated to dryness. The title was compound isolated by preparative HPLC) as a white solid (5 mg, 18%). 1H NMR (400 MHz, d6-DMSO) δ 13.03 (s, 1H), 10.58 (d, 1H, J=8.3 Hz), 8.02 (s, 1H), 7.74 (s, 1H), 7.40 (d, 1H, J=8.9 Hz), 7.11 (d, 1H, J=8.6 Hz), 6.98 (t, 1H, J=7.7 Hz), 6.83 (d, 1H, J=7.6 Hz), 6.50 (t, 1H, J=7.3 Hz), 5.94 (d, 1H, 7.5 Hz), 3.17-3.13 (m, 1H), 2.27-2.23 (m, 1H), 1.98-1.95 (m, 1H); MS ESI 276.1 [M+H]+, calcd for [C17H13N3O+H]+ 276.3.
Reaction SMILES: O=[C:2]1[N:21]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2=[N:6][C:7]([C:10]3[CH:11]=[N:12][N:13]4[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=34)=[CH:8][CH:9]=[C:4]2[NH:3]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(OCC)OCC>CCO>[O:25]1[CH2:24][CH2:23][CH:22]([N:21]2[C:5]3=[N:6][C:7]([C:10]4[CH:11]=[N:12][N:13]5[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=45)=[CH:8][CH:9]=[C:4]3[N:3]=[CH:2]2)[CH2:27][CH2:26]1
Reactant: N#Cc1ccn2ncc(-c3ccc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(OCC)OCC
Solvent: CCO
Product: N#Cc1ccn2ncc(-c3ccc4ncn(C5CCOCC5)c4n3)c2c1
Temperature: 145 °C
Reaction time: 2.5 h
Yield: 41 %

Procedure:
To a suspension of the compound obtained in example 2 section d (33.6 mg, 0.1 mmol) in EtOH (1.5 mL), citric acid (2 mg, 0.1 mmol) and triethyl orthoformate (340 μL, 2 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 145° C. and 270 W for 2.5 hours. The crude residue was cromategraphed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 14.2 mg of the desired product (41% yield).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[C@H:3]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)[C:4]([O:6]C)=[O:5].[O:20]1CCC[CH2:21]1>>[CH3:1][CH:2]([CH3:19])[C@H:3]([N:8]1[CH2:9][CH2:10][N:11]([CH2:12][C:13]2[N:14]=[C:15]([CH3:18])[S:16][CH:17]=2)[C:21]1=[O:20])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@@H](NCCNCc1csc(C)n1)C(C)C
Reactant: C1CCOC1
Product: Cc1nc(CN2CCN([C@H](C(=O)O)C(C)C)C2=O)cs1

Procedure:
A solution of the product of Example 143C (5.4 g) in tetrahydrofuran (80 mL) was treated with carbonydiimidazole (6.1 g, 2 equivalents) at 25° C. for 2 hrs. The mixture was quenched with 10% citric acid, the organic layer was separated, washed with water, brine, dried over Na2SO4, filtered, and the solvents were evaporated A solution of the residue (3.3 g) in dioxane (20 mL) was treated with 1M LiOH (20 mL) at 25° C. for 2 hrs. The solvents were evaporated, and the residue was acidified with 10% HCl, extracted with dichloromethane/2-propanol (3:1), the organic layer was separated, dried over Na2SO4, filtered, and the solvents evaporated to give 1.5 g of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:21]2[CH2:25][C:24](OC)=[CH:23][C:22]2=[O:28])[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30][O:31][CH2:32][C@@H:33]([OH:35])[CH3:34].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH:1]1([CH2:6][C@H:7]([N:21]2[CH2:25][C:24]([O:35][C@@H:33]([CH3:34])[CH2:32][O:31][CH3:30])=[CH:23][C:22]2=[O:28])[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:18])[CH3:19])[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Reactant: COC[C@H](C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COC[C@H](C)OC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Yield: 7.4 %

Procedure:
A solution of (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (prepared as in Example 1, 35 mg, 0.09 mmol) in a hydrochloric acid (gas) saturated acetic acid (5 mL) solution was heated in a sealed tube at 75° C. for 2 h. After that, the reaction mixture was cooled to room temperature, and concentrated. The residue was added to (S)-1-methoxy-propan-2-ol (162 mg, 1.76 mmol), and toluene-4-sulfonic acid hydrate (10 mg). The mixture was heated to 90° C., for 18 h. The reaction mixture was concentrated and the residue was dissolved in dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over magnesium sulfate. The crude product was purified using reverse phase HPLC (Biosystems MDS-SCIEX LC/MS, Pursuit C-18 2×10 mm, water/acetonitrile 0.05% trifluoroacetic acid) to afford (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-((S)-2-methoxy-1-methyl-ethoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionamide (3 mg, 9%) as a white foam: LR-ES-MS m/z calculated for C23H36N4O5 [M]+ 448, observed [M+H]+ 449; 1H NMR (300 MHz, CDCl3) δ ppm 1.08-1.25 (m, 2H) 1.16 (s, 6H) 1.32 (d, J=6.3 Hz, 3H) 1.43-2.07 (m, 9H) 3.40 (s, 3H) 3.44-3.59 (m, 2H) 3.66 (br. s., 1H) 3.90-4.00 (d, J=17.8 Hz, 1H) 3.95 (s, 2H) 4.08 (d, J=17.8 Hz, 1H) 4.34-4.47 (m, 1H) 4.80 (dd, J=8.9, 6.5 Hz, 1H) 5.12 (s, 1H) 6.67 (d, J=2.0 Hz, 1H) 7.30 (d, J=2.0 Hz, 1H) 8.85 (br. s., 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>C(O)C.O1CCOCC1>[ClH:25].[ClH:25].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][N:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cn2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(NC2CCNCC2)nc1

Procedure:
A solution of 4-(5-trifluoromethyl-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.69 g, 2.00 mmol) in ethanol (40 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 246.1 [M+H]+.