Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:26])=O)[CH:19]=2)[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC1C=CC2C(=CC=CC=2)[N:36]1C(OCC)=O)C>CN(C=O)C.[OH-].[NH4+]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:36])=[O:26])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N(Cc2cccnc2)c2cccc(C(=O)O)c2)cc1OC1CCCC1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(N(Cc2cccnc2)c2cccc(C(N)=O)c2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a solution of 3-cyclopentyloxy-4-methoxy-N-(3-carboxyphenyl)-N-(3-pyridylmethyl)aniline (50 mg, 0.125 mmol) in 1 mL of DMF at room temperature was added 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (50 mg, 0.20 mmol). The mixture was warmed slightly until everything was in solution, then cooled to room temperature and stirred for 1 h. 5 drops of ammonium hydroxide (28-30%) was added and the mixture was stirred for an additional hour. The mixture was partitioned between water (25 mL) and EtOAc (25 mL). The EtOAc fraction was separated, washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography eluting with a linear gradient from 0% to 10% MeOH in EtOAc to give 3-cyclopentyloxy-4-methoxy-N-(3-aminocarbonylphenyl)-N-(3-pyridylmethyl)aniline (28 mg, 54% yield) as a white solid. EIMS (m/z) 418 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([N:15]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH2:26][C:27]3C=CC=CC=3)=[O:24])=[CH:18][C:17]=2[F:33])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[C:52](OC[C@@H]1OC1)(=[O:56])CCC>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH:13]([N:15]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][C@H:26]([CH2:52][OH:56])[O:25][C:23]3=[O:24])=[CH:18][C:17]=2[F:33])[CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: O=C(Nc1ccc(N(C(=O)OCc2ccccc2)C2CN(C(=O)OCc3ccccc3)C2)c(F)c1)OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(N(C(=O)OCc2ccccc2)c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.916 g of 3-(benzyloxycarbonyl-(4-benzyloxycarbonylamino-2-fluoro-phenyl)-amino]-azetidine-1-carboxylic acid benzyl ester (1.56 mmol) in 5 ml THF were added at −15° C. 0.767 ml of a 2.25M LDA (1.7 mmol) solution in THF. The mixture was allowed to warm up to 0° C. and stirred for 5 min. Then, 0.26 ml of (R)-glycidyl butyrate (1.87 mmol) was added and the yellow solution was stirred for 2 h at RT. The reaction was quenched with a saturated solution of ammonium chloride. The mixture was diluted with ethyl acetate, the org. layer washed with water and brine and dried over Mg sulfate. The residue was purified by chromatography using a 95/5 dichloromethane/methanol mixture as eluent.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C=O)C>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)[CH:20]=[CH2:19]
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 g, 9.19 mmol) in DMF (20 mL), K2CO3 (2.54 g, 18.39 mmol) and allyl bromide (0.955 mL, 11.03 mmol) were added. The reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was dissolved in ethyl acetate, washed with 10% NaOH solution, water, and brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated to give 6-(allyloxy)-3,4-dihydroquinolin-2(1H)-one as a white solid (1.7 g, 89%). 1HNMR: 400 MHz, DMSO-d6: δ 2.40 (q, J=7.60 Hz, 2H), 2.83 (t, J=8.00 Hz, 2H), 4.48-4.50 (m, 2H), 5.22-5.26 (m, 1H), 5.35-5.40 (m, 1H), 5.97-6.07 (m, 1H), 6.72-6.80 (m, 3H), 9.89 (s, 1H), LCMS (ES-API), RT 1.566 min, m/z 204.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C@H:13]3[CH2:16][C@H:15]([O:17][CH3:18])[CH2:14]3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([CH:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)[C:6]=2[CH:19]=1
Reactant: CO[C@H]1C[C@H](n2c([C@H](C)N)nc3ccc(F)cc32)C1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC1CC(n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3ccc(F)cc32)C1
Temperature: 90 °C
Yield: 32.3 %

Procedure:
To a solution of (S)-1-[6-fluoro-1-(trans-3-methoxycyclobutyl)-1Hbenzoimidazol-2-yl]ethylamine (79 mg, 0.3 mmol) in IPA (1 mL) was added 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (72 mg, 0.3 mmol) and DIPEA (0.26 mL, 1.5 mmol) and the reaction mixture heated at 90° C. for 16 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford 397 as a white solid (37 mg, 32%). 