Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[N:8]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:7]1=[O:23].C=O.[B-][C:32]#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[N:8]([CH:17]2[CH2:18][CH2:19][N:20]([CH3:32])[CH2:21][CH2:22]2)[C:7]1=[O:23]
Reactant: COc1ccc(Cn2c(=O)n(C3CCNCC3)c3ccc(C#N)cc32)cc1Cl
Reactant: [B-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(Cn2c(=O)n(C3CCN(C)CC3)c3ccc(C#N)cc32)cc1Cl
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a suspension of 3-(3-chloro-4-methoxybenzyl)-1-(piperidin-4-yl)-5-cyano-2,3-dihydro-1H-benzimidazole-2-one (91 mg) in methanol (5 mL) were added 37% formaldehyde aqueous solution (220 mg), sodium cyanotrihydroborate (43.2 mg) and acetic acid (5 drops) under nitrogen at ambient temperature. After stirring for 2 hours at same temperature, the reaction mixture was poured into saturated sodium bicarbonate solution and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diethyl ether to give 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-(1-methylpiperidin-4-yl)-2,3-dihydro-1H-benzimidazole-2-one (75 mg) as an amorphous powder.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[CH:16]=O)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[CH2:16][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc(N2CCC(CN3CCCC3)CC2)c1
Reactant: C1CCNCC1
Product: c1cc(CN2CCCCC2)cc(N2CCC(CN3CCCC3)CC2)c1

Procedure:
Prepared from the product of Example 20 and piperidine.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@@H:22]4[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:24]1([C:27]([N:5]2[CH2:4][CH2:3][C:2]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]4[C@@H:22]5[C@H:17]([CH2:18][CH2:19][CH2:20][CH2:21]5)[CH2:16][C:15]4=[O:23])[CH2:10][CH2:9]3)([CH3:1])[CH2:7][CH2:6]2)=[O:28])[CH2:26][CH2:25]1
Reactant: O=C(O)C1CC1
Reactant: CC1(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution of (3aR,7aS)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-indol-2-one (70 mg, 0.22 mmol) in DMF (3 mL) was added with cyclopropane carboxylic acid (18.86 mg, 0.22 mmol) and diisopropylethyl amine (0.046 mL, 0.26 mmol) at room temperature. After 5-10 minutes HATU (83 mg, 0.22 mmol) was added and the mixture stirred at room temperature over night. The solvent was removed in vacuo, the residue dissolved in dichloromethane (60 mL) and washed with 1N NaOH (7 mL) and brine and concentrated in vacuo. The residue was purified by preparative LC/MS (high pH) to provide the title compound (58 mg, 69%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.54-0.74 (m, 2H), 0.77-0.95 (m, 2H), 0.84 (s, 3H), 1.01-1.44 (m, 6H), 1.45-1.84 (m, 11H), 2.01-2.15 (m, 2H), 2.19-2.40 (m, 2H), 2.73-3.06 (m, 3H), 3.17-3.32 (m, 1H), 3.37 (s, 1H), 3.44-3.68 (m, 2H), 3.69-3.80 (m, 1H), 3.81-3.97 (m, 1H). MS (M+1): 388.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]2[C:21]([CH3:27])=[N:22][CH:23]=[N:24][C:25]=2[CH3:26])=[O:19])[CH2:10][CH2:9]1)#[N:2].CCN(CC)CC.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]2[C:25]([CH3:26])=[N:24][CH:23]=[N:22][C:21]=2[CH3:27])=[O:19])[CH2:12][CH2:13]1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:46](=[O:48])[CH3:47])=[CH:31][CH:30]=1)#[N:2]
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of the above phenol (45 mg, 0.087 mmol) in CH2Cl2 (2 mL) were added Et3N (0.04 mL, 0.29 mmol) followed by acetic anhydride (0.02 mL, 0.21 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 138 as a white solid (43 mg, 80%) following work-up and purification. 1H NMR (CDCl3) δ 0.82-1.12 (m, 5H), 1.54-1.58 (m, 1H), 1.76-1.79 (m, 3H), 2.18 (t, 1H, J=11.7 Hz), 2.25 (s, 3H), 2.51 (s, 6H), 2.57 (t, 1H, J=10.5 Hz), 2.74-2.86 (m, 3H), 3.30-3.36 (m, 1H), 3.56-3.62 (m, 1H), 3.82-3.87 (m, 1H), 3.89 (s, 2H), 6.53 (d, 2H, J=8.1 Hz), 6.87 (d, 2H, J=8.4 Hz), 7.41-7.46 (m, 1H), 7.52-7.55 (m, 3H), 8.60 (br s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 12.37, 20.06, 20.93, 28.06, 29.26, 29.75, 38.92, 42.58, 47.57, 50.96, 55.43, 59.14, 111.59, 113.16, 117.91, 121.16, 128.32, 128.89, 129.64, 129.83, 129.94, 140.71, 141.26, 145.13, 156.53, 162.07, 165.32, 169.07. ES-MS m/z 555 (M+H). Anal. Calcd. for C32H38N6O3.0.8CH2Cl2: C, 63.27; H, 6.41; N, 13.50. Found. C; 63.46; H, 6.39; N, 13.29.
Reaction SMILES: [CH:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][C:7](=O)[CH2:8]2)([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:20][OH:21]>C(O)C>[CH:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][C:7](=[N:20][OH:21])[CH2:8]2)([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)N1C2CCC1CC(=O)C2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)N1C2CCC1CC(=NO)C2
Temperature: 23 °C

