Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]C1C=CC(B(O)O)=CC=1>>[Cl:21][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccc(Cl)cc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 4-chlorophenylboronic acid (195 mg, 1.24 mmol) were coupled to yield 2-(4-chloro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 223 mg (66%) as an off-white solid: m.p. 250-252° C.; 1H NMR (300 MHz, d6-DMSO) δ3.04 (m, 2H), 3.39 (m, 2H), 7.23 (app t, J=7.5 Hz, 1H), 7.58 (m, 3H), 7.68 (m, 3H), 8.10 (br t, 1H), 11.66 (br s, 1H). MS (FAB, MH+) 297. Anal. (C17H13ClN2O.0.8 H2O) C, H, N.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:30])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([CH:23]=[C:24]3[CH2:27]C(C#N)[CH2:25]3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:5]1([NH:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][CH:43]([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:42][CH2:41]1)[CH2:4][CH2:3]2.[OH-:50].[K+].[CH2:52]([OH:54])[CH3:53]>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:30])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([CH:23]=[C:24]3[CH2:27][CH:53]([C:52]([OH:50])=[O:54])[CH2:25]3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:5]1([NH:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][CH:43]([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:42][CH2:41]1)[CH2:4][CH2:3]2
Reactant: [OH-]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=C6CC(C#N)C6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCO
Agent: [K+]
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=C6CC(C(=O)O)C6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 76 °C
Reaction time: 7 h
Yield: 29.2 %

Procedure:
To a solution of 3-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)methylene)cyclobutanecarbonitrile (30 mg, 0.043 mmol) in ethanol (2 mL) was added potassium hydroxide (1 mL, 0.043 mmol). A white precipitate was formed. The mixture became clear after warming up to 76° C. The reaction solution was stirred at 76° C. for 7 h. The crude product was purified without further work up by prep HPLC (method 4) to give 3-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)methylene)cyclobutanecarboxylic acid as a white solid (9 mg, 29.2%). MS: m/e 709.55 (M+H)+, 2.54 min (method 4). 1H NMR (400 MHz, METHANOL-d4) δ 5.72 (br. s., 1H), 5.38 (d, J=5.5 Hz, 1H), 4.78 (s, 1H), 4.68 (s, 1H), 3.28-2.75 (m, 14H), 2.96 (s, 3H), 2.65-2.52 (m, 1H), 2.42-2.27 (m, 1H), 2.23-1.80 (m, 11H), 1.75 (s, 3H), 1.69-1.27 (m, 14H), 1.22 (s, 3H), 1.10 (br. s., 3H), 1.01 (br. s., 3H), 0.96-0.93 (m, 3H), 0.90-0.87 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[NH:19][CH2:18][CH:15]1[CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:17]=2[O:16]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(-c2cccc3c2OC(CN)C3)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)cc1
Yield: 84.6 %

Procedure:
Treatment of 1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.727 g, 2.49 mmol) with diisopropylethylamine (0.483 g, 3.73) and benzyl chloroformate (0.510 g, 2.99 mmol) generally according to the procedure described for Intermediate 12 provided 0.820 g of (±)-benzyl[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil. Rf=0.48 (silica, ethyl acetate:hexanes 1:5); Anal. calcd. for C24H23NO4: C, 74.02; H, 5.95; N, 3.60. Found: C, 73.66H, 6.13; N, 3.42. Chiral HPLC separation of (±)-benzyl[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel AD, methanol) provided two fractions. Fraction 1 (Rt=7.386 min, Chiralcel AD, methanol); Fraction 2 (Rt=10.882 min, Chiralcel AD, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[N+:14]([O-:16])=[O:15].Cl.[CH3:18][NH:19][O:20][CH3:21].N1C=CC=CC=1.O>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([N:19]([O:20][CH3:21])[CH3:18])=[O:13])=[C:7]2[N+:14]([O-:16])=[O:15]