1H NMR δ (DMSO-d6): 12.82 (1H, s), 8.25 (1H, s), 8.14 (1H, s), 7.92 (1H, s), 7.67-7.57 (2H, m), 7.05 (1H, td, J=9.30, 2.38 Hz), 5.86 (1H, s), 5.44-5.33 (1H, m), 4.17 (1H, t, J=6.72 Hz), 3.12 (3H, s), 3.07-2.96 (1H, m), 2.88-2.86 (1H, m), 2.56-2.45 (1H, m), 2.27-2.18 (1H, m), 1.65 (3H, d, J=6.69 Hz)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][P:9]([O:12][CH2:13][CH:14]1[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)([CH3:11])=[O:10]>ClCCl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[CH3:8][P:9]([CH3:11])(=[O:10])[O:12][CH2:13][CH:14]1[CH2:17][NH:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(COP(C)(C)=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CP(C)(=O)OCC1CNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (120 mL) was added dropwise to the product of Step 1 (80 g) in dichloromethane (120 mL) at 0° C. over a period of 30 min. The reaction mixture was stirred at room temperature for 2 h. After completion of reaction, reaction mixture was concentrated to remove excess trifluoroacetic acid under vacuum to afford azetidin-3-ylmethyl dimethylphosphinate TFA salt (90 g) as brown liquid. LC ESI: [M+H]+ m/z 164.2; HPLC purity; >97%. 1H NMR (400 MHz, CD3OD) δ: 1.62 (s, 3H), 1.65 (s, 3H), 3.23-3.27 (m, 1H), 4.02 (dd, J=7.7, 11.1 Hz, 2H), 4.11-4.19 (m, 4H).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)[C:2]([NH2:4])=[NH:3].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][O:11][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N=C(N)Nc1nc(CO)cs1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCc2csc(NC(=N)N)n2)cc1
Yield: 45.9 %

Procedure:
To a solution of 2-guanidino-4-hydroxymethylthiazole (0.69 g) in pyridine (5 ml) is gradually added 4-toluenesulfonyl chloride (0.763 g), and the resultant mixture is stirred at room temperature for 4 hours. The resultant mixture is concentrated in vacuum, and the residue is chromatographed on a column of silica gel, which is eluted with methanol. The eluate is concentrated in vacuum to give 2-guanidino-4-(4-toluenesulfonyloxymethyl)thiazole (0.6 g) as an oil. The yield is 45.8%.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1CCCCC1.C1CCN2C(=NCCC2)CC1.[CH:27]([OH:31])(CC)[CH3:28]>>[CH:3]1[CH:2]=[CH:9][C:8]2[O:31][CH2:27][CH2:28][C:6](=[O:7])[C:5]=2[CH:4]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: CCC(C)O
Solvent: C1CCNCC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCOc2ccccc21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of protected hydroxyarylketone (1.0 equiv), 4-iodobenzaldehyde (1.0 equiv), piperidine (0.35 equiv), and DBU (0.35 equiv) in s-butanol (1.0 M) was heated at reflux. Using a Dean-Stark trap, half of the solvent was removed over 30-40 min, and the reaction was kept at reflux without further concentration for additional 4-8 h. The reaction mixture was cooled to 90° C., i-propanol (0.7-1.0 fold of s-butanol v/v) was added, and the reaction was allowed to cool to room temperature. Any large pieces of material were broken down with a spatula, and the suspension was stirred overnight (Note #1 & 2). The precipitate was collected by filtration to give the corresponding chromanone.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@@H:15]([C@@H:16]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:17]([N:27]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21](F)[CH:20]=2)[CH2:14][O:13][C@@H:12]([O:50][CH2:51][C:52]([CH3:56])([CH3:55])[CH2:53][F:54])[C@@H:11]1[CH3:57])=[O:9])([CH3:6])([CH3:5])[CH3:4].O.CN1C[CH2:63][CH2:62][C:61]1=[O:65]>C(O)CC>[C:3]([O:7][C:8]([N:10]1[C@@H:15]([C@@H:16]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:17]([N:27]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([O:65][CH2:61][CH2:62][CH3:63])[CH:20]=2)[CH2:14][O:13][C@@H:12]([O:50][CH2:51][C:52]([CH3:56])([CH3:55])[CH2:53][F:54])[C@@H:11]1[CH3:57])=[O:9])([CH3:4])([CH3:6])[CH3:5]
Reactant: C[C@H]1[C@H](OCC(C)(C)CF)OC[C@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Reactant: CN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCO
Solvent: O
Product: CCCOc1cc(F)cc(C[C@@H]([C@H](OCc2ccccc2)[C@H]2CO[C@@H](OCC(C)(C)CF)[C@H](C)N2C(=O)OC(C)(C)C)N(Cc2ccccc2)Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
Stir a mixture of sodium hydride (115 mg, 2.89 mmol, 60% in mineral oil) in N-methyl-2-pyrrolidinone (960 μL) and 1-propanol (234 μL) for 10 minutes and then add a solution of (2R,3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(3-fluoro-2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (440 mg, 0.57 mmol) in N-methyl-2-pyrrolidinone (1 mL) and stir in a sealed vial at 90° C. for 4 hours. Cool to room temperature and pour reaction mixture into water and extract well with ethyl acetate. Wash the organic phase with water followed by saturated aqueous sodium chloride and concentrate under reduced pressure. Subject the resulting residue to silica gel chromatography, eluting with hexane containing from 0-50% ethyl acetate to provide the desired compound.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:29]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:30])[C:20]=2[N:19]=[C:18]1[CH2:31][CH2:32][CH2:33][CH3:34].ClCCl>N1C=CC=CC=1>[NH2:30][C:21]1[C:20]2[N:19]=[C:18]([CH2:31][CH2:32][CH2:33][CH3:34])[N:17]([CH2:16][CH2:15][CH2:14][CH2:13][NH:12][S:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:9])[C:29]=2[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
