Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.[CH2:51](O)[CH2:52][CH2:53][CH2:54][CH2:55][CH3:56].C([O-])(O)=O.[Na+]>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:28][CH2:29][N:30]([CH2:33][C:34]([O:36][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:35])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: CCCCCCO
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 4d from 934 mg (1.35 mmol) (R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 190 μL (0.11 mmol) 1-hexanol. The reaction solution was combined with 30 mL semisaturated NaHCO3 solution, extracted with 50 mL EtOAc and the organic phase was dried on Na2SO4. After the elimination of the desiccant and solvent the residue was purified by chromatography (silica gel, EtOAc/MeOH/NH3 90:10:1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[N:5][N:4]=[C:3]1[C:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[N:5][N:4]=[C:3]1[C:14]1([NH:19][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccccc1-c1nnc(C2(N)CCCC2)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1nnc(C2(NC(=O)c3ccccc3)CCCC2)n1C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
1-[4-Methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]cyclopentanamine (270 mg) was dissolved in chloroform (5 ml) and then diisopropylethylamine (1.7 ml) and benzoyl chloride (0.48 ml) were added thereto, followed by stirring at room temperature for 19 hours. The reaction solution was diluted with a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform (10 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography (methanol:chloroform=1:19) and the resulting solid was dissolved in ethanol (1 ml) and then a 1M aqueous sodium hydroxide solution (2 ml) was added thereto, followed by stirring at room temperature for 6 days. The resulting solid was collected by filtration and washed with water to obtain 51 mg of N-{1-[4-methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]cyclopentyl}benzamide (white solid).
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH3:14])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[NH2:15][C:16]1[S:20][C:19]2[CH2:21][CH2:22][CH2:23][C:18]=2[C:17]=1[C:24]#[N:25]>>[C:24]([C:17]1[C:18]2[CH2:23][CH2:22][CH2:21][C:19]=2[S:20][C:16]=1[NH:15][C:4](=[O:5])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]([CH3:1])[CH2:13][CH3:14])#[N:25]
Reactant: CCC(C)C(C(=O)Cl)c1ccccc1
Reactant: N#Cc1c(N)sc2c1CCC2
Product: CCC(C)C(C(=O)Nc1sc2c(c1C#N)CCC2)c1ccccc1
Reaction time: 20 h

Procedure:
Reaction of 3-methyl-2-phenylvaleryl chloride (Prepared in Example 7, Step1) and 2-Amino-3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophene (164 mg; 1.0 mmol) according to the procedure outlined in Example 5 for 20 h at room temperature provided after workup, crude which triturated with diethylether to give 94 mg of crude 3-Methyl-2-phenyl-pentanoic acid (3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-amide which was further purified by dissolving in methylene chloride and passing through a short plug of Merck Silica gel 60 to provide 82 mg (24%) of 3-Methyl-2-phenyl-pentanoic acid (3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-amide as a mixture of diastereomers. ES-HRMS m/e calcd for C26H38N2O2 (M+Ht) 411.3006, found 411.3011.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=2)=[CH:16][CH:15]=1)([CH3:13])[CH3:12])=[O:9])([CH3:6])([CH3:5])[CH3:4].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH:39]=[CH:38][N:37]=[CH:36]2)=[CH:31][CH:30]=1>C1COCC1>[C:3]([O:7][C:8]([NH:10][C:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)=[CH:33][CH:34]=3)[N:21]=2)=[CH:18][CH:19]=1)([CH3:13])[CH3:12])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Cl)ncc2Cl)cc1
Reactant: Nc1ccc(-n2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc(-n4ccnc4)cc3)ncc2Cl)cc1
Yield: 23.4 %

