Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][C:28]([NH2:30])=[O:29].C([O-])([O-])=O.[K+].[K+]>CC#N.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:26][CH2:27][C:28]([NH2:30])=[O:29])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: NC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: NC(=O)CCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 225 mg; 0.66 mmol), 3-bromopropanamide (302 mg; 1.99 mmol), KI (20 mg; 0.12 mmol) and K2CO3 (274 mg; 1.98 mmol) in CH3CN (20 mL) and DMF (10 mL) was stirred at 100° C. overnight. The reaction mixture was cooled to r.t., filtered, and concentrated to afford 272 mg (100%) of the title compound as a white solid, which was used directly without further purification.
Reaction SMILES: O[C@H:2]([CH:22]([CH3:24])[CH3:23])[C@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[CH:22]([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)[C@@H](O)[C@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 37.9 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2S*,3R*)-3-hydroxy-4-methyl-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid (0.14 g, 0.43 mmol) in dry CH2Cl2 (20 mL), at 0° C., Et3N (0.18 mL, 1.3 mmol) and subsequently TBTU (0.17 g, 0.55 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 100:0 to 80:20) to afford the pure title compound (0.052 g, 40%), as pure syn diastereoisomer, as a white solid. MS (ESI) m/z: 337 [M−NH4]+; (ESI) m/z: 318 [M−H]−. 1H NMR (DMSO-d6) δ 0.75 (d, J=6.57 Hz, 3H), 0.96 (d, J=6.51 Hz, 3H), 1.25-1.39 (m, 2H), 1.52-1.65 (m, 4H), 2.03 (dt, J=6.53, 10.83 Hz, 1H), 2.57 (t, J=7.67 Hz, 2H), 4.01 (t, J=6.58 Hz, 2H), 4.24 (dd, J=5.92, 10.84 Hz, 1H), 5.44 (dd, J=5.92, 9.53 Hz, 1H), 7.13-7.34 (m, 5H), 8.27 (d, J=9.52 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.N1CCCC1>C1(C)C=CC=CC=1.CCOCC>[C:11]12([CH2:9][C:8](=[O:10])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:1]1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2
Reactant: O=C1CCCCC1
Reactant: CC(=O)c1ccccc1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C1CC2(CCCCC2)Oc2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 2′-hydroxyacetophenone (Aldrich, CAS# 118-93-4, 2.72 g, 20 mmol), cyclohexanone (2.7 mL, 26.1 mmol), and pyrrolidine (1.66 mL, 19.9 mmol) was stirred in 6 mL toluene at room temperature for 1 h and at reflux (Dean-Stark trap) for 4 h. After cooling to room temperature, the mixture was diluted with ether (30 mL), washed sequentially with 2N HCl (10 mL), 2NNaOH (10 mL), and H2O (10 mL), dried over Na2SO4, and filtered. Evaporation of volatiles in vacuo afforded the crude title compound, which was used without further purification.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].OC1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.C(N(CC)CC)C>CCO.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:3]([O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:21]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)=[O:19])=[CH:22][CH:23]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CN(C)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
KOH (3.78 g, 67.6 mmol) was added to a solution of 1 (12.0 g, 41.0 mmol) dissolved in 250 mL of hot EtOH, and the mixture was refluxed for 24 hours. The solvent was filtered off, and following drying over P2O5 the white solid was suspended in 300 mL of toluene, and refluxed with oxalyl chloride (13.4 mL, 158.54) for 6 hours. Volatile components were removed, the yellow solid was taken in CH2Cl2 (100 mL), and added to a stirred solution containing p-hydroxybenzaldehyde (5.26 g, 43.1), triethylamine (36 mL, 0.261 mol), and DMAP (0.28 g, 2.3 mmol) in CH2Cl2 (100 mL). The mixture was let to stir at room temperature for three hours, and then heated to reflux for twelve hours. Following cooling to room temperature, the organic layer was washed with 1 M HCl (2×100 mL), and then distilled water (100 mL). The solvent was removed, and the product was obtained as an off-white solid following recrystallization from ethanol. Yield (8.5 g, 54%). 1H NMR: δH (CDCl3; 300 MHz): 0.91 (3 H, t, 3J=6.8 Hz, CH3), 1.21-1.58 (14 H, m, CH2), 1.85 (2 H, m, O—CH2—CH2), 4.07 (2 H, t, 3J=6.5 Hz, O—CH2), 7.00 (2 H, d, 3J=9.0 Hz, Ar—H), 7.42 (2 H, d, 3J=8.5 Hz, Ar—H), 7.98 (2 H, d, 3J=8.6 Hz, Ar—H), 8.16 (2 H, d, 3J=9.0 Hz, Ar—H), 10.03 (1 H, s, COH). 13C NMR: δC (CDCl3; 75 MHz): 14.5, 23.1, 26.4, 29.5, 29.7, 29.8, 30.0, 32.3, 68.8, 114.8, 121.2, 123.0, 131.6, 132.8, 134.3, 156.3, 164.3, 164.6, 191.4.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7](OS(C(F)(F)F)(=O)=O)=[CH:8][C:9]=2[OH:13])[O:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:8][C:9]=2[OH:13])[O:4][C:3]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C1COCCN1
Reactant: O=c1c(O)c(-c2ccccc2)oc2cc(OS(=O)(=O)C(F)(F)F)cc(O)c12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1c(O)c(-c2ccccc2)oc2cc(N3CCOCC3)cc(O)c12
Temperature: 85 °C
Reaction time: 9 h
Yield: 9.2 %