Procedure:
A mixture of 8-isopropyl-8-aza-bicyclo[3.2.1]octan-3-one (CAS 3423-28-7)(20.0 g, 120 mmol) in ethanol (500 ml) and pyridine (14.5 ml, 179 mmol) with hydroxylamine hydrochloride (8.81 g, 127 mmol) was refluxed for 16 h. Cooled to 23° C., the precipitate was filtered off, washed with diethyl ether leaving a solid, which was partitioned between dichloromethane and sodium carbonate solution, the organic layers dried over sodium sulfate, filtered and the solvents evaporated to give the title compound as a white solid. (17.7 g, 82%), MS: m/e=183.2 (M+H+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([F:17])[C:10]=1[F:16])[CH2:28]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: COc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc2c1CN(c1c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 46 %

Procedure:
210 mg of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 115 mg of 4-methoxyisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 138 mg of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[O:14][N:13]=[C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:16]=2)=[CH:22][CH:21]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(O)cc2)on1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(OCc3ccccc3)cc2)on1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-hydroxyphenyl)isoxazole (0.2 g) was dissolved in dimethylformamide (2 ml), and 55% sodium hydride (oil, 0.03 g) was added thereto at 5° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture at the same temperature for 10 minutes. Then, benzyl bromide (0.08 ml) was added dropwise thereto and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain the title compound (0.14 g, 54%) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[F:12][CH2:13][CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: OCCCF
Reactant: O=C1CCc2ccc(O)cc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2ccc(OCCCF)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.1 %

Procedure:
To a solution of 6-hydroxy-2,3-dihydro-1H-inden-1-one (3.0 g, 20 mmol) in THF (140 mL) were 3-fluoropropan-1-ol (1.67 mL, 22.3 mmol), triphenylphosphine (7.97 g, 30.4 mmol) and diisopropyl azodicarboxylate (5.98 mL, 30.4 mmol) added. The mixture was stirred at r.t. for two days. More 3-fluoropropanol (0.5 mL) was added and the mixture was heated to 45° C. After 2 h the mixture was concentrated, and the crude product was purified by flash chromatography using 0-20% EtOAc in heptane as eluent, affording 3.42 g (81% yield) of the title compound: 1H NMR (500 MHz, CDCl3) δ 2.12-2.26 (m, 2 H), 2.68-2.76 (m, 2 H), 3.04-3.12 (m, 2 H), 4.14 (t, 2 H), 4.61 (t, 1 H), 4.70 (t, 1 H), 7.17-7.22 (m, 2 H), 7.38 (d, 1 H); MS (EI) m/z 208 M+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([Cl:12])=[CH:5][C:3]=1[NH2:4].[ClH:13].O.OO>C(O)C>[Cl:13][C:5]1[C:6]([Cl:12])=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=[C:2]([Cl:1])[C:3]=1[NH2:4]
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: Cl
Agent: OO
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)cc([N+](=O)[O-])c(Cl)c1Cl
Temperature: 50 °C
Yield: 88 %