Procedure:
Sodium hydride (330 mg, 8.25 mmol) was added to a solution of 4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2,5-dichloropyrimidine (1.0 g, 2.62 mmol) and 1-(4-aminophenyl)-1H-imidazole (438 mg, 2.75 mmol) in dry THF (40 ml) under N2 and the mixture heated to reflux for 3 h. The reaction was quenched with H2O (5 ml), diluted with brine (50 ml) and extracted with ethyl acetate (2×150 ml). The ethyl acetate extracts were dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography (silica; 2% ethyl acetate in CH2Cl2) to give 4-[4-(1-tert-butoxy carbonylamino-1-methylethyl)phenyl]-5-chloro-N-[4-(1-imidazolyl)-phenyl]pyrimidine-2-amine as a yellow solid (310 mg) m.p. 218-220°. This intermediate was stirrd at room temperature in trifluoroacetic acid (4 ml) for 3 h before concentrating the reaction in vacuo. The residue was diluted with 2M NaOH (aq) (50 ml) and extracted with CH2Cl2-ethanol (20:1) (3×50 ml), the extracts dried (MgSO4) and concentrated in vacuo. Trituration of the resultant solid with diethylether-ethyl acetate (4:1) gave the title compound as a pale yellow solid (175 mg) m.p. 199-201°. δH (d6DMSO) 10.05 (1H, bs), 8.62 (1H, s),8.15 (1H, s), 7.88 (2H, d, J 7.9 Hz), 7.78 (2H, d, J 8.5 Hz), 7.69 (2H, d, J 8.5 Hz), 7.65 (1H, s), 7.55 (2H, d, J 8.8 Hz), 1.42 (6H, s). MS (ESI) 405 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2].[NH2:23][C:24]1[C:28]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:27][NH:26][N:25]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[N:25]3[N:26]=[CH:27][C:28]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[C:24]3[N:23]=2)=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2]
Reactant: CCOc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C(F)(F)F
Reactant: Nc1n[nH]cc1-c1cccnc1
Product: CCOc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)cc1C(F)(F)F
Yield: 68.5 %

Procedure:
Reaction of 1-(4-ethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (164 mg, 0.5 mmol), prepared from 4-ethoxy-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (155 mg, 68%). MS (ISP) 453.5 [(M+H)+]; mp 178° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10][C:9]1([CH3:17])[CH3:16].C(O[Cl:23])(C)(C)C>CO>[Cl:23][N:10]1[C:11]([CH3:15])([CH3:14])[C:12](=[O:13])[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]1([CH3:17])[CH3:16]
Reactant: CC(C)(C)OCl
Reactant: COCCOCCN1C(=O)C(C)(C)NC1(C)C
Solvent: CO
Product: COCCOCCN1C(=O)C(C)(C)N(Cl)C1(C)C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A solution of 3-(2-(2-methoxyethoxy)ethyl)-2,2,5,5-tetramethyl-imidazolidin-4-one (715 mg, 2.9 mmol) in methanol (7 ml) was cooled to 0° C. tert-Butylhypochlorite (393 ul, 3.5 mmol) was added. The resulting solution was stirred for 30 minutes, and then concentrated under reduced pressure. The crude material was purified by column chromatography (0 to 12% methanol in dichloromethane) to give the title compound as a clear liquid (666 mg, 2.39 mmol, 82%). 1H NMR (400 MHz, D2O) δ 1.26 (s, 6H), 1.43 (s, 6H), 3.27 (s, 3H), 3.44-3.46 (m, 2H), 3.49-3.51 (m, 2H), 3.57-3.63 (m, 4H). 13C NMR (100 MHz, D2O) δ 22.5, 24.0, 40.1, 57.9, 66.0, 67.6, 69.4, 71.0, 83.7, 175.0. LRMS (ESI/APCI) m/z 279 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].S(=O)(=O)(O)O.[C:18](=O)([O-])O.[Na+]>CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1F
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(F)c(OC)c1
Temperature: 25 °C

Procedure:
A mixture of 4-fluoro-3-methoxybenzoic acid (2.33 g) and sulfuric acid (0.2 mL) in methanol (20 mL) was heated under reflux for 10 hr, and allowed to cool to room temperature. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, the solvent was evaporated under reduced pressure, and water was added to the residue. The resultant precipitate was collected by filtration to give the title compound (2.31 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[CH3:11][O:12][C:13]([C:15]1[CH:20]=[N:19][C:18](Cl)=[CH:17][N:16]=1)=[O:14].O>CN(C=O)C>[CH3:11][O:12][C:13]([C:15]1[CH:20]=[N:19][C:18]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:17][N:16]=1)=[O:14]
Reactant: Oc1ccccc1F
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Oc2ccccc2F)cn1
Temperature: 0 °C