Procedure:
A solution of trifluoromethanesulfonic acid 3,5-dihydroxy-4-oxo-2-phenyl-4H-chromen-7-yl ester (90 mg, 0.224 mmol), morpholine (0.024 mL, 0.269 mmol), tris(dibenzylideneacetone) dipalladium(0) (10 mg, 0.011 mmol), biphenyl-2-yl-di-tert-butyl-phosphane (13 mg, 0.045 mmol), and K3PO4 (67 mg, 0.314 mmol) in THF (1.2 mL) was capped and heated to 85° C. After 9 h, the reaction mixture was allowed to cool to room temperature, then filtered through a ½″ silica gel (60 Å) plug. The plug was washed with EtOAc (40 mL) and the filtrate concentrated. The concentrate was purified via Biotage chromatography eluting with 100% CH2Cl2 to yield 7 mg (9%) of 3,5-dihydroxy-7-morpholin-4-yl-2-phenyl-chromen-4-one.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[C:10]([CH3:13])[N:6]2[C:7](=[O:9])[CH:8]=1.ClCC1N(C)N=C(C)N=1.[Cl:23][C:24]1[C:25]([O:47][CH3:48])=[CH:26][C:27]([O:45][CH3:46])=[C:28]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[O:37][C:36](=[O:38])[CH2:35][C:34](=[O:39])[CH2:33]2)[CH:29]=1>>[Cl:23][C:24]1[C:25]([O:47][CH3:48])=[CH:26][C:27]([O:45][CH3:46])=[C:28]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[O:37][C:36](=[O:38])[C:35]([CH2:2][C:3]3[N:4]=[C:5]4[S:12][CH:11]=[C:10]([CH3:13])[N:6]4[C:7](=[O:9])[CH:8]=3)=[C:34]([OH:39])[CH2:33]2)[CH:29]=1
Reactant: Cc1csc2nc(CCl)cc(=O)n12
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cc1nc(CCl)n(C)n1
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3cc(=O)n4c(C)csc4n3)C(=O)O2)cc1Cl
Yield: 18 %

Procedure:
The title compound was prepared as described in Example B(53), using 7-(chloromethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (prepared according to a reported procedure: Doria, G.; Passarotti, C.; Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari, G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 18%. 1H NMR (300 MHz, DMSO-d6) δ 1.23-1.73 (m, 8H), 1.78-2.0 (m, 2H), 2.35 (m, 1H), 2.48-2.58 (m, 2H, overlap with DMSO-d5), 2.64 (s, m, overlap, 4H), 2.78 (d, J=18 Hz, 1H), 3.44 (s, 2H), 3.78 (s, 3H, overlap with H2O peak), 3.85 (s, 3H), 5.80 (s, 1H), 6.70 (s, 1H), 6.97 (s, 1H), 7.11 (s, 1H), 10.96 (br s, 1H). LC-MS (APCI) calcd for C28H31ClN2O6S: 558.16; found (M+H+) 559.0 m/z.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:13]([OH:15])=O)[C:3]1=2.C(N(CC)CC)C.ClC(OCC)=O.[F:29][C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32].Cl>CN(C)C=O>[F:29][C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH:32][C:13]([C:4]1[C:3]2[C:2](=[O:1])[CH2:10][C:9]([CH3:11])([CH3:12])[CH2:8][C:7]=2[NH:6][CH:5]=1)=[O:15]
Reactant: CC1(C)CC(=O)c2c(C(=O)O)c[nH]c2C1
Reactant: Nc1ccccc1F
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)c2c(C(=O)Nc3ccccc3F)c[nH]c2C1
Reaction time: 0.75 h
Yield: 24.4 %