Procedure:
To a suspension of 2,5-dichloro-4-nitroaniline (4.0 g, 19.3 mmol) in ethanol (50 ml) was added concentrated hydrochloric acid (20 ml) and water (20 ml). The mixture was heated to 50° C. and 27.5% hydrogen peroxide (6 ml) added over 15 min. The mixture was maintained at this temperature for a further 2 h, cooled to room temperature, and the solid filtered and washed with water (2×20 ml) to give the title compound (D11) (4.1 g, 88%), MH+ 241/243.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:27]=[CH:26][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([OH:25])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:28])[CH:9]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].O>CN(C=O)C>[Br:7][C:8]1[CH:27]=[CH:26][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:42][CH:39]4[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:35])[CH2:37][CH2:38]4)=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:28])[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
Potassium carbonate (414 mg, 3 mmol) was added to a suspension of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (546 mg, 1.5 mmol) in DMF (5 ml). After stirring for 10 minutes at ambient temperature, 1-(tert-butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (636 mg, 1.72 mmol) was added and the mixture was heated at 95° C. for 2 hours. After cooling, the mixture was poured onto cooled water (20 ml). The precipitate was collected by filtration, washed with water, and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (665 mg, 79%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2].[CH2:17]([O:19][CH:20]=[CH:21][Sn](CCCC)(CCCC)CCCC)[CH3:18].[F-].[Cs+].CCOCC>O1CCOCC1.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>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[CH2:18])[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(Cl)cc(NC(C)=O)c1Cl
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(NC(C)=O)c(Cl)c(C(=O)OC)n1
Temperature: 100 °C
Yield: 65 %

Procedure:
A solution of methyl 4-acetamido-3,6-dichloropyridine-2-carboxylate (0.988 g, 4.0 mmol), ethoxyvinyltributyltin (2.70 mL, 8.0 mmol) and cesium fluoride (1.34 g, 8.8 mmol) in dioxane (20 mL) was sparged with nitrogen for 15 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.140 g, 0.2 mmol) was then added and the mixture was heated at 100° C. for 5 hours. After cooling, ether was added and the reaction mixture filtered through a silica plug. The solvents were removed and the crude product was purified by chromatography (ethyl acetate:hexane (1:2)) to give methyl 4-acetamido-3-chloro-6-(1-ethoxyvinyl)pryidine-2-carboxylate (0.780 g, 2.6 mmol). 1H NMR (CDCl3): δ 8.85 (s, 1H), 7.90 (br.s, 1H), 5.47 (d, J=2.0 Hz, 1H), 4.44 (d, J=2.0 Hz, 1H), 4.01 (s, 3H), 3.98 (q, J=7.0 Hz, 2H), 2.32 (s, 3H), 1.46 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:42][O:43][C:44](=[O:61])[C@@H:45]([NH2:60])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)=[CH:49][CH:48]=1>>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:19])[NH:60][C@H:45]([C:44]([O:43][CH3:42])=[O:61])[CH2:46][C:47]2[CH:52]=[CH:51][C:50]([C:53]3[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=3)=[CH:49][CH:48]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(F)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 72.5 %

Procedure:
(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]-isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (50 mg) was coupled with (S)-2-amino-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (29 mg) according to General Procedure L to give (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-8-[(S)-2-(4′-fluoro-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (52 mg). This intermediate was deprotected as described in General Procedure C to give (S)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl esterhydrochloride. This compound was further reacted with 2-acetyl-amino-4-methyl-thiazole-5-sulfonyl chloride to furnish (S)-2-({(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester as described in General Procedure E. This compound, upon reaction with ethyl iodide and K2CO3 in DMF, gave (S)-2-({(S)-7-[2-(acetyl-ethyl-amino)-5-methyl-thiazole-4-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure O. This product (15 mg) was hydrolyzed according to General Procedure B to furnish the title compound. LCMS (m/z): 934.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:8]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([CH:15]=1)[C:12](O)=[O:13].C[N:30](C=O)C>>[CH3:5][O:6][C:7]1[C:8]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([CH:15]=1)[C:12]([NH2:30])=[O:13]
Reactant: CN(C)C=O
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Temperature: 50 °C

Procedure:
Thionyl chloride (15 ml) and DMF (0.05 ml) were added to 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzoic acid (7.54 g). The mixture was heated at 50° C. for 1 hour, the excess thionyl chloride was removed by evaporation and by azeotroping with toluene (×2). The resulting solid was suspended in THF (200 ml) and ammonia was bubbled through the mixture for 30 minutes. The precipitate was removed by filtration and washed with THF. After concentration of the filtrate by evaporation, the product crystallised and was collected by filtration to give 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzamide (5.25 g) as light yellow crystals which were used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:11]([C:19]2[CH:28]=[CH:27][C:22]3[B:23]([OH:26])[O:24][CH2:25][C:21]=3[CH:20]=2)C(=O)OC(C)(C)C)=[N:7][C:8]=1[O:9][CH3:10])#[N:2].[OH-].[Na+].O>Cl.O1CCOCC1>[OH:26][B:23]1[C:22]2[CH:27]=[CH:28][C:19]([NH:11][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[C:8]([O:9][CH3:10])[N:7]=3)=[CH:20][C:21]=2[CH2:25][O:24]1
Reactant: COc1nc(N(C(=O)OC(C)(C)C)c2ccc3c(c2)COB3O)ccc1C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(Nc2ccc3c(c2)COB3O)ccc1C#N
Yield: 12.3 %