Procedure:
2-Fluorophenol (21.6 g, 233 mmol) was dissolved in DMF (250 mL) under a calcium chloride drying tube. The solution was cooled to 0° C., and then 60% NaH in paraffin oil (9.3 g, 233 mmol) was added in small portions. After the main portion of NaH had dissolved, 5-chloro-pyrazine-2-carboxylic acid methyl ester (Preparation 41, 40.2 g, 233 mmol) was added. The mixture was refluxed for 1 hour and then poured into water (1 L). The aqueous mixture was extracted with ether (3×300 mL), and the combined organic layers were washed with 2% sodium hydroxide aqueous solution (400 mL) and filtered through a layer of silica gel (40/60 μm). The filtrate was concentrated in vacuo to yield the title compound which was used without further purification.
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.P(Br)(Br)[Br:17]>CCOCC>[Br:17][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC#CCO
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCC#CCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 202.6 %

Procedure:
A solution of 2-octyne-1-ol (37.8 g) in ether (150 mL) containing pyridine (3 ml) was cooled to -35° and treated with a solution of phosphorous tribromide (28.9 g) over 45 min. The mixture was then stirred at -30° for 2 hours, 3 hours at room temperature and 1/2 hour at 40°. The reaction mixture was then cooled to room temperature, poured onto ice and extracted with ether. The combined ether extracts were washed with aqueous NaHCO3 solution, brine and dried (MgSO4). Removal of the solvents and distillation of the residue yielded 1-bromo-2-octyne (40.9 g), bp, 106°-110° (25 mmHg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C1CCCCC1>ClCCl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)=[O:1]
Reactant: OCc1cccc2[nH]ccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCCCC1
Solvent: ClCCl
Product: O=Cc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.3 %

Procedure:
Manganese dioxide (MnO2) is added slowly with stirring to a solution of 74 g of 4-hydroxymethylindole (2) in 3 litres of dichloromethane, and the mixture is subsequently stirred at room temperature for 72 hours. The reaction mixture is subsequently filtered through kieselguhr, and the filtrate is evaporated. The crystalline residue obtained is stirred with cyclohexane and filtered under reduced pressure. Drying gives 63 g (86% of theory) of crystalline 4-formylindole (3).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].NC(N)=[S:15]>CC(C)=O>[SH:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: NC(N)=S
Reactant: COC(=O)c1cccc(CBr)c1
Solvent: CC(C)=O
Product: COC(=O)c1cccc(CS)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 3-bromomethylbenzoate (6.9 g, 30 mmol; Lancaster) in dry acetone (10 mL) was added via dropwise addition a solution of thiourea (2.28 g, 30 mmol) in dry acetone (40 mL) at room temperature. After 15 minutes the precipitated thiouronium salt was collected by filtration; the solids were washed with acetone and dried. The thiouronium salt was dissolved in H2O (65 mL) and the pH was adjusted to 10.5 by the addition of 10% NaOH. The mixture was refluxed for 2 hours. After cooling to room temperature the solution was extracted with EtOAc and the organic layer was discarded. The aqueous solution was acidified to pH 1.5 and extracted three times with EtOAc. The organic extracts were dried (MgSO4), filtered and the solvent evaporated. The crude acid was then dissolved in anhydrous MeOH (125 mL), cooled to 0° C., and dry HCl gas was bubbled through the solution for 30 minutes. The reaction was then left for two days at room temperature. The mixture was concentrated in vacuo and the product was purified by flash column chromatography (silica, 5% EtOAc in hexane) providing a colorless oil: 1H NMR (250 MHz, CDCl3) δ 8.00 (s, 1H, 2-phenyl), 7.91 (d, J=7.6 Hz, 1H, 6-phenyl), 7.52 (d, J=7.6 Hz, 1H, 4-phenyl), 7.39 (dd, J=7.6 Hz, 1H, 5-phenyl), 3.92 (s, 3H, methyl ester), 3.78 (d, J=7.7 Hz, 2H, SCH2), 1.79 (t, J=7.7 Hz, 1H, SH).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([O:22][CH3:23])=[CH:9][C:10]([CH:20]=[O:21])=[C:11]([CH:19]=2)[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([Mg]Br)[CH3:25]>>[CH2:15]([N:14]([CH2:17][CH3:18])[C:12](=[O:13])[C:11]1[CH:19]=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:8]([O:22][CH3:23])=[CH:9][C:10]=1[CH:20]([OH:21])[CH2:24][CH3:25])[CH3:16]
Reactant: CCN(CC)C(=O)c1cc(OC2CCCC2)c(OC)cc1C=O
Reactant: CC[Mg]Br
Product: CCC(O)c1cc(OC)c(OC2CCCC2)cc1C(=O)N(CC)CC
Yield: 76 %