Procedure:
To a stirred solution of 4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (155 mg, 0.75 mmol) and triethylamine (209 μL, 1.5 mmol) in dimethylformamide (4 mL) at 0° C. was added ethyl chloroformate (143 μL, 1.5 mmol). After stirring an additional 45 minutes, 2-fluoroaniline (145 μL, 1.5 mmol) was added. The reaction mixture was stirred for 30 minutes, then poured into aqueous 3.6N hydrochloric acid and extracted 2× with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated it vacuo. To the residue was added aqueous 5N sodium hydroxide (5 mL) and ethyl alcohol (1 mL), and the mixture was heated at reflux for 30 minutes. After cooling in an ice water bath, the reaction mixture was acidified with hydrochloric acid, the precipitate was collected, rinsed with water, and dried to give 55 mg of N-(2-fluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 2).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:15][C:16]1[CH:17]=[C:18]([NH:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=1>CC(O)C>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([C:4]2[O:3][C:2]([NH:15][C:16]3[CH:17]=[C:18]([NH:22][S:23]([C:26]([F:29])([F:27])[F:28])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)=[N:6][CH:5]=2)=[CH:8][CH:9]=1)#[N:12]
Reactant: Nc1cccc(NS(=O)(=O)C(F)(F)F)c1
Reactant: N#Cc1ccc(-c2cnc(Cl)o2)cc1
Solvent: CC(C)O
Product: N#Cc1ccc(-c2cnc(Nc3cccc(NS(=O)(=O)C(F)(F)F)c3)o2)cc1
Temperature: 80 °C
Yield: 76 %

Procedure:
A mixture of 4-(2-chlorooxazol-5-yl)benzonitrile 2 (0.30 g, 1.47 mmol) and N-(3-aminophenyl)-1,1,1-trifluoromethanesulfonamide 43 (0.35 g, 1.45 mmol) in 2-propanol (25 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide N-(3-((5-(4-cyanophenyl)oxazol-2-yl)amino)phenyl)-1,1,1-trifluoromethane sulfonamide 44 (0.45 g, 75% yield) as a solid. MS (ES) m/z 409 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[S:22][CH:23]=[N:24][N:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([NH:20][C:21]1[S:22][CH:23]=[N:24][N:25]=1)=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.7 %

Procedure:
26.5 g of N-benzyloxycarbonyl-DL-leucine and 10 g of 2-amino-1,3,4-thiadiazole were dissolved in 80 ml of dioxane, to which was added dropwise 20 ml of a dioxane solution of 20.6 g of N,N'-dicyclohexylcarbodiimide, followed by stirring at room temperature for 24 hours. The solvent was removed from the reaction solution by distillation under reduced pressure, and the residue was recrystallized from diluted ethanol to obtain 20.9 g (yield: 56%) of 2-(N-benzyloxycarbonyl-DL-leucylamino)-1,3,4-thiadiazole as colorless crystals having a melting point of 121° C. (dec.).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:36])[CH2:6][NH:7][C:8]([C:10]1[S:11][C:12]([C:16]([CH2:34][CH3:35])([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([OH:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:21]([CH3:33])[CH:20]=2)[CH2:17][CH3:18])=[CH:13][C:14]=1[CH3:15])=[O:9]>>[CH2:17]([C:16]([C:12]1[S:11][C:10]([C:8]([NH:7][CH2:6][C:5]([OH:36])=[O:4])=[O:9])=[C:14]([CH3:15])[CH:13]=1)([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([OH:32])[C:28]([CH3:30])([CH3:31])[CH3:29])=[C:21]([CH3:33])[CH:20]=1)[CH2:34][CH3:35])[CH3:18]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)NCC(=O)OC)s1
Agent: [Li+]
Agent: [OH-]
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)NCC(=O)O)s1