Procedure:
A solution of tert-butyl 5-cyano-6-methoxypyridin-2-yl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)carbamate (0.944 g, 2.48 mmol) in 4 mol/L hydrogen chloride in dioxane (20 mL) was stirred at room temperature for three hours. The solution was then neutralized with 6 mol/L sodium hydroxide until pH=6 to 7. Water was added and the solution was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The aqueous layer contained precipitate, which was collected by filtration and dried under reduced pressure. The residue was purified by Combiflash to give 6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-ylamino)-2-methoxynicotinonitrile (0.086 g, 9.1%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.95 (s, 2H), 6.50 (d, J=8.4 Hz, 1H), 7.52 (d, J=1.4 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 9.00 (s, 1H), 9.94 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH:4]([S:9][CH2:10][CH2:11][C:12](=[O:14])[CH3:13])OC(=O)C.C([O-])([O-])=[O:18].[K+].[K+]>CO>[CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][S:9][CH2:10][CH:11]([OH:18])[C:12](=[O:14])[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: COC(OC)C(OC(C)=O)SCCC(C)=O
Agent: [K+]
Solvent: CO
Product: COC(CSCC(O)C(C)=O)OC
Reaction time: 0.17 h

Procedure:
To a solution of 200 mg. (0.8 mmol) of 2-acetoxy-3-oxobutylmercaptoacetaldehyde dimethylacetal in 2 ml. of methanol was added 110 mg. (0.8 mmol) of K2CO3. The reaction mixture was stirred 10 minutes, filtered, diluted with water and extracted with CHCl3. The CHCl3 extract was dried over Na2SO4, filtered and evaporated to 123 mg. (75%) of keto alcohol product: 1H-NMR (CDCl3) delta 2.20 (s, 3), 2.85 (m, 4), 3.32 (s, 6), 4.32 (m, 1), 4.45 (t, 1).
Reaction SMILES: [Br:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1>CS(C)=O.[Cu]I>[Br:1][C:2]1[N:6]=[CH:5][N:4]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Brc1nc[nH]n1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Temperature: 100 °C
Yield: 56.2 %

Procedure:
To a 100 mL round bottomed flask, equipped with a stir bar, was added copper(I) iodide (0.397 g, 2.08 mmol), 3-bromo-1H-1,2,4-triazole (4.62 g, 31.2 mmol), and cesium carbonate (6.79 g, 20.83 mmol), as solids. These solids were diluted with anhydrous dimethyl sulfoxide (34.7 mL). Then 1-iodo-4-(trifluoromethoxy)benzene (1.65 mL, 10.4 mmol) was added as a liquid. The flask was placed under nitrogen atmosphere, and the suspension was heated to an internal temperature of 100° C. for 20 hours. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite®, washing with excess ethyl acetate (200 mL). The filtrate was poured into a brine solution (200 mL), and the layers were partitioned. The aqueous phase was extracted with additional ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified via flash column chromatography using 10-50% ethyl acetate/hexanes as eluent to afford the title compound as a white solid (1.80 g, 54%): 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 7.97 (d, J=8.9 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −57.06; ESIMS m/z 308, 310 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C(=O)=O.CC(C)=O.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[Cl:1][C:2]1[S:3][C:4]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)Cl
Reactant: Clc1cccs1
Agent: O=C=O
Solvent: CC(C)=O
Product: O=S(=O)(Cl)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
An 80-g (0.68 mol) sample of 2-chlorothiophene was added dropwise to a cooled (dry ice/acetone bath, about -10° to -15° C.) and stirred solution of 160 g (1.38 mol) of chlorosulfonic acid. After the addition was completed, the reaction mixture was stirred at 50° C for 2 hours, cooled, and then poured into 250 g of ice. The aqueous reaction mixture was extracted with methylene chloride. The methylene chloride extract was washed with saturated aqueous sodium bicarbonate solution, washed with water, dried over magnesium sulfate, and evaporated to give 40 g of 5-chloro-2-thienylsulfonyl chloride.