Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][C:3]1=[O:15].I[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[H-].[Na+]>O1CCCC1>[Br:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:3]1=[O:15]
Reactant: O=C1NC(c2ccccc2)CCCC1Br
Reactant: CC(C)(C)OC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)C(Br)CCCC1c1ccccc1

Procedure:
A solution of 15.5 g of the lactam from Step A and 14.7 t-butyl iodoacetate in 150 ml tetrahydrofuran was added dropwise to a slurry of 1.45 g sodium hydride in 20 ml tetrahydrofuran. After 3 hr at room temperature the reaction was quenched by the addition of 15 ml sat. NH4Cl solution. The mixture was filtered and concentrated and the residue partitioned between CHCl3 and H2O. The crude product was obtained after drying and concentrating the CHCl3 solution. Chromatography over silica gel with hexane: ethyl acetate (4:1) afforded two isomers of 3-bromo-1-t-butoxycarbonylmethyl-7-phenylperhydroazepin-2-one: isomer A (minor, elutes first), and isomer B (major, elutes second).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].O>CN(C)C(=O)C.O1CCCC1>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])[CH:3]=2)[NH:7]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc2c(c1)CC(=O)N2
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: O=C1Cc2cc(NC(=O)OCC(Cl)(Cl)Cl)ccc2N1
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 5-amino-1,3-dihydro-2H-indol-2-one (1.00 g, 6.75 mmol) and pyridine (1.64 ml, 20.3 mmol) in N,N-dimethylacetamide (6 ml) and tetrahydrofuran (50 ml) was added 2,2,2-trichloroethyl chloroformate (1.40 ml, 10.2 mmol) with ice-cooling, the mixture was stirred for 1 hour with ice-cooling, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (1.90 g, 87.2%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]([CH3:31])[C:16]([NH:18][C:19]2[C:24]([Cl:25])=[C:23]([O:26][CH3:27])[CH:22]=[C:21]([O:28][CH3:29])[C:20]=2[Cl:30])=[O:17])[CH:10]=1.C(N(CC)CC)C.[C:39](O)(=[O:43])/[CH:40]=[CH:41]\[CH3:42].C(Cl)Cl.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>>[Cl:25][C:24]1[C:23]([O:26][CH3:27])=[CH:22][C:21]([O:28][CH3:29])=[C:20]([Cl:30])[C:19]=1[NH:18][C:16](=[O:17])[N:15]([C:11]1[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:39](=[O:43])/[CH:40]=[CH:41]\[CH3:42])[CH:10]=1)[CH3:31]
Reactant: C/C=C\C(=O)O
Reactant: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2cc(Nc3ccccc3N)ncn2)c1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C=C\C(=O)Nc1ccccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
The title compound was synthesized following the approach outlined in Procedure 2A (Example 100), modifying step (i) to the following procedure: To a solution of 1-(6-((2-aminophenyl)amino)pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylurea (20 mg, 0.043 mmol), triethylamine (21.8 g, 0.22 mmol), and (Z)-but-2-enoic acid (4.5 g, 0.052 mmol) in DCM (0.86 ml, 13.3 mmol) was added a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (49.4 g, 0.78 mmol, 50% solution EtOAc) at 0° C., and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified by silica gel column to obtain the title compound (8.5 mg, yield: 37%). 