Procedure:
Using LiOH hydrolysis as described in Example 136, [(5-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid methyl ester gives the title compound (quant). 1H NMR (CDCl3) δ 7.07 (d, 1H, J=8.7 Hz), 7.00 (d, 1H, J=8.7 Hz), 6.99 (s, 1H), 6.63 (s, 1H), 6.21 (t, 1H), 4.20 (d, 2H, J=5.3 Hz), 3.26 (bd, 1H, J=9.3 Hz), 2.88 (m, 1H), 2.56 (m, 1H), 2.47 (s, 3H), 2.28 (s, 3H), 2.08 (m, 4H), 1.78 (m, 1H), 1.58 (m, 1H), 0.90 (s, 9H), 0.70 (t, 6H);
Reaction SMILES: Br.[NH:2]([C:4]1[NH:5][CH2:6][CH2:7][N:8]=1)[NH2:3].[OH:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@:16]3([OH:31])[CH2:17][CH2:18][C@@H:19]2[CH:29]=O)[CH2:11]1>O.O1CCOCC1>[NH:8]1[CH2:7][CH2:6][N:5]=[C:4]1[NH:2]/[N:3]=[CH:29]/[C@H:19]1[CH2:18][CH2:17][C@:16]2([OH:31])[C@H:15]3[C@H:24]([CH2:23][CH2:22][C@:20]12[CH3:21])[C@:25]1([CH3:28])[C@@H:12]([CH2:11][C@@H:10]([OH:9])[CH2:27][CH2:26]1)[CH2:13][CH2:14]3
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Reactant: NNC1=NCCN1
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=N/NC3=NCCN3)CC[C@]12O
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a solution of 0.93 g of 2-hydrazino-2-imidazoline hydrobromide in 45 ml of water and 30 ml of dioxane a solution of 1.10 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723) in 30 ml of dioxane was added dropwise at room temperature. After 2 hrs, the solution was evaporated to dryness under reduced pressure. The crude product was crystallized from ethanol/water and then from ethanol to give 0.60 g of the title compound (I-aa) as hydrobromide, white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH2:12])[CH2:4][CH2:3]1.[CH:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14]>ClCCl>[CH:13]([NH:16][C:17]([NH:12][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH2:3][CH2:4]1)=[O:18])([CH3:15])[CH3:14]
Reactant: CC(C)N=C=O
Reactant: NC1CCC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)NC(=O)NC1CCC(=O)c2ccccc21

Procedure:
A 13 g sample of 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine is dissolved in 100 ml of dichloromethane and stirred under nitrogen atmosphere. A solution of 6.86 g of isopropyl isocyanate in 45 ml of CH2Cl2 is then added over a 48 minute period at 20° C. to 28° C. The mixture is stirred for 16 hours at room temperature and filtered to give the title compound, melting point 185° C. to 188° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[F:28].[S:29]1[CH2:33][C@@H:32]([C:34]([OH:36])=[O:35])[NH:31][CH2:30]1>>[F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([N:31]3[C@H:32]([C:34]([OH:36])=[O:35])[CH2:33][S:29][CH2:30]3)=[O:21])=[CH:26][CH:27]=2)=[CH:4][C:3]=1[F:28]
Reactant: O=C(O)c1cccc(COc2ccc(-c3cc(F)c(F)c4ccoc34)cc2)c1
Reactant: O=C(O)[C@@H]1CSCN1
Product: O=C(O)[C@@H]1CSCN1C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)c4ccoc34)cc2)c1
Yield: 2.8 %

Procedure:
An operation similar to that in Step 4 of Example 10 was performed using the compound (38.0 mg, 0.100 mmol) of Step 2 of Example 59 in place of 3-{[4-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)phenoxy]methyl}benzoic acid, and (4R)-1,3-thiazolidine-4-carboxylic acid (40.0 mg, 0.300 mmol) in place of L-proline to thus obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([OH:16])=O)[N:10]([CH2:17][C:18]([F:21])([CH3:20])[CH3:19])[N:9]=[CH:8]2.C1C=C2N=NN(O)C2=CC=1.O.C1C=CC2N(O)N=NC=2C=1.[NH2:48][C@H:49]1[CH2:53][CH2:52][NH:51][C:50]1=[O:54].C(Cl)CCl>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:48][C@H:49]1[CH2:53][CH2:52][NH:51][C:50]1=[O:54])=[O:16])[N:10]([CH2:17][C:18]([F:21])([CH3:20])[CH3:19])[N:9]=[CH:8]2
Reactant: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Reactant: N[C@H]1CCNC1=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 241.5 %

