Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([S:6]([OH:9])(=[O:8])=[O:7])[C:3]1=[O:10].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+:25]>O.O1CCCC1>[C:11]1([CH2:17][C:18]([NH:1][CH:2]2[CH2:5][N:4]([S:6]([O-:9])(=[O:8])=[O:7])[C:3]2=[O:10])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+:25]
Reactant: NC1CN(S(=O)(=O)O)C1=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC1CN(S(=O)(=O)[O-])C1=O
Yield: 45.6 %

Procedure:
In 1 ml of water is dissolved 50 mg of the above 3-amino 2-oxoazetidine-1-sulfonic acid, followed by addition of a solution of 69 mg phenylacetyl chloride in 1 ml tetrahydrofuran and 101 mg of sodium hydrogen carbonate in alternate portions with ice-cooling and stirring. After stirring at room temperature for 30 minutes, the mixture is adjusted to pH 5.8 with phospheric acid. The tetrahydrofuran is then distilled off under reduced pressure. The water layer is washed with ethyl acetate and purified by XAD-II chromatography, whereby 42 mg of sodium 3-phenylacetamido-2-oxoazetidine-1-sulfonate is obtained.
Reaction SMILES: CO[CH2:3][NH:4][CH2:5][CH2:6][C@@H:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[OH:8]>CO.[Ni]>[CH3:3][NH:4][CH2:5][CH2:6][C@@H:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[OH:8]
Reactant: COCNCC[C@H](O)c1cccs1
Agent: [Ni]
Solvent: CO
Product: CNCC[C@H](O)c1cccs1

Procedure:
(S)-3-methoxymethylamino-1-(2-thienyl)propan-1-ol obtained in example 2 was dissolved in 10 ml of methanol with 8 mg of Raney-nickel. The resulting solution was provided in a glass autoclave and hydrogenated at 50° C. for 12 hours. Upon completion of hydrogenation, the reaction mixture was filtered and the solvent was removed under reduced pressure to obtain the objective compound as a crystal compound (122 mg, 95% ee; purity; 90.8% by HPLC assay). The crude product was further purified by re-crystallization in toluene to give a product with optical purity as high as 100% ee.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[S:13]([O-:16])([OH:15])=[O:14].[Na+:17].C(O)C>O>[F:10][C:9]([F:12])([F:11])[C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([S:13]([O-:16])(=[O:15])=[O:14])=[N:3][CH:4]=1.[Na+:17]
Reactant: O=S([O-])O
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])c1ncc(C(F)(F)F)cc1Cl
Yield: 103 %

Procedure:
In a flask, 2,3-dichloro-5-(trifluoromethyl)pyridine (10.8 g, 50 mmol), sodium hydrogen sulfite (20.8 g, 200 mmol), ethanol (100 ml) and water (100 ml) were charged and heated under reflux for 41 hours. After evaporating off the solvent from the reaction mixture, conc. hydrochloric acid was added to the residue and then evaporated to dryness. This residue was extracted with methanol, and the metanol phase was filtered and evaporated to dryness to obtain quantitatively sodium 5-trifluoromethyl-3-chloropyridine-2-sulfonate (14.6 g). Decomposition point, 322°-334° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:19]=[CH:18][N:8]([C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:7](=[O:20])[N:6]=1)(=[O:3])[CH3:2].[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([NH:4][C:5]1[CH:19]=[CH:18][N:8]([C@@H:9]2[O:17][C@H:14]([CH2:15][O:16][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@@H:12]([OH:13])[C@H:10]2[OH:11])[C:7](=[O:20])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(=O)Nc1ccn([C@@H]2O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 36 h
Yield: 79.8 %

