Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.O[CH2:10][C:11]1[CH:12]2[CH:20]=[CH:19][C:15]([CH3:21])([C:16]=1[CH2:17]O)[C:14](=[O:22])[C:13]2([CH3:24])[CH3:23]>[Pd].C(O)(C)C>[CH3:21][C:15]12[CH2:19][CH2:20][CH:12]([C:11]([CH3:10])=[C:16]1[CH3:17])[C:13]([CH3:24])([CH3:23])[C:14]2=[O:22]
Reactant: CC12C=CC(C(CO)=C1CO)C(C)(C)C2=O
Agent: [Pd]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C)C2(C)CCC1C(C)(C)C2=O
Temperature: 80 °C
Reaction time: 0.07 h
Yield: 119.9 %

Procedure:
To a 450 ml Parr mini-pressure reactor is charged 15 grams of 5,6-bis(hydroxymethyl)-1,3,3-trimethylbicyclo[2.2.2]-octa-5,7-dien-2-one diacetate produced according to Example IV, 60 ml of isopropyl alcohol and 0.3 grams of 10% palladium on charcoal. After flushing with nitrogen and hydrogen, the hydrogen is charged to a pressure of 195 psig while maintaining the reaction mass temperature at 22°-27° C. Within four minutes, the pressure drops to 140 psig and holds steady for six minutes. Hydrogen is again charged to 195 psig and the temperature is gradually raised to 80° C. At 80° C. the pressure begins to drop. The temperature is raised to 85° C. and maintained at 85° C. until the pressure holds constant at 102 psig (1.7 hours). After cooling to room temperature, the reaction mass is filtered and the toluene is removed in vacuo to yield 10.1 grams of 1,3,3,5,6-pentamethyl-bicyclo[2.2.2]octa-5-en-2-one. This material is identical to that prepared from 2,6,6-trimethylcyclohexa-2,4-dien-1-one and 2-butyne according to Examples I and II, supra.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[OH-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(I)cc2)CC1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
4-Iodobenzoyl chloride (7.99 g) and piperazine-1-carboxylic acid tert-butyl ester (5.87 g) were dissolved in tetrahydrofuran (75 ml), 1N aqueous sodium hydroxide solution (36 mL) was added, and the mixture was stirred at room temperature. The reaction mixture was poured into water under cooling and 1N aqueous sodium hydroxide solution and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine, then washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. To the residue was added hexane and the mixture was stirred at room temperature. The crystals were collected by filtration to give the title compound (11.67 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](Cl)=[O:22]>ClCCl.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:19]=[C:18]([Cl:17])[CH:26]=[C:25]([Cl:27])[CH:24]=2)[CH:7]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Nc1cc(Cl)ccc1O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Cl)ccc1O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.4 %