Reactant: CNOC
Reactant: O=C(O)c1[nH]c2c(Cl)cccc2c1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1[nH]c2c(Cl)cccc2c1[N+](=O)[O-]
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A solution of 7-chloro-3-nitroindole-2-carboxylic acid (step 1, 400 mg, 1.7 mmol) in thionyl chloride (2 ml) was heated at 70° C. for 3 h, the mixture cooled and concentrated. The residue was dissolved in dichloromethane (20 ml). To the solution was added N,O-dimethylhydroxylamine hydrochloride (326 mg, 3.4 mmol) and pyridine (0.27 ml, 3.4 mmol). After stirring for 16 h, the mixture was poured into water (100 ml) and extracted with ethyl acetate (200 ml). The organic layer was washed with 2N aqueous HCl (100 ml), water (100 ml), saturated aqueous sodium bicabonate (100 ml), brine (100 ml), and dried (MgSO4). After removal of solvent, the residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1:10˜1:1) to give 420 mg (87%) of the title compound. tlc: Rf=0.55 (25% ethyl acetate in hexanes)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.C(=O)([O-])[O-].[Ca+2].[I:18](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[NH2:1][C:2]1[C:11]([I:18])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=I(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(I)c(N)cc1Cl
Reaction time: 18 h

Procedure:
A solution of methyl 4-amino-2-chloro-benzoate (1.14 g, 6.16 mmol) in dichloromethane (30 mL) and methanol (15 mL) was treated sequentially with calcium carbonate (1.85 g, 18.5 mmol) and benzyl trimethylammonium dichloroiodate (3.22 g, 9.24 mmol), stirred for 18 hours, treated with additional benzyl trimethylammonium dichloroiodate (2 g, 5.75 mmol), stirred for 3 days, filtered into a separatory funnel, washed with saturated NaHSO3, dried (MgSO4), filtered, and concentrated. The concentrate was recrystallized from ethyl acetate to provide the majority of the desired product. The filtrate was concentrated, and the concentrate was purified on silica gel with a gradient of from 10% to 20% ethyl acetate/hexanes to provide a total of 1.3 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:23][C:13]2=[C:14]3[C:19](=[CH:20][CH:21]=[C:12]2[CH2:11]1)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:24]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:23][C:13]2=[C:14]3[C:19](=[C:20]([I:24])[CH:21]=[C:12]2[CH2:11]1)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)NCC1Cc2ccc3[nH]c(=O)ccc3c2O1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1Cc2cc(I)c3[nH]c(=O)ccc3c2O1
Reaction time: 2 h
Yield: 73.2 %

Procedure:
2-(t-Butoxycarbonyl)aminomethyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (882 mg) and N-iodosuccinimide (756 mg) were dissolved in a solvent mixture (44 ml) of chloroform-methanol (5:1). After refluxing for 2.5 hours with heat, N-iodosuccinimide (756 mg) was added to the mixture, followed by further 2 hour refluxing with heat. Further, N-iodosuccinimide (400 mg) was added to the mixture, which was then refluxed for 1.5 hours with heat. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent=chloroform:methanol=200:1) to obtain 903 mg of 2-(t-butoxycarbonyl)aminomethyl-5-iodo -2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (73.2%). This compound was recrystallized from a solvent mixture of chloroform-n-hexane to obtain pale yellow powdery crystals (mp.: 173°-174° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:21](C([O-])=O)[C:22]([O-:24])=O)([O-])=O.Cl>CCO.C(Cl)(Cl)Cl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([C:8]2[CH:9]=[C:4]3[C:5]([CH2:21][C:22](=[O:24])[NH:1]3)=[CH:6][CH:7]=2)=[O:20])=[CH:12][CH:13]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(C(C(=O)[O-])C(=O)[O-])c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Temperature: 25 °C
Yield: 51 %

Procedure:
[2-Nitro-4-(4-nitrobenzoyl)phenyl]malonate (4.15 g, 9.61 mmol) was dissolved in EtOH (24 mL) after which Sn powder (9.16 g, 77 mmol) was added followed by dropwise addition of concentrated HCl(aq) (26 mL). The reaction mixture was allowed to reflux for 3 hours, filtered while hot and then allowed to cool to room temperature. The cooled reaction mixture was diluted with CHCl3 (400 mL) and then extracted once with H2O (400 mL). The aqueous layer was then neutralized with NaHCO3 (pH=7) and then extracted with a 95% EtOAc/5% i-prOH solution (3×400 mL). The organic layers were combined and dried over anhydrous Na2SO4. The solution was then concentrated in vacuo affording the 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one in 51% yield (1.24 g, 4.90 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH2:16])[CH:10]=2)[O:3]1.[CH2:18]([Zn]CC)C.ICI.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH:15]1([C:11]2[CH:10]=[C:9]([B:4]3[O:3][C:2]([CH3:17])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:14]=[CH:13][CH:12]=2)[CH2:18][CH2:16]1
Reactant: CC[Zn]CC
Reactant: C=Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2cccc(C3CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 4,4,5,5-tetramethyl-2-(3-vinyl-phenyl)-[1,3,2]dioxaborolane (300 mg, 1.3 mmol) in toluene (10 ml) were added diethylzinc solution (1.1 N in toluene, 5.22 ml, 5.74 mmol) and diiodomethane (8.7 ml, 33 mmol). The reaction mixture was stirred for 1 hour at room temperature and then refluxed for 3 hours. The reaction mixture was poured on sat. NH4Cl solution (20 ml) and was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide 2-(3-cyclopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (69% yield), 1H-NMR (300 MHz, CDCl3): δ=7.12-7.82 (m, 4H), 1.35 (s, 12H), 1.28 (t, 1H), 0.90-0.96 (m, 2H), 0.72-0.78 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH2:21][C@@H:20]2[C@:7]([CH3:27])([CH2:8][CH2:9][C@H:10]3[C@H:19]2[CH2:18][CH:17]=[C:16]2[C@:11]3([CH3:26])[CH2:12][CH2:13][C@H:14]([O:22][C:23](=[O:25])[CH3:24])[CH2:15]2)[C:3]=1[C:4](=O)[CH3:5].Cl.[NH2:29][OH:30].O>C(O)C.N1C=CC=CC=1>[CH3:1][C:2]1[CH2:21][C@@H:20]2[C@:7]([CH3:27])([CH2:8][CH2:9][C@H:10]3[C@H:19]2[CH2:18][CH:17]=[C:16]2[C@:11]3([CH3:26])[CH2:12][CH2:13][CH:14]([O:22][C:23](=[O:25])[CH3:24])[CH2:15]2)[C:3]=1[C:4](=[N:29][OH:30])[CH3:5]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=C(C)C[C@@H]32)C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=NO)=C(C)C[C@@H]32)C1

Procedure:
A solution of 16-methyl-3β-acetoxy-5,16-pregnadien-20-one (3.70 g, 10 mmoles) was refluxed in a mixture of ethanol (100 ml) and pyridine (10 ml) containing 3.50 g (50 mmoles) of hydroxylamine hydrochloride for one hour. The reaction mixture was added to water and the crude product was filtered and washed with water. Solution in methylene chloride, filtration through anhydrous sodium sulfate, and concentration to dryness in vacuo gave the crude oxime.