Procedure:
N-Acetylcytidine (see D. M. Brown et al., J. Chem. Soc. 1956, 2384) (1.000 g, 3.5057 mmol), trityl chloride (1.0751 g, 3.8563 mmol) and a small stirring bar were placed in a dry round-bottomed flask fused onto a reflux condenser. The flask was closed with a septum and flushed with argon. Pyridine (10.2 mL) was injected and the mixture was stirred at room temperature for 36 h. The mixture was evaporated, diluted with CH2Cl2, and again evaporated. The gummy residue was washed with water and the residue was dissolved in acetone. The solution was dried (MgSO4) and evaporated. Flash chromatography of the residue over silica gel (4.5×30 cm), using 7% MeOH in CH2Cl2, gave the product (1.4752 g, 80%). (Cf. H. U. Blank et al., Justus Liebigs Ann. Chem. 1970, 742, 16).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>ClCCl>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[S:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22])[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(N)=O)cc1Sc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
A mixture of 4-amino-3-(2,4-difluorophenylthio)benzamide (0.82 g), methanesulfonyl chloride (0.64 g) and triethylamine (0.6 g) in dichloromethane (10 ml) was stirred for 2 hours at room temperature. The reaction mixture was evaporated. To the residue were added methanol (10 ml) and potassium hydroxide (0.6 g). The mixture was kept overnight and evporated. The residue was treated with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue obtained was recrystallized from ethanol to give 3-(2,4-difluorophenylthio)-4-(methanesulfonamido)benzamide (0.54 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CC(O)C>>[C:4]1([C@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: CC(C)O
Product: C[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.1 %

Procedure:
To the reaction solution obtained in (3) were added acetophenone (0.56 ml, 4.81 mmol) and 2-propanol (9.4 ml, 121 mmol), and the mixture was stirred at 25° C. for 24 hours. The reaction mixture was purified by means of Kugelrohr distillation to give (R)-1-phenylethanol (0.541 g, 92% yield). The asymmetric yield of the product was measured in a HPLC using a CHIRALCEL OD column (4.6×250 mm, Daicel Chemical Industries Ltd) and found to be not less than 99% e.e. In the table below, the results obtained by using a metal-ligand complex 4 (described on page 9800 of J. Am. Chem. Soc. 1993, 115, 9800-9801 and hereinafter referred to as the comparative compound) are also given for comparison.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:30][C:31]1([CH2:34][O:35][CH3:36])[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]2([CH2:34][O:35][CH3:36])[CH2:33][CH2:32]2)=[CH:4][CH:3]=1
Reactant: COCC1(CBr)CC1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: COCC1(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)CC1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with 1-bromomethyl-1-methoxymethyl-cyclopropane (described in WO 2001032633) gave the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.N>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@H:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[NH:17][CH:18]=[CH:19]4)=[CH:7][N:6]=1)[CH2:10]2
Reactant: Brc1cnc(O[C@@H]2CN3CCC2CC3)nc1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: N
Product: c1cc2cc(-c3cnc(O[C@@H]4CN5CCC4CC5)nc3)ccc2[nH]1