1H NMR (400 MHz, CDCl3) δ 2.20 (dd, J=7.28, 1.76 Hz, 3H) 3.30 (s, 3H) 3.92 (s, 6H) 5.85 (dd, J=11.42, 1.76 Hz, 1H) 5.99 (s, 1H) 6.29 (dd, J=11.36, 7.34 Hz, 1H) 6.52 (s, 1H) 7.23-7.34 (m, 2H) 7.46 (d, J=7.40 Hz, 1H) 7.55 (br. s., 1H) 7.78 (d, J=7.53 Hz, 1H) 8.40 (d, J=0.88 Hz, 1H) 12.50 (s, 1H); MS (ESI): 531.3 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([OH:28])=O)=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@H:7]2[CH2:31][CH3:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:33]1([CH2:36][N:37]2[CH2:42][CH2:41][N:40]([C@H:43]3[CH2:48][CH2:47][C@H:46]([NH2:49])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)[CH2:35][CH2:34]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:49][C@H:46]5[CH2:45][CH2:44][C@H:43]([N:40]6[CH2:39][CH2:38][N:37]([CH2:36][CH:33]7[CH2:34][CH2:35]7)[CH2:42][CH2:41]6)[CH2:48][CH2:47]5)=[O:28])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@H:7]2[CH2:31][CH3:32])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CC[C@H](N2CCN(CC3CC3)CC2)CC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@H](N5CCN(CC6CC6)CC5)CC4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 2 h

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (140 mg, 0.346 mmol), (trans)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 16b (76 mg, 0.35 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (102 mg, 0.32 mmol) and diisopropylethylamine (103 mg, 0.80 mmol) were dissolved in 25 mL of dichloromethane. The reaction solution was stirred for 2 hours. The resulting solution was added dropwise with saturated sodium bicarbonate solution to adjust pH to 8 to 9 and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(trans)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-2,3-dihydrobenzofuran-4-carboxamide 34 (50 mg, yield: 40.0%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:20]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]1[C:33](O)=[O:34])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]1[C:33](=[O:34])[NH:18][C:16]1[CH:17]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[C:13]([Cl:19])=[CH:14][CH:15]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)[C@H]3CCCCN3C(=O)OC(C)(C)C)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
A mixture of 5′-amino-2′-chloro-biphenyl-4-carboxylic acid ethyl ester (750 mg), (R)-N-Boc-2-piperidinecarboxylic acid (664 mg) and HBTU (1.37 g) in dry DMF (40 ml) containing N-methylmorpholine (1.2 ml) was stirred at room temp for 18 h. The mixture was then evaporated and the residue was purified by chromatography. Elution with 5:1 petrol:ethyl acetate gave a yellow oil (310 mg)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][O:20][C:21]2[C:25]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:24][N:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:22]=2)=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[C:25]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][N:23]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:22]=2)=[CH:37][CH:38]=1
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A mixture of methyl [3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetate (662 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetic acid (583 mg, yield 91%), which was then recrystallized from acetone-hexane. melting point: 151–152° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]1[CH:32]=[CH:31][C:11]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[C:25]([C:28]([OH:30])=O)=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:10][CH:9]=1.C(Cl)(=O)C(Cl)=O.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C.CN(C)C=O>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[C:25]([C:28]([N:43]4[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]4)=[O:30])=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:31][CH:32]=1
Reactant: CC1=C(c2ccc(C(=O)N3Cc4ccc(C(=O)O)n4Cc4ccccc43)cc2)CCCC1
Reactant: CN1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1=C(c2ccc(C(=O)N3Cc4ccc(C(=O)N5CCN(C)CC5)n4Cc4ccccc43)cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