Procedure:
Operating analogously to example 31 using 5-cyclopentyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide, obtained as described in example 4, product B, and ethyl-magnesium bromide the title product was obtained (yield 76%).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C:12]1[C:13]2[CH2:14][C@H:15]3[CH2:28][C@H:16]3[C:17]=2[N:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[N:19]=1)=[O:11].I[CH3:30]>CN(C=O)C>[CH3:30][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[C:10]([C:12]1[C:13]2[CH2:14][C@H:15]3[CH2:28][C@H:16]3[C:17]=2[N:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[N:19]=1)=[O:11]
Reactant: CI
Reactant: O=C(Nc1ccccn1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.1 %

Procedure:
To a reaction vial containing NaH (2.3 mg, 0.057 mmol) was added (1aR,5aR)-2-(2,4-difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid pyridin-2-ylamide (10 mg, 0.028 mmol) in DMF (0.5 mL) under nitrogen protection. After 15 min, iodomethane (2.7 μL, 0.043 mmol) in DMF (0.1 mL) was added. The reaction mixture was stirred at room temperature overnight, and then purified by preparative LCMS to give the title compound (3.5 mg). LCMS m/z=367.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.52 (td, J=4.7 and 3.4 Hz, 1H), 1.15-1.22 (m, 1H), 2.19-2.23 (m, 1H), 2.28-2.34 (m, 1H), 2.97 (dd, J=16.6 Hz, 1H), 3.08 (dd, J=16.4 and 6.3 Hz, 1H), 4.39 (s, 3H), 6.97-7.08 (m, 2H), 7.49 (t, J=6.6 Hz, 1H), 7.88-7.94 (m, 1H), 8.22 (t, J=8.0 Hz, 1H), 8.50-8.55 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=O)[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.O>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[S:32])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=S)CC[C@@H]12
Yield: 35.9 %

Procedure:
A solution of 1.09 g (3.63 mmol) of 3-hydroxy-2-methoxy-estra-1,3,5(10)-trien-17-one in 60 ml of toluene (abs.) was mixed with 3.7 g of Lawesson's reagent, and it was refluxed for four hours. After water was added, it was extracted with dichloromethane (3×), and the combined organic phases were washed with water, dried on sodium sulfate, and concentrated by evaporation in a rotary evaporator. Flash chromatography (n-hexane/ethyl acetate) yielded 412 mg (36%) of the desired product as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8]C(=O)C)=[CH:4][C:3]=1[N:12]([CH2:30][CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:16]([F:29])[CH:15]=1.C([Sn](CCCC)(CCCC)[C:37]1[S:38][C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1)CCC>>[S:38]1[C:39]2[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=[C:37]1[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:12]([CH2:30][CH3:31])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[C:16]([F:29])[CH:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Reactant: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC(C)=O)ccc1Br
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1-c1nc2ccccc2s1
Yield: 5.9 %