Procedure:
To a stirred solution of 5-(2,4-Difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylic acid (16.3 g, 44.7 mmol) in a mixture of DCM (180 mL) and DMF (60 mL) at ambient temperature was added HOBt hydrate (6.85 g, 44.7 mmol). Once all of the HOBt had dissolved, (S)-3-aminopyrrolidin-2-one 4.84 g, 48.3 mmol) was added. To the resulting stirred solution at ambient temperature was added EDC (9.43 g, 49.2 mmol), and the resulting cloudy mixture was stirred at ambient temperature. After stirring for a total of 24 hr the DCM was evaporated under reduced pressure. The residual DMF solution was stirred and diluted with water (300 mL), and the resulting mixture was stirred at ambient temperature. The precipitate that formed was collected by filtration, washed with water, and dried under vacuum to afford the crude product (20.7 g, 104%). This material was combined with a second batch (37.8 g) and recrystallized as follows: The two batches were combined in a 1000 mL Erlenmeyer flask. Acetone (250 mL) was added, and the mixture stirred with gentle heating on a hot plate. All solid dissolved as the solution boiled (52° C.). While the solution was boiling and stirring on the hot plate, hexanes (250 mL, 20° C.) was added slowly from a separatory funnel. Shortly after completion of addition, the product began to crystallize. A second portion of hexanes (250 mL) was added slowly as crystallization continued. The resulting mixture was stored at 2° C. for 14 hr. The crystals that formed were collected by filtration, washed with cold 2:1 hexane:acetone, and dried under vacuum to afford the title compound as an off-white powder (48.2 g, 83% recovery). 1H NMR (CDCl3). δ 1.37 (d, J=2.8 Hz, 3H); 1.42 (d, J=3.2 Hz, 3H); 2.02-2.17 (m, 1H); 2.85-2.91 (m, 1H); 3.42-3.46 (m, 2H); 4.53-4.60 (m, 3H); 5.97 (broad s, 1H); 6.88-6.93 (m, 1H); 6.98-7.03 (m, 2H); 7.12-7.18 (m, 1H); 7.90 (s, 1H); 8.20 (d, J=5.2 Hz, 1H); 8.42 (s, 1H). MS (LC/MS/pos): 469.1 (M+Na)+. Chiral purity is >99% ee (done by chiral HPLC).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)=[O:10])[CH2:5][CH2:4]1)[CH3:2]>[Pd].CO>[NH2:17][C:13]1[CH:12]=[C:11]([C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)=[O:10])[CH:16]=[CH:15][CH:14]=1
Reactant: CCN1CCN(C(=O)c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Product: CCN1CCN(C(=O)c2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To methanol solution (5 ml) of (4-ethyl-piperazin-1-yl)-(3-nitro-phenyl)-methanone (365.3 mg) obtained in Step A, palladium black was added, followed by stirring at room temperature for 14 hours under a hydrogen gas atmosphere. This was filtered through Celite, and subsequently the solvent was distilled off under reduced pressure, to obtain the desired compound as a crude product (241.8 mg, 51%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=1.Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41])=[CH:24][CH:25]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccnc1
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4cccnc4)ccc3n2C)cc1
Yield: 35 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-octyl chloroformate. Yield: 35% of theory, C36H45N7O5 (655.8); Rf value: 0.28 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=656; (M+2H)++=328.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[C:9]=1I.[C:18]([Cu])#[N:19]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[C:9]=1[C:18]#[N:19]
Reactant: Fc1ccccc1-c1[nH]c2cncnc2c1I
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccccc2F)[nH]c2cncnc12
Yield: 17 %

Procedure:
6-(2-fluorophenyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine and CuCN in DMF were heated for 30 min at 175° C. in a microwave vial. The reaction mixture was filtered through a metal scavenging resin column, rinsed with DMF (˜10 mL), and purified by HPLC (10-75% MeCN/H2O with 1% formic acid) to give 29 mg of desired (17% yield). LC-MS calculated for C13H7FN4: 238.2, found 239.09 [M+H]+.