10-[4-(2-Methyl-cyclohex-1-enyl)-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step F (0.0510 g, 0.120 mmol) and oxalyl chloride (0.011mL, 0.126 mmol) were combined in anhydrous dichloromethane (1.2 mL) followed by dropwise addition of N,N-dimethylformamide (0.0003 mL, 0.0036 mmol). The reaction was refluxed for 3 hours, then the solvent was removed and the residue dried in vacuo. The crude acid chloride thus prepared was combined with N-methylpiperazine (0.0146 mL, 0.132 mmol) and N,N-diisopropylethyl amine (0.025 mL, 0.144 mmol) in anhydrous dichloromethane (1.2 mL). After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 5% methanol in chloroform to afford the title compound (0.025 g) as a white solid from a mixture of diethyl ether and hexane,
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[N:19](C3CCCCO3)[CH:18]=[N:17][N:16]=2)[CH:12]=[CH:11][C:10]=1[C:26]1[N:31]=[C:30]2[NH:32][C:33]3([CH2:38][CH2:37]3)[C:34](=[O:36])[NH:35][C:29]2=[N:28][CH:27]=1.CC1(C)C(=O)NC2=NC=C(C3C=CC(C4NC=NN=4)=CC=3C)N=C2N1CCC1CCOCC1.BrC1N=C2NC3(CC3)C(=O)NC2=NC=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(O)(C)C.O1CCOCC1>[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:19][CH:18]=[N:17][N:16]=2)[CH:12]=[CH:11][C:10]=1[C:26]1[N:31]=[C:30]2[NH:32][C:33]3([CH2:37][CH2:38]3)[C:34](=[O:36])[NH:35][C:29]2=[N:28][CH:27]=1
Reactant: Cc1cc(-c2nncn2C2CCCCO2)ccc1-c1cnc2c(n1)NC1(CC1)C(=O)N2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cc1cc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)N(CCC1CCOCC1)C(C)(C)C(=O)N2
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)NC1(CC1)C(=O)N2
Temperature: 100 °C
Yield: 38 %

Procedure:
7′-(2-Methyl-4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one Trifluoroacetate. 3-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazole (See Example 2. C) (0.201 g, 0.545 mmol), 7′-bromo-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one (0.139 g, 0.545 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.045 g, 0.054 mmol), sodium carbonate (1 M in water, 1.635 mL, 1.635 mmol), 1,4-dioxane (1.2 mL) and isopropanol (0.4 mL) were combined in a sealable vessel with a stirbar. The system was purged with nitrogen. The resulting mixture was sealed, stirred vigorously and heated at 100° C. for 1 h. The resulting mixture was diluted with water and extracted three times with dichloromethane. The combined organics were concentrated under reduced pressure. The residue was taken up in DMSO and methanol, filtered and purified using reverse-phase preparatory HPLC (20-70% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined and the solvent removed under reduced pressure. The residue was dried under high vacuum to give the desired product (0.109 g, 0.205 mmol, 38% yield) as an orange solid. MS (ESI) m/z 418.4 [M+1]+.
Reaction SMILES: O1C=CC(C2C=CC(NC(=O)OCC3C=CC=CC=3)=CC=2)=N1.C([Li])CCC.C(OC[C@@H]1OC1)(=O)CCC.C([O-])(O)=O.[Na+].[OH:43][CH2:44][C@@H:45]1[O:49][C:48](=[O:50])[N:47]([C:51]2[CH:56]=[CH:55][C:54]([C:57]3[CH:61]=[CH:60][O:59][N:58]=3)=[CH:53][CH:52]=2)[CH2:46]1.C(N(CC)CC)C.[CH3:69][S:70](Cl)(=[O:72])=[O:71]>CCOC(C)=O.[Cl-].[Na+].O.C(Cl)Cl.CO.C1COCC1>[CH3:69][S:70]([O:43][CH2:44][C@@H:45]1[O:49][C:48](=[O:50])[N:47]([C:51]2[CH:56]=[CH:55][C:54]([C:57]3[CH:61]=[CH:60][O:59][N:58]=3)=[CH:53][CH:52]=2)[CH2:46]1)(=[O:72])=[O:71]
Reactant: O=C1O[C@@H](CO)CN1c1ccc(-c2ccon2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CCCC(=O)OC[C@H]1CO1
Agent: O=C(Nc1ccc(-c2ccon2)cc1)OCc1ccccc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(-c3ccon3)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