Procedure:
2-Amino-4-chlorophenol (316 mg, 2.2 mmol) and triethylamine (243 mg, 2.4 mmol) were dissolved in dichloromethane (5 mL). A solution of 3,5-dichlorobenzoyl chloride (419 mg, 2 mmol) in dichloromethane (2 mL) was added dropwise under ice cooling and argon atmosphere, and the mixture was stirred at room temperature for 15 hours. After the reaction mixture was diluted with ethyl acetate, washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give a light brown solid. The solid was suspended and washed with n-hexane-ethyl acetate under heating at reflux to give the title compound (205 mg, 32.4%) as a white crystal.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][NH:15][CH2:14]2)[CH3:12])[CH2:5][CH2:4]1.[O:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37][CH2:36]2)[CH2:31][CH2:30]1>>[F:28][C:2]([F:1])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][N:15]([C:41]([CH:38]3[CH2:39][CH2:40][N:35]([CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)[CH2:36][CH2:37]3)=[O:42])[CH2:14]2)[CH3:12])[CH2:5][CH2:4]1
Reactant: CN(C(=O)OC1CCC(C(F)(F)F)CC1)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCN(C2CCOCC2)CC1
Product: CN(C(=O)OC1CCC(C(F)(F)F)CC1)[C@@H]1CN(C(=O)C2CCN(C3CCOCC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound {(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(tetrahydro-pyran-4-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester was prepared from [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(tetrahydro-pyran-4-yl)-piperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 634.2 [M]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:29][S:30]([CH2:33][CH2:34][C:35]1[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=1)(=[O:32])=[O:31]>>[ClH:1].[CH3:29][S:30]([CH2:33][CH2:34][C:35]1[CH:36]=[C:37]([NH:41][C:2]2[N:7]=[C:6]([N:8]([CH3:28])[C:9]3[CH:27]=[CH:26][C:12]4[N:13]([CH3:25])[C:14]([NH:16][CH:17]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH3:18])=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:38]=[CH:39][CH:40]=1)(=[O:31])=[O:32]
Reactant: CC(Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C)c1ccccc1
Reactant: CS(=O)(=O)CCc1cccc(N)c1
Product: CC(Nc1nc2cc(N(C)c3ccnc(Nc4cccc(CCS(C)(=O)=O)c4)n3)ccc2n1C)c1ccccc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-(1-phenyl-ethyl)-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 3-(2-methanesulfonyl-ethyl)-phenylamine (50 mg, 0.25 mmol) as a white solid (48 mg, 32%). 1H NMR (300 MHz, d6-DMSO) δ 9.08 (s, 1H), 7.73-7.77 (m, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 7.29-7.34 (m, 2H), 7.12-7.23 (m, 4H), 7.05 (d, J=1.5 Hz, 1H), 6.79-6.84 (m, 2H), 5.59 (d, J=5.7 Hz, 1H), 5.14 (m, 1H), 3.60 (s, 3H), 3.41 (s, 3H), 3.32-3.41 (m, 2H), 2.90-2.96 (m, 5H), 1.53 (d, J=6.9 Hz, 3H). MS (ESI) m/z=556 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[C:34]([NH:37][CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)(=[O:36])[CH3:35]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:40]5[CH2:41][CH2:42][CH:38]([NH:37][C:34](=[O:36])[CH3:35])[CH2:39]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)NC1CCNC1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: CC(=O)NC1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)C1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 3-acetamidopyrrolidine. A yellow solid 124 was obtained (0.0369 g, 72%). 1H NMR (CDCl3, 400 MHz) δ 2.01 (s, 3H), 2.24-2.31 (m, 1H), 2.34-2.41 (m, 1H), 3.78-3.90 (m, 3H), 4.01-4.10 (m, 1H), 4.28-4.34 (m, 4H), 4.62-4.68 (m, 1H), 6.78 (s, 1H), 6.93-6.97 (m, 2H), 7.05 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.09-7.13 (m, 2H), 7.18 (br s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.83 (s, 1H), 8.07 (d, J=6.6 Hz, 1H), MS (APCI) m/z 516 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[N:17][CH:16]=[CH:15][N:14]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[Cl:41]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:41][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1cccc(S(=O)(=O)Nc2nccnc2OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cccc(S(=O)(=O)Nc2nccnc2OC)c1Cl
Yield: 46.1 %

Procedure:
Prepared as for Example 130, 3-methoxy-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide (Example 132a) (0.295 g), lithium di-iso-propylamide (prepared from di-iso-propylamine (0.30 g) and n-butyl lithium (0.96 mL of a 2.5M solution in hexanes)) and hexachloroethane (0.994 g) in anhydrous tetrahydrofuran (20 mL) afforded the titled compound (0.152 g) as a white solid after re-crystallisation from tert-butyl methylether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27]I>>[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1cc(F)cc(F)c1
Yield: 85.3 %