Procedure:
The product of Example 13E (283 mg, 1 mmol) was coupled with 5-indolylboronic acid (193 mg, 1.2 mmol) according to the procedure of Example 3A, The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (120 mg, yield, 38%). 1H NMR (300 MHz, CD3OD) δ 1.50-1.63 (m, 1H), 1.66-1.92 (m, 2H), 2.03-2.18 (m, 1H), 2.24-2.32 (m, 1H), 2.75-3.07 (m, 5H), 3.38-3.49 (m, 1H), 5.13-5.21 (m, 1H), 6.53 (dd, J=3.0, 0.7 Hz, 1H), 7.30 (d, J=3.4 Hz, 1H), 7.35 (dd, J=8.5, 1.7 Hz, 1H), 7.51 (dt, J=9.2, 0.7 Hz, 1H), 7.80 (dd, J=1.7, 0.7 Hz, 1H), 8.81 (s, 2H) ppm. MS (DCI/NH3): m/z 321 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].Br[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][OH:40])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][OH:40])=[CH:34][CH:33]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:30])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:29])(=[O:28])[CH3:27]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: OCCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)N1c2ccc(-c3ccc(CCO)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 31 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (136. mg, 0.327 mmol), 2-(4-bromophenyl)ethanol (79 mg, 0.392 mmol), potassium carbonate (113 mg, 0.817 mmol) and tetrakis(triphenylphosphine)palladium(0) (18.87 mg, 0.016 mmol) was degassed under house vacuum for 15 min and quenched several times with nitrogen, then was then stirred at 100° C. under nitrogen for 50 min before being cooled to room temperature. Most of the solvent was removed in vacuo and the residue was partitioned between AcOEt (20 mL) and water (15 mL). The layers were separated and the aqueous phase was extracted with AcOEt (15 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 50 to 80% AcOEt in Hexanes) gave a residue which was further purified by MDAP (modifier ammonium formate) to give 1-methylethyl {(2S,4R)-1-acetyl-6-[4-(2-hydroxyethyl)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (42 mg, 0.102 mmol, 31%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[C:46]([NH2:47])=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:47][C:46]1[CH:45]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:43]=[N:42][C:41]=1[O:40][CH3:39]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ncc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1N
Yield: 58.1 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (101 mg, 0.4 mmol), sodium carbonate (43 mg, 0.41 mmols) and bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.02 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 63 mg (59% yield) of the title compound. Purity 100%.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:19]=1)(C)(C)C>C(Cl)Cl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][C:18]2[N:19]=[C:15]([NH2:14])[S:16][CH:17]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(CCOc2ccc(F)cc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(CCOc2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
TFA (12 ml) was added to a solution of {4-[2-(4-Fluoro-phenoxy)-ethyl]-thiazol-2-yl}-carbamic acid tert-butyl ester (2.55 g, 7.5 mmol) in DCM (100 ml) at 0° C. and stirred at r.t. for 4 h. The reaction was quenched with saturated aqueous NaHCO3 solution (15 ml) and extracted in DCM, dried over Na2SO4, evaporated under reduced pressure to yield 4-[2-(4-Fluoro-phenoxy)-ethyl]-thiazol-2-ylamine (1.55 g, 86%). 1H NMR (400 MHz, CDCl3): δ 3.0 (t, J=6.8 Hz, 2H), 4.20 (t, J=6.8 Hz, 2H), 4.88 (brs, 2H), 6.26 (s, 1H), 6.83-6.86 (m, 2H), 6.94-6.98 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=2[CH:24]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=2[CH:24]=1)[CH3:2]
Reactant: CCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)O)CCS2(=O)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 73.5 %

Procedure:
Into a solution of methyl 7-[(2-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (220 mg) in THF-methanol (5-2.5 ml) was added at room temperature an aqueous solution (1.0 ml) of potassium carbonate (151 mg), and the resulting mixture was stirred at 60° C. for 20 hours. After cooling to room temperature, the reaction mixture was mixed with 1 N hydrochloric acid (10 ml) and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[(2-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (156 mg) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[O:33]1[CH2:36][C:35](=O)[CH2:34]1>>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([CH:35]5[CH2:36][O:33][CH2:34]5)[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: O=C1COC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C4COC4)C3)n(C)c2n1

Procedure:
Following General Procedure L for reductive amination 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine 530 and 3-oxetanone were reacted to give 529. LCMS m/z: 489.2 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH2:14][CH2:13][CH2:12][C:11]=1[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:9].N[C:21]1C=CC=C[CH:22]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH2:14][CH2:13][CH2:12][C:11]=1[NH:15][C:19]1[CH:18]=[CH:17][CH:16]=[CH:22][CH:21]=1)=[O:9]
Reactant: O=C(C1=C(N2CCCC2)CCC1)c1ccccc1Br
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(C1=C(Nc2ccccc2)CCC1)c1ccccc1Br