α-Toluenesulfonyl chloride (0.5 g in 10 ml dichloromethane, 2.7 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (0.75 g, 2.4 mmol), dichloromethane (115 ml), and pyridine (1 ml). The reaction was maintained at room temperature for 4 hours and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9:1 dichloromethanemethanol, Rf 0.16). The fractions containing product were combined and washed with saturated aqueous bicarbonate. The organic layer was dried (MgSO4), filtered, and concentrated. A final recrystallization from dichloromethanediethyl ether provided 0.65 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]phenylmethanesulfonamide as a white crystalline solid, m.p. 197.0-199.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.02 (d, J=7.6 Hz, 1H), 7.62 (dd, J=8.3, 1.1 Hz, 1H), 7.42 (dt, J=7.5, 1.1 Hz, 1H), 7.35-7.23 (m, 7H), 7.12 (t, J=5.4 Hz, 1H), 6.46 (broad s, 2H), 4.49 (t, J=7.5 Hz, 2H), 4.29 (s, 2H), 2.91 (m, 4H), 1.83-1.42 (m, 8H), 0.96 (t, J=7.4 Hz 3H); IR (KBr) 3460, 3293, 3226, 3158, 2955, 2931, 2867, 1632, 1586, 1534, 1482, 1437, 1389, 1331, 1152, 1094, 752, 700 cm−1; MS (EI) m/e 465.2204 (465.2198 calcd for C25H31N5O2S); Anal calcd for C25H31N5O2S: C, 64.49; H, 6.71; N, 15.04. Found: C, 64.15; H, 6.71; N, 15.00.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)=[CH:4][N:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(C#Cc2ccc(-c3cccc(F)c3)nc2)cs1
Temperature: 150 °C

Procedure:
2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (0.43 mmol, 100 mg), 3-fluorophenylboronic acid (0.47 mmol, 66 mg), dichlorobis(triphenylphosphine)palladium(II) (0.03 mmol, 18 mg), and potassium carbonate (1.72 mmol, 238 mg) were added to deoxygenated DME:water (1:1, 3 mL) at room temperature. The reaction was heated for 5 min at 150° C. via microwave irradiation, then partitioned in a separatory funnel with EtOAc (100 mL) and water (30 mL). The organic layer was washed with one additional portion of water (20 mL) and the combined aqueous layers back extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with a 10 to 40% EtOAc gradient in hexanes, to afford the title compound as a tan solid, which was dissolved in ether and precipitated as the hydrochloride salt with 1M HCl in ether. 1H-NMR (CD3OD, 500 MHz) δ 8.99 (s, 1H), 8.58 (d, 1H), 8.28 (d, 1H), 7.95 (s, 1H), 7.74 (m, 2H), 7.60 (m, 1H), 7.38 (m, 1H), 2.73 (s, 3H). MS (ESI) 295.13 (M+H+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C@H:34]([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31]>>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([NH:33][C@H:34]([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31])=[CH:10][CH:11]=2)=[CH:16][N:17]=1
Reactant: C[C@H](CO)NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Product: C[C@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and (R)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide. MS (ESI): mass calcd. for C18H19N5O3S, 385.12; m/z found, 386.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.92 (s, 2H), 8.66-8.56 (m, 1H), 8.19 (dd, J=8.0, 1.4, 1H), 7.95 (dd, J=8.2, 2.3, 1H), 7.83 (dd, J=8.2, 0.9, 1H), 7.72 (m, 1H), 7.64 (m, 1H), 7.43 (dd, J=7.5, 1.4, 1H), 3.43-3.16 (m, 4H), 1.03 (d, J=6.6, 3H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1)=[N+]=[N-].C(N(CC)CC)C.[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>CO.[Pd]>[C:26]([O:25][C:23]([NH:1][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1)=[O:22])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])nc1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)nc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a degassed solution of methyl 6-(azidomethyl)nicotinate from Example G2 (1.6 g, 8.30 mmol) in methanol (50 ml) was added 10% palladium-on-carbon (0.15 g). Hydrogen gas was bubbled through the mixture for 2 h at room temperature. The catalyst was removed by filtration through a pad of celite and the filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane and cooled to 0° C. To this solution were added triethylamine (1.67 g, 16.0 mmol) and (BOC)2O (2.17 g, 9.96 mmol). The mixture was allowed to warm to room temperature and stirred for 18 h, then concentrated in vacuo. The residue was dissolved in EtOAc and washed with water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 50:50) to give a yellow solid; yield 1.57 g (71%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][NH2:14])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:21]=1.[Cl:24][CH2:25][C:26](=O)[CH2:27][CH2:28][Cl:29]>O1CCCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][N:14]=[C:26]([CH2:27][CH2:28][Cl:29])[CH2:25][Cl:24])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Reactant: O=C(CCl)CCCl