Procedure:
Step AL (1): 2-(3,5-Difluorophenyl)acetic acid (2.5 g, 14.5 mmol) was deprotonated with NaHMDS (1.0 M in THF, 29.0 mL, 29.0 mmol) and reacted with 1-chloro-4-iodobutane (1.78 mL, 14.5 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(3,5-difluorophenyl)hexanoic acid (3.25 g, 85% yield). LC-MS (m-H)− 261.1. The crude product was used for subsequent chemistry without purification.
Reaction SMILES: [C:1]1([NH:7][C:8](=O)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:20])=O>ClCCl>[C:1]1([N:7]=[C:8]([Cl:20])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(=O)Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(Cl)=Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-phenylpropionamide(7.46 g, 0.05 mol) and pyridine(13.8 g, 0.18 mol) were dissolved in dichloromethane(300 g), and the mixture was cooled to 0° C. And then phosphorus oxychloride(8.43 g, 0.05 mol) was added dropwise thereto for 2 hours, and then the mixture was stirred at room temperature (20° C.) for 2 hours to produce N-phenylpropionimidoylchloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=[CH:5][CH:4]=1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[C:9]([O:11][N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19])=[O:10]
Reactant: COc1ccccc1C(=O)O
Reactant: O=C1CCC(=O)N1O
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
O-anisic acid (1.0 g), N-hydroxysuccinimide (0.76 g) and water-soluble carbodiimide hydrochloride (1.39 g) were dissolved in methylene chloride (15 ml), and the solution was stirred overnight at room temperature. The precipitate was removed by filtration. The mother liquor was concentrated under reduced pressure, and the residue was crystallized from isopropanol to give 1.47 g of N-(2-methoxybenzoyloxy)succinimide (mp. 180°-182° C.).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[N:25]=[N:26][N:27]([CH3:29])[N:28]=4)[CH:19]=3)[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])C.[CH2:30]([CH2:32][NH2:33])[OH:31]>CS(C)=O>[OH:31][CH2:30][CH2:32][NH:33][C:4]([C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[N:25]=[N:26][N:27]([CH3:29])[N:28]=4)[CH:19]=3)[C:8]=2[C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cccc(-c4nnn(C)n4)c3)csc12
Reactant: NCCO
Solvent: CS(C)=O
Product: Cn1nnc(-c2cccc(OCc3csc4c(C(=O)NCCO)cnc(N)c34)c2)n1
Temperature: 160 °C

Procedure:
A solution of 4-amino-3-[3-(2-methyl-2H-tetrazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.050 g, 0.12 mmol) (from Example 32 supra) in dimethylsulfoxide (0.5 mL) was treated with ethanolamine (1.5 mL) (Aldrich) and heated at 160° C. for 2 hours in a microwave reactor. The precipitate was filtered, washed with methanol and dried to give 4-amino-3-[3-(2-methyl-2H-tetrazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white powder. (Yield 39.0 mg, 75%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:22][O:23][CH3:24])[C:3]=1[C:25]([O:27][CH3:28])=[O:26].[C:29](#[N:31])[CH3:30]>Cl>[F:19][C:18]([F:21])([F:20])[C:17]1[CH:16]=[CH:15][C:29]([NH:31][C:2]2[C:11]3[C:6](=[N:7][C:8]([C:12]4[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=4)=[CH:9][CH:10]=3)[N:5]=[C:4]([CH2:22][O:23][CH3:24])[C:3]=2[C:25]([O:27][CH3:28])=[O:26])=[CH:30][CH:12]=1
Reactant: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(Cl)c1C(=O)OC
Reactant: CC#N
Agent: Cl
Product: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(Nc2ccc(C(F)(F)F)cc2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve methyl 4-chloro-2-methoxymethyl-7-[3-(trifluoromethyl)pyridin-2-yl]-[1,8]naphthyridine-3-carboxylate (212 mg, 0.52 mmol) in acetonitrile (5 mL) and add 4 drops 2M HCl (Et2O). Stir the mixture for 3 hours at room temperature. Filter off the resulting yellow precipitate to yield the title compound as its hydrochloride salt. MS 537.20 (M+1). 1H NMR δ (Free base, CDCl3) 9.91 (1H, s), 8.88 (1H, m), 8.16 (2H, m), 7.67-7.55 (4H, m), 7.12 (1H, d), 6.99 (1H, d), 4.42 (2H, s), 4.02 (3H, s), 3.95 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[C:28]([O:30][CH3:31])=[O:29])(=[O:17])=[O:16])=[S:13])[N:4]=1.O([CH3:34])[Na].CO.CI>O1CCCC1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([NH:11][C:12](=[N:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[C:28]([O:30][CH3:31])=[O:29])(=[O:17])=[O:16])[S:13][CH3:34])[N:6]=1
Reactant: COC(=O)c1ccc2ccccc2c1S(=O)(=O)NC(=S)Nc1nc(OC)cc(OC)n1
Reactant: CO[Na]
Solvent: CI
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2ccccc2c1S(=O)(=O)N=C(Nc1nc(OC)cc(OC)n1)SC