Procedure:
Reflux a solution of (2-bromophenyl)[2-(1-pyrrolidinyl)-1-cyclopenten-1-yl]-methanone (14.1 g) (from Preparative Example 1) in benzene (100 ml) containing aniline (4.5 ml) and p-toluenesulfonic acid monohydrate (8.8 g) for 19 hrs. Remove water continuously with a Dean-Stark trap. Wash the cooled solution with water, 1M NaHCO3 solution, and with water. Dry the benzene solution, filter it, and evaporate the solvent. Crystallize to obtain (2-bromophenyl)[2-(phenylamino)-1-cyclopenten-1-yl]-methanone, m.p. 106.5°-108.5° from CH3CN.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[O:25])[C:21](O)=[O:22]>>[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=1)=[O:25])[C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CC(C(=O)O)C(=O)NCc1cccc(C(F)(F)F)c1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CC(C(=O)NCc1cccc(C(F)(F)F)c1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=496.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(3-trifluoromethyl-benzyl)-malonamic acid.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.[CH2:21](O)[CH2:22][CH3:23].S(=O)(=O)(O)O>CCOCC>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19])=[CH:16][C:3]1=2
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CCCO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCOC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2

Procedure:
A mixture of 7.0 g of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid, Example 2, 175 ml of n-propanol, and 4.6 ml of concentrated sulfuric acid is refluxed for 17 hours. The reaction mixture is permitted to cool and the solvent removed leaving an oil. The oil is dissolved in ether and washed successively with water, a 5% sodium hydroxide solution and water and dried and the ether removed to give a yellow oil which crystallizes upon standing. The solid is dried on a porous plate resulting in an off-white solid, mp 30°-32° C, of n-propyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.ClCCl.[CH3:34][NH:35][CH2:36][C:37]#[CH:38]>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.[Cu]I.CCN(CC)CC>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:38]=[C:37]([CH2:36][NH:35][CH3:34])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#CCNC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNCc1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 240 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (35 mg), and CuI (12 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (5 mL), Et3N (0.15 mL), and N-methylpropargylamine (0.055 mL). The reaction is stirred at room temperature for 10 days. The reaction is concentrated under reduced pressure, treated with ethanol (5 mL) and heated to 70° C. for 2 days. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed eluting with 2% to 10% methanol in dichloromethane. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid which is crystallized from acetonitrile. The crystals are treated with hydrochloric acid (2 mL, 4 N in dioxane). The suspension is diluted with methanol and concentrated under reduced pressure. The residue is triturated with small volumes of methanol-toluene, methanol-ether, toluene, and ether. The solid is treated with dichloromethane and partitioned against saturated aqueous sodium carbonate. The basic aqueous layer is extracted with two additional portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 0.09 g of the title compound as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([C:8](O)(O)[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]([CH:8]([N:23]=[CH:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1
Reactant: Cc1cc(C(O)(O)C(F)(F)F)ncc1Br
Reactant: COc1ccc(CN)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(C=NC(c2cc(C)c(Br)cn2)C(F)(F)F)cc1
Temperature: 110 °C
Yield: 74.4 %

Procedure:
A solution of 1-(5-bromo-4-methylpyridin-2-yl)-2,2,2-trifluoroethane-1,1-diol (163.1 mg; 0.5702 mmol) in 2.0 mL toluene was added at room temperature to a solution of 4-methoxybenzylamine (118 μL; 0.858 mmol) and acetic acid (49 μL; 0.854 mmol) in 2.0 mL toluene. A scoop of oven-dried 3A molecular sieves was added, and the reaction mixture heated at 110° C. for 3 days. The mixture was poured into saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified via flash chromatography on silica gel (24 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to yield 164.2 mg of the title compound. LCMS (ESI): M-(4-methoxybenzaldehyde)+H=269.2; 1H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 8.57 (s, 1H), 7.80 (d, J=8.7 Hz, 2H), 7.66 (s, 1H), 7.05 (d, J=8.7 Hz, 2H), 5.28 (q, J=8.0 Hz, 1H), 3.82 (s, 3H), 2.41 (s, 3H).