Reaction SMILES: [CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:35])[CH2:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][Br:33])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Br-:33].[CH2:1]([NH:19][C:20]([O:22][CH2:23][C:24](=[CH2:35])[CH2:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N+:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=C(COC(=O)CCCCCBr)COC(=O)NCCCCCCCCCCCCCCCCCC
Reactant: c1ccncc1
Product: C=C(COC(=O)CCCCC[n+]1ccccc1)COC(=O)NCCCCCCCCCCCCCCCCCC
Product: [Br-]
Temperature: 60 °C

Procedure:
1-Octadecylaminocarbonyloxy-3-(6-bromohexanoyloxy)-2-methylenepropane (from Preparation 9) (0.84 g) was dissolved in dry pyridine (20 ml) and heated to 60° C. for 22 hours. Excess pyridine was removed in vacuo.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])=[O:24])[C:5]1=[O:32].C(N([CH:39]([CH3:41])C)CC)(C)C.CN(C=[O:46])C>>[C:39]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])=[O:24])[C:5]1=[O:32])(=[O:46])[CH3:41]
Reactant: CN(C)C=O
Reactant: NCCn1c(=O)c(C(=O)NCCOCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CCN(C(C)C)C(C)C
Product: CC(=O)NCCn1c(=O)c(C(=O)NCCOCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[(2-hydroxyethyl)oxy]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.057 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (3 mL) under nitrogen was treated with N,N-dimethyl carbonyl chloride (0.06 mL, 0.63 mmol) (40° C. After 2½ h the reaction was cooled, concentrated in vacuo, and the resulting residue treated with 1N NaHSO4. Extracted the mixture 3× with EtOAc and concentrated the organics. The residue was then purified on silica gel by prep TLC (9:1 CH2Cl2:MeOH). Pure bands were collected to provide the title compound as an off-white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.98 (s, 3 H), 3.46-3.54 (m, 2 H), 3.68 (d, J=4.76 Hz, 2 H), 3.71 (s, 4 H), 3.77-3.88 (m, 2 H), 4.17 (s, 2 H), 4.36 (t, J=7.23 Hz, 2 H), 5.31 (s, 1 H), 6.14 (s, 1 H), 7.02 (t, J=8.79 Hz, 2 H), 7.22-7.25 (m, 2 H), 8.07 (s, 1 H), 8.58 (s, 1 H), 10.51 (s, 1 H); ES+ MS: 487 (M+H+).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15](=O)[CH3:16])[CH2:10][C@H:9]1[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:7].Cl.Cl.[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][O:43][NH2:44].C([O-])(=O)C.[Na+]>CO>[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][O:43][N:44]=[C:15]([CH3:16])[CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=2)[C@H:9]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:10]1
Reactant: CN(C)CCON
Reactant: CC(=O)CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)=NOCCN(C)C
Yield: 104 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-propanon-1-yl)piperazine (255 mg), O-[2-(dimethylamino)ethyl]hydroxylamine dihydrochloride (89 mg), sodium acetate (catalytically), and methanol (10 mL) was heated under reflux for 2 h. The solvent was removed in vacuo, and the residue was treated with dichloromethane and NAOH (aq, 2N). The layers were separated, the organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH4OH 92/7.5/0.5) to afford 1-{(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone O-[2-(dimethylamino)-ethyl]oxime 0.31 g (>95%) as an E/Z mixture. Rf 0.26 (CH2Cl2/MeOH/NH4OH 92/7.5/0.5).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1Cl
Reactant: c1cn[nH]c1
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(C)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCNCCC
Reactant: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)[C@@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 30.7 %

Procedure:
A solution of (R)-2-(4Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole). 1,1'-carbonyldiimidazole (2.69 g, 0.0166 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 2.25 hours with nitrogen bubbling through it. A solution of dipropylamine (5.04 g, 0.050 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was refluxed under nitrogen for two days. The solvents were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was washed twice with water, twice with a 5% potassium hydroxide solution, and twice again with water. It was then dried over magnesium sulfate, charcoaled, filtered, and evaporated to an oil which crystallized upon trituration with isopropyl ether. The solid was collected by filtration and dried under high vacuum at 50° C. overnight to give 1.96 g (31%) of title compound, mp 95°-97° C.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH:8]1([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:24])=[C:18]([F:23])[C:19]=3[O:21][CH3:22])[C:14](=[O:25])[C:13]([C:26]([OH:28])=[O:27])=[CH:12]2)[CH2:10][CH2:9]1.[C:29]1([CH2:35]Cl)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.O>[CH2:35]([O:27][C:26]([C:13]1[C:14](=[O:25])[C:15]2[C:20](=[C:19]([O:21][CH3:22])[C:18]([F:23])=[C:17]([F:24])[CH:16]=2)[N:11]([CH:8]2[CH2:9][CH2:10]2)[CH:12]=1)=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClCc1ccccc1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COc1c(F)c(F)cc2c(=O)c(C(=O)OCc3ccccc3)cn(C3CC3)c12
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
NaH (2.6 g, 0.065 mol) was suspended and dissolved into DMF (dimethylformamide; 25 ml) and the reaction solution was stirred for about 10 minutes. A DMF solution (100 ml) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (I) (14 g, 0.047 mol) was slowly dropped therein. After the completion of adding, the reaction mixture was stirred at room temperature for about 10 minutes and further PhCH2Cl (benzylchloride; 6.0 ml, 0.052 mol) was dropped therein. The reaction mixture was heated on an oil bath at 100° C. for 6 hours. After the completion of heating, the reaction mixture was poured into water (500 ml) slowly to separate crystals. Separated crystals were washed with water three times and then with MeOH to obtain 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid benzyl ester (II) (13.6 g, yield: 74%).
Reaction SMILES: O[CH2:2][C@@H:3]([NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].CS(Cl)(=O)=O.CCN(CC)CC.S([O-])(=O)(=O)C>C(Cl)Cl.COCCOC>[C:9]([N@@:8]1[CH2:2][CH:3]1[C:4]([O:6][CH3:7])=[O:5])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)C1C[N@]1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
(S. Kato et al., J. Chem. Soc., Perkin Trans. 1997, 1, 3219-3225; J. Smrt et al., Experientia 1957, 15, 291). Crude (R)-methyl 3-hydroxy-2-(N-tritylamino)propanoate (45.20 g, 0.13 mol) was dissolved in CH2Cl2 (300 mL) and cooled to 0° C. under Ar. Methanesulfonyl chloride (10.64 mL, 0.14 mol) was added to the cooled solution, followed by the dropwise addition of Et3N (26.14 mL, 0.19 mol). The resulting solution was allowed to stir at 0° C. (30 min) and then successively washed with 10% aqueous citric acid (200 mL) and saturated aqueous brine (200 mL). After drying (Na2SO4) and evaporation of the solvent, the crude mesylate (53.30 g, 0.12 mol) was dissolved in DME (300 mL) and Et3N (33.73 mL, 0.24 mol) was added. The reaction mixture was stirred at 80° C. (48 h) and then evaporated in vacuo. The residue was dissolved in EtOAc (300 mL) and washed with 10% aqueous citric acid (200 mL) and saturated aqueous brine (200 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo. The crude product was recrystallized (EtOH) to yield 30.81 g (74%) of desired product as a transparent crystal: mp 127-128° C. (Kato, S. et al., J. Chem. Soc., Perkin Trans. 1997, 1, 3219-3225; mp 129-131° C.); [α]20D +94.7° (c 1.5, CHCl3) (Smrt, J. et al., Experientia 1957, 15, 291; [α]20D +95 (c 1, CHCl3)); Rf=0.45 (1/5 EtOAc/hexanes); 1H NMR (CDCl3) δ 1.41 (dd, J=1.7, 6.4 Hz, NCHH′CH), 1.89 (dd, J=2.8, 6.4 Hz, CHH′CHN), 2.26 (dd, J=1.7, 2.8 Hz, NCHH′CH), 3.76 (s, OCH3), 7.20-7.31 (m, 9 PhH), 7.48-7.52 (m, 6 PhH); 13C NMR (CDCl3) δ 28.8 (NCH2CH), 31.8 (CH2CHN), 52.2 (OCH3), 74.5 (NCPh3), 127.1, 127.8, 129.4, 143.7 (3 C6H5), 172.0 (C(O)).