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2c(c1)C(c1ccccc1)=NCC(NN=C(CCl)CCCl)=N2

Procedure:
In the manner given in Example 1, 7-(trifluoromethyl)-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1,4-dichloro-2-butanone under nitrogen to give 7-(trifluoromethyl)-2-[[2-chloro-1-(2-chloroethyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[C@H:7]([CH2:22][CH:23]=[CH2:24])[CH2:6][C:5]=2[CH:4]=1.[F:25][C:26]([F:52])([C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])[CH2:27][CH2:28][CH:29]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]C=C)[C:30]([O:32]CC)=[O:31]>>[OH:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[C@H:7]([CH2:6][CH2:5][CH2:4][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH:29]([CH2:28][CH2:27][C:26]([F:25])([F:52])[C:42]([F:50])([F:51])[C:43]([F:48])([F:49])[C:44]([F:45])([F:47])[F:46])[C:30]([OH:32])=[O:31])[CH2:22][C:23]=2[CH:24]=1
Reactant: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O)[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
Starting with the 3-methoxy-7α-(2-propenyl)estra-1,3,5(10)-trien-17β-ol prepared in Example 13 and ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared separately, the same procedure as shown in Example 13 was repeated to give 10-[3,17β-dihydroxyestra-1,3,5(10)-trien-7α-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][NH2:16].C([O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=O)=O)C>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=2[C:20](=[O:19])[NH:16]1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: NNc1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CC(=O)O
Product: O=c1[nH]n(-c2cc(OC3CCCC3)c(Cl)cc2F)c2c1CCCC2
Reaction time: 2 h
Yield: 72.1 %

Procedure:
2-Fluoro-4-chloro-5-cyclopentyloxyphenylhydrazine (24.5 g, 0.10 mol), 2-ethoxycarbonylcyclohexanone (17.0 g, 0.10 mol) were dissolved in acetic acid (200 ml), and stirred for 2 hours while heating under refluxing. After completion of the reaction, the solvent was distilled off to obtain a crude product (37 g). The product was washed with a mixed solvent of benzene/hexane to obtain 2N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one as a white solid (25.3 g, 72.3% yield)
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH2:22])=[O:21])[C:3]1=[O:23].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33](ON1C(=O)CCC1=O)=[O:34]>CN(C)C=O>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33]([NH:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([NH2:22])=[O:21])[C:3]1=[O:23])=[O:34]
Reactant: O=C(ON1C(=O)CCC1=O)c1cc2ccccc2[nH]1
Reactant: NC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Cc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)[C@H](c2ccccc2)Cc2ccccc21
Yield: 68.4 %

Procedure:
In 5 ml of dimethylformamide are dissolved 0.2 g of trans-3-amino-2-oxo-4-phenyl 2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetamide and 0.18 g of succinimido 2-indolecarboxylate, and the same reaction and treatment as in Example 12 is carried out to give 0.2 g of trans-3-(2-indolecarboxamido)-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetamide, m.p. 280°-283° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([OH:26])[CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22]C(=O)C)[CH2:8]2)=[CH:4][CH:3]=1.[ClH:29]>CO.C(OCC)C>[ClH:1].[ClH:29].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][CH:13]([OH:26])[CH2:12][N:9]1[CH2:10][CH2:11][CH:7]([O:6][C:5]2[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:8]1
Reactant: CC(=O)Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)cc2)C1
Temperature: 102.5 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A mixture of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)acetamide (0.95 g, 2.34 mmol) and concentrated hydrochloric acid (25 mL) was heated (100-105° C.) for 3 hours then allowed to stand at room temperature overnight. The mixture was concentrated at reduced pressure to a third of its volume basified with saturated sodium hydrogen carbonate. The resulting suspension was extracted twice with ethyl acetate. The organic extracts were dried, the solvent was evaporated at reduced pressure to give a pale brown oil. This oil was dissolved in a minimum amount of methanol, diluted with ethyl ether and the product precipitated by addition of HCl-saturated ethyl ether. The product was filtered to afford the subtitle product (0.93 g, 91.2%).