Procedure:
To a suspension of methyl 1-[[(4,6-dimethoxypyrimidin-2-yl)aminothiocarbonyl]aminosulfonyl]-2-naphthalenecarboxylate in 200 ml of anhydrous tetraydrofuran can be added 16.7 ml of 3M NaOCH3 /MeOH solution. The resulting reaction mixture can be heated to reflux, 3.1 ml of methyl iodide in 10 ml of anhydrous tetrahydrofuran can be added; and the reaction mixture can be refluxed for 3 hours. The reaction mixture can be cooled to cause the formation of a precipitate which can be filtered off and washed with tetrahydrofuran to afford the desired product.
Reaction SMILES: [Cl:1]C1C=CC(N)=CC=1C.[Br:10][C:11]1[CH:16]=[C:15](C)[C:14]([CH3:18])=[CH:13][C:12]=1[N:19](C(C)C)[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]>>[Br:10][C:11]1[CH:16]=[C:15]([Cl:1])[C:14]([CH3:18])=[CH:13][C:12]=1[NH:19][C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]
Reactant: Cc1cc(Br)c(N(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C(C)C)cc1C
Reactant: Cc1cc(N)ccc1Cl
Product: Cc1cc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(Br)cc1Cl

Procedure:
Tert-butyl 4-{[(2-bromo-4-chloro-5-methylphenyl)amino]carbonyl}-piperidine-1-carboxylate 2-5 was prepared from 4-chloro-3-methylaniline 2-1 following a similar procedure to that described for 4-{[(2-bromo-4,5 dimethylphenyl)(isopropyl)amino]carbonyl}piperidine-1-carboxylate 1-12.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[O:25][N:24]=[C:23]([CH2:26]OS(C)(=O)=O)[CH:22]=1>CC#N.O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:26][C:23]2[CH:22]=[C:21]([CH3:20])[O:25][N:24]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1cc(COS(C)(=O)=O)no1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)no1
Yield: 89.1 %

Procedure:
To a solution of N-BOC-piperazine (300 mg) in MeCN (5 mL) was added potassium carbonate (289 mg) followed by methanesulfonic acid 5-methyl-isoxazol-3-ylmethyl ester (369 mg). The reaction mixture was heated to reflux for 24 h. After cooling the reaction mixture was diluted with water extracted into ethyl acetate, dried (MgSO4) and the solvent was removed in vacuo to yield 4-(5-methyl-isoxazol-3-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (404 mg).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:27]3[CH:26]=[C:25]([CH3:28])[C@:24]([CH2:30][CH:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[OH:32])([CH3:29])[CH2:23][C:22]=3[CH:21]=[N:20]2)=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[C:27]3[CH:26]=[C:25]([CH3:28])[C@:24]([CH2:30][CH:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N+:34]=4[O-:6])[OH:32])([CH3:29])[CH2:23][C:22]=3[CH:21]=[N:20]2)=[CH:17][CH:18]=1
Reactant: CC1=Cc2c(cnn2-c2ccc(F)cc2)C[C@]1(C)CC(O)c1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1=Cc2c(cnn2-c2ccc(F)cc2)C[C@]1(C)CC(O)c1cccc[n+]1[O-]
Reaction time: 3 h