Benzyl 4-isoxazol-3-ylphenylcarbamate (Intermediate 6, 2.26 g, 7.61 mmol) was added to THF and cooled to −78° C. n-Butyl lithium (1.6 M, 5.23 ml, 8.37 mmol) was added. The mixture was allowed to stir for 30 min and then (R)-(−)-glycidyl butyrate (1.19 ml, 8.37 mmol) was added drop wise. The reaction was allowed to stir overnight warning to room temperature, then methanol (5 ml) was added. Saturated NaHCO3 was then added and the product was extracted into EtOAc. The organic layers were washed with brine, then dried over Na2SO4 and concentrated under vacuum to yield crude product. The crude material was dissolved in EtOAc (10 ml) and hexane (10 ml) and the precipitate was collected by filtration. The resulting ((5R)-5-(hydroxymethyl)-3-(4-isoxazol-3-ylphenyl)-1,3-oxazolidin-2-one (780 mg, 2.98 mmol) was added to CH2Cl2 (10 ml) followed by addition of triethylamine (0.496 ml, 3.58 mmol). The solution was cooled to 0° C., and methanesulfonyl chloride (0.253 ml, 3.27 mmol) was added and the reaction was allowed to stir or 2 hours at 0° C. Brine was added and the mixture extracted with CH2Cl2. The organic layers were collected, dried over Na2SO4 and then concentrated under vacuum to yield the product (400 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:8]([C:13]2[CH:14]=[C:15]([CH:17]=[C:18]([C:20]3[NH:28][C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]=3)[CH:19]=2)[NH2:16])=[N:9][CH:10]=[CH:11][CH:12]=1.CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:13]2[CH:14]=[C:15]([NH:16][S:2]([CH3:1])(=[O:4])=[O:3])[CH:17]=[C:18]([C:20]3[NH:28][C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]=3)[CH:19]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cc(-c2nc3cccnc3[nH]2)cc(-c2ncccc2Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(-c2nc3cccnc3[nH]2)cc(-c2ncccc2Cl)c1
Reaction time: 8 h
Yield: 37.5 %

Procedure:
Methanesulfonyl chloride (10.0 μL, 0.12 mmol) was added to a solution of Example 183 (32.1 mg, 0.1 mmol) in CH2Cl2 (2 mL) followed by Et3N (20.0 μL, 0.15 mmol) at 0° C. The resulting mixture was stirred overnight and saturated NH4Cl solution (50 mL) was added and the mixture extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting material was purified by LCMS (acetonitrile-water gradient) to give the title compound (15 mg, 38%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.99 (s, 3H) 7.33 (dd, J=7.21, 4.42, Hz, 1 H) 7.52 (dd, J=5.27, 3.48 Hz, 1 H) 7.83 (t, J=5.21 Hz, 1 H) 7.87 (d, J=5.11 Hz, 2 H) 8.03 (t, J=5.11 Hz, 1 H) 8.21 (t, J=5.11 Hz, 1 H) 8.34 (d, J=5.11 Hz, 2 H) 8.51 (d, J=5.42, Hz, 1 H) 8.56 (d, J=5.91 Hz, 1 H). MS (ES) [M+H] calculated for C18H15ClN5O2S, 400.06; found 400.02.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=[O:12])=[CH:5][NH:6]2.[CH2:13](OC(C1NC2C(C=1)=CC=CC=2)=O)C>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=[O:12])=[CH:5][N:6]2[CH3:13]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=Cc1c[nH]c2cccc(F)c12
Product: Cn1cc(C=O)c2c(F)cccc21
Yield: 54 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting 4-fluoro-1H-indole-3-carboxaldehyde (0.41 g, 2.5 mmole) for the ethyl-indole-2-carboxylate, the title compound (0.24 g, 54%) was prepared as a viscous oil: MS (ES) m/e 178 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([CH2:9][N:10]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16](=[O:23])[CH2:15][CH2:14][N:13]([C:24](=[O:33])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)[CH2:12][C:11]1=[O:34])(O)=[O:7].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:32][C:28]1[CH:27]=[C:26]([NH:25][C:24]([N:13]2[CH2:14][CH2:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:10]([CH2:9][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[C:11](=[O:34])[CH2:12]2)=[O:33])[CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cccc(NC(=O)N2CCC(=O)c3ccccc3N(CC(=O)O)C(=O)C2)c1