Procedure:
Synthesized from acetic acid 4-bromo-3-{ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amino}phenyl ester (50 mg) and 2-tributylstannylbenzothiazole (100 mg) according to an analogous synthetic method to Example 19, the title compound (3 mg) was obtained.
Reaction SMILES: N[CH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.C(Cl)CCl.ON1C2C=CC=CC=2N=N1.C[N:23]([CH:25]=[O:26])C>ClCCl>[NH:7]1[C:3]([CH2:2][C:25]([NH2:23])=[O:26])=[N:4][N:5]=[N:6]1
Reactant: NCc1nnn[nH]1
Reactant: CN(C)C=O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: NC(=O)Cc1nnn[nH]1

Procedure:
Carboxylic acid 14.4 can be coupled with 5-aminomethyltetrazole 19.1 (available commercially from Dynamit Nobel GmbH, Leverkusen, Germany) using any of a variety of peptide coupling reagents, including EDC and 1-hydroxybenzotriazole in dichloromethane or DMF, to give 1H-tetraazol-5-ylmethyl carboxamide 19.2. Under similar reaction conditions, 14.4 can be coupled with 5-aminotetrazole 19.3 to afford 1H-tetraazol-5-yl carboxamide 19.4.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:17][N:18]1C(=O)CCC1>>[C:17]([C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1)#[N:18]
Reactant: Clc1ccc2nc(-c3ccccc3)oc2n1
Reactant: CN1CCCC1=O
Product: N#Cc1ccc2nc(-c3ccccc3)oc2n1
Temperature: 175 °C

Procedure:
A mixture of 2.3 g. of 5-chloro-2-phenyloxazolo[5,4-b]pyridine, 1.6 g. of cuprous cyanide and 15 ml. of N-methyl pyrrolidinone is stirred under nitrogen and then heated in an oil bath of 175° C. (bath temperature). It is maintained at that temperature for 5 hours. The cooled, dark mixture is diluted with 75 ml. of 10% ammonium hydroxide and a dark precipitate removed by filtration. The solid is extracted with methylene dichloride. The methylene dichloride is evaporated and the residue crystallized from ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](=O)[C:12]([C:15]#[N:16])=[CH:11][NH:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([Cl:21])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cn2[nH]cc(C#N)c(=O)c2c1C
Product: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Temperature: 75 °C

Procedure:
A 15 mL round bottom flask containing the compound 1C (370 mg, 1.51 mmol) was charged with POCl3 (1 mL) and heated to 75° C. for 2 h. The reaction mixture was concentrated in vacuo and the resulting yellow residue was dissolved in dichloromethane (10 mL) and added, via pipette, to a saturated aqueous solution of NaHCO3 with stirring at 0° C. The heterogeneous mixture was stirred for 10 min at 0° C. then warmed to room temperature and stirred for an additional 1 h. The mixture was poured into a separatory funnel and the layers were separated. The aqueous phase was extracted with dichloromethane (2×20 mL) and the combined organic extracts were washed with NaHCO3 (sat. aq., 1×20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was dissolved in EtOAc (20 mL) and filtered through a pad of silica using EtOAc (100 mL) to wash the silica pad. The filtrate was concentrated in vacuo to afford compound 1D as a yellow solid which was used without further purification. HPLC: 100% at 4.160 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[N:29]1[C:37]2[C:32](=[CH:33][C:34]([C:38]3[N:42]=[CH:41][N:40]([C:43]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:39]=3)=[CH:35][CH:36]=2)[C:31]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)=[N:30]1>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([NH:68][C:64]1[CH:65]=[CH:66][CH:67]=[C:62]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[C:34]([C:38]4[N:42]=[CH:41][N:40]([C:43]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)[C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)[N:39]=4)[CH:33]=3)[N:29]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[N:30]=2)[CH:63]=1)=[O:9]
Reactant: O=C(O)C(=O)c1ccco1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-furyl)-2-oxoacetic acid (0.070 g, 0.496 mmol) in 2.0 mL of dichloromethane, was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) as a solid (0.098 g, 0.510 mmol). The solution was stirred at room temperature for 15 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol), dissolved in 1 mL of dichloromethane was added. The reaction was stirred at room temperature overnight. The reaction mixture was then partitioned between dichloromethane and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 725 [M+H]+.