Procedure:
3-chloroperoxybenzoic acid (28 mg, 1.5 eq) was added to a solution of the diastereomer mixture of the alcohols from Examples 75 and 76 in chloroform (3 mL) at room temperature. After 3 h, the mixture was quenched with saturated NaHCO3 (1 mL), diluted with EtOAc (60 mL), washed with water (5 mL), brine (5 mL), dried (MgSO4) and concentrated. Reverse phase HPLC purification (MeOH-water, 50 to 100%) yielded the desired N-oxide as a mixture of two diastereomers (5 mg), which was separated by chiral OD column (isocratic, i-PrOH/heptane, 15%) to give Examples 78 (1.3 mg, 3%, isomer A, faster eluent) and 79 (1.5 mg, 4%, isomer B, slower eluent). MS found: (M+H)+=380.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=[C:9]2[CH:8]=1)=[O:6].Cl>C(O)C.O>[C:16]1([C:14]2[N:15]=[C:9]3[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:12]=[CH:11][N:10]3[CH:13]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccn2cc(-c3ccccc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccn2cc(-c3ccccc3)nc2c1
Temperature: 0 °C

Procedure:
A solution of NaOH in water (1N, 54 ml, 54 mmol) was added to a suspension of 2-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (6.8 g, 27 mmol) in a mixture of ethanol (50 ml) and water (25 ml). The mixture was heated to reflux (2 h). The obtained clear solution was cooled, poured onto crushed ice (50 g); HCl (25%, 10 ml) was added. The mixture was then filtered, and the precipitate was washed (ethanol) and dried under vacuum. The obtained solid (6.36 g, 99%) was used in the next step without further purification. MS (m/e)=239.1 [M+H+].
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:57])[CH:45]([NH:52][C:53]([O:55][CH3:56])=[O:54])[C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)=[N:37][CH:38]=5)=[CH:30][CH:29]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.[CH3:59][O:60][C:61]([NH:63][CH:64]([CH2:68][CH:69]1[CH2:74][CH2:73][O:72][CH2:71][CH2:70]1)[C:65]([OH:67])=O)=[O:62].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:59][O:60][C:61](=[O:62])[NH:63][CH:64]([CH2:68][CH:69]1[CH2:74][CH2:73][O:72][CH2:71][CH2:70]1)[C:65]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:29]=[CH:30][C:31]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:57])[CH:45]([NH:52][C:53]([O:55][CH3:56])=[O:54])[C:46]6[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=6)=[N:37][CH:38]=5)=[CH:32][CH:33]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:67]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Reactant: COC(=O)NC(CC1CCOCC1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(CC1CCOCC1)C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
To a solution of 2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.15 mmol) in CH2Cl2 (1.5 mL) and MeOH (0.2 mL) was added HCl (in dioxanes, 4 M, 0.75 mL, 3.0 mmol). The solution was stirred at room temperature for 2 h and concentrated to dryness. The resulting solid was dissolved in DMF (1.5 mL). 2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionic acid (0.05 g, 0.22 mmol), HATU (0.07 g, 0.19 mmol) and DIPEA (0.13 mL, 0.74 mmol) were added. The resulting solution was stirred at room temperature for 18 h. The solution was purified twice by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% TFA)) and lyophilized to provide [2-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-ylmethyl)-ethyl]-carbamic acid methyl ester (0.024 g, 18%). LCMS-ESI+: calc'd for C50H54N8O7: 878.41 (M+); Found: 879.97 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[CH3:11].[K].[O-:13]CCCC.[CH:18]([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:13][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(C)C
Reactant: CCCC[O-]
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Agent: [K]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of the above 4-bromo-3-methylbenzoyl chloride residue in THF (100 mL), a solution of potassium ten-butoxide (6.0 g, 53.5 mmol) in THF (60 mL) was added dropwise at 0° C. under nitrogen. The mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over Na2SO4. The compound was purified by silica column chromatography using heptane and ethyl acetate as eluent to give a yield of 96%. 1HNMR (300 MHz, CD2Cl2): δ 7.88 (s, 1H), 7.53-7.7 (m, 2H), 2.42 (s, 3H, CH3), 1.57 (s, 9H, CH3); MS (m/e): calculated 215.96/213.96 (1:1). found 215.0/217.0 (1:1), for [M+H−tBu]+.