Reactant: C1CCNC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: Cc1cccc(NC(=O)N2CCC(=O)c3ccccc3N(CC(=O)N3CCCC3)C(=O)C2)c1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
Pyrrolidine (117 μl, 1.41 mmol) was added to a solution of 1-carboxymethyl-4-(3-methylphenyl)carbamyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonin(373 mg, 0.94 mmol), EDC (181 mg, 0.94 mmol) and HOBt (127 mg, 0.94 mmol) in DMF (3 ml) at room temperature. The reaction mixture was stirred at room temperature for 28 hours, diluted with water (50 ml), and extracted with ethyl acetate (50 ml). The organic extract was washed with 10% citric acid solution (50 ml), brine (2×50 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with ethyl acetate as eluant. (138 mg, 34%).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][CH:6]=[CH:7][N:8]=1.[CH3:9][N:10]([CH2:12][CH2:13][NH2:14])[CH3:11]>C(O)(C)C>[CH3:9][N:10]([CH3:11])[CH2:12][CH2:13][NH:14][C:3]1[N:4]=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: CN(C)CCN
Reactant: CSc1nccnn1
Solvent: CC(C)O
Product: CN(C)CCNc1nccnn1

Procedure:
3-Methylthio-1,2,4-triazine (19.1 g, 0.15 mole) and unsym-dimethylethylene diamine (35.2 g, 0.40 mole) are dissolved in 100 ml of isopropyl alcohol and the mixture is heated under reflux in a nitrogen atmosphere for five days. The solvent is removed under reduced pressure and the residue is distilled at 0.5 mm of Hg. 3-(2-Dimethylaminoethylamino)-1,2,4-triazine is collected at 168°-169° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Nc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 26.5 mg (0.06 mmol) ethyl 4[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 35) in 3.0 ml EtOH and 4.0 ml of THF was added 240.1 mg NaOH (6.00 mmol, 3.0 ml of a 2M aqueous solution). After stirring at room temperature for 72 hours, the reaction was quenched by the addition of 10% HCl. Extraction with EtOAc, and drying of the organic layers over MgSO4, provided a solid after removal of the solvent under reduced pressure. Crystallization from CH3CN afforded the title compound as a colorless solid. 1H NMR (d6-DMSO): δ10.4 (1H, s), 7.91-7.81 (5H, m), 7.54 (1H, d, J=8.1 Hz), 7.45 (1H, d, J=1.7 Hz), 7.23 (4H, s), 6.04 (1H, t, J=4.7 Hz), 2.35 (5H, s), 1.33 (6H, s).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([F:24])[C:14]=1[CH:25]([OH:27])[CH3:26]>ClCCl>[Cl:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([F:24])[C:14]=1[C:25](=[O:27])[CH3:26]
Reactant: CCOC(=O)c1ccc(Cl)c(C(C)O)c1F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Cl)c(C(C)=O)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Pyridinium chlorochromate (27.6 g) was suspended in dichloromethane and ethyl 4-chloro-2-fluoro-3-(1-hydroxyethyl)benzoate (14.1 g) was added. The mixture was stirred at room temperature for 2 hours and then heated at reflux for 2 hours. After cooling the solvent was evaporated and the residue purified by column chromatography eluted with a mixture of ethyl acetate and n-hexane (1:5) to give ethyl 4-chloro-3-acetyl-2-fluorobenzoate as a yellow oil (13 g), NMR (CDCl3) 1.3(t,3H), 2.5(s,3H), 4.3(q,2H), 7.1(d,1H), 7.8(t,1H).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[C:10]([CH2:24][CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: CCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Product: CCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 40.3 %

Procedure:
Using cyclohexyl{3-ethyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.55 g) synthesized in Example 3(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.39 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.35 g, 41%) was obtained as a white solid.