Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:52])([F:51])[F:50])[CH:39]=1.[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:10][CH:11]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:18]=2)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:51])([F:50])[F:52])[CH:39]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: c1cc(CNc2ccc(OCCN3CCCC3)cc2)cc(OC2CCCCO2)c1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)cc1OC(F)(F)F)N(Cc1cccc(OC2CCCCO2)c1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101 %

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.060 g, 0.15 mmol) in 0.4 mL methylene chloride was added triethylamine (0.06 mL, 0.45 mmol) and 4-bromo-2-trifluoromethoxybenzenesulfonyl chloride (0.103 g, 0.3 mmol). The reaction mixture was stirred at room temperature for 24 hr. PS-isocyanate resin (0.050 g) and PS-trisamine resin (0.050 g) were added and the reaction mixture was stirred for 2 hr. at room temperature. The resin was filtered off with the aid of methylene chloride. The filtrate was concentrated to afford the title compound of Step A (0.106 g). MS 700.8 (M+1)+
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[C:12]([NH:16][C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20])[CH:13]=[CH:14][CH:15]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:24][N:25]([CH2:27][C:28]1[O:32][C:31]([CH2:33][S:34][CH2:35][CH2:36][NH2:37])=[CH:30][CH:29]=1)[CH3:26]>>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[C:12]([NH:16][C:17]([NH:37][CH2:36][CH2:35][S:34][CH2:33][C:31]3[O:32][C:28]([CH2:27][N:25]([CH3:26])[CH3:24])=[CH:29][CH:30]=3)=[CH:18][N+:19]([O-:21])=[O:20])[CH:13]=[CH:14][CH:15]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CSC(=C[N+](=O)[O-])Nc1cccc(-c2csc(NC(=N)N)n2)c1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])Nc2cccc(-c3csc(NC(=N)N)n3)c2)o1
Temperature: 100 °C

Procedure:
A mixture of 1-[3-(2-guanidinothiazol-4-yl)phenylamino]-1-methylthio-2-nitroethylene (0.16 g.) and 2-[(5-dimethylaminomethylfuran-2-yl)methylthio]ethylamine (1 g.) was heated at 100° C. for 2 hours. The product was extracted 10 times with 5 ml. portions of diethyl ether and the residual gum was applied to Merck 60 F254 preparative plates and eluted with ethyl acetate/methanol/concentrated aqueous ammonia 6:1:1 v/v/v. The solid obtained (0.05 g.) was crystallised twice from acetonitrile to give 1-[3-(2-guanidinothiazol-4-yl)phenylamino]-1-[2-[(5-dimethylaminomethylfuran-2-yl)methylthio]ethylamino]-2-nitroethylene, m.p. 175°-180° C. (decomp.).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:7]=1.[C:25]1([CH2:31][C@H:32]([NH2:35])[CH2:33][NH2:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>>[NH2:35][C@@H:32]([CH2:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:33][NH:34][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)c(NC(=O)c2ccccc2)c1=O
Reactant: NC[C@@H](N)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(NC[C@@H](N)Cc2ccccc2)nc(-c2ccncc2)c(NC(=O)c2ccccc2)c1=O

Procedure:
N-(2-Chloro-1-methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-5-yl)-benzamide (0.07 mmol) was stirred as a solution with 3-phenyl-propane-1,2(S)-diamine (0.15 mmol) and diisopropylethylamine (0.1 mmol) at 0° C. for 2 h. The material was purified on reverse phase HPLC. M+1=455.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:10]([N:13]1[C:17]2[C:18]([NH2:26])=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=2[N:15]=[C:14]1[CH3:27])([CH3:12])[CH3:11]>C1(C)C(C)=CC=CC=1>[CH3:2][C:1](=[N:26][C:18]1[C:17]2[N:13]([CH:10]([CH3:12])[CH3:11])[C:14]([CH3:27])=[N:15][C:16]=2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: Cc1nc2cc(C(F)(F)F)cc(N)c2n1C(C)C
Solvent: Cc1ccccc1C
Product: CC(=Nc1cc(C(F)(F)F)cc2nc(C)n(C(C)C)c12)c1ccccc1

Procedure:
Acetophenone (2.8 g.) was reacted with 1-isopropyl-2-methyl-5-trifluoromethyl-7-aminobenzimidazole (4.0 g.) in 50 ml. of xylene for 21 hours according to the procedure of Example 1. After drying over sodium sulfate, the solvent was removed and the crude residue was recrystallized from benzene-cyclohexane (1:1) to give 3.38 g. of the desired product, m.p. 164°-166° C.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([O:15]CC)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][CH:20]([OH:32])[CH2:19][NH:18][C:13](=[O:15])[CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1cccc2ccccc12
Solvent: CCO
Product: O=C(COc1cccc2ccccc12)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
To a stirred mixture of ethyl 2-(naphthalen-1-yloxy)acetate (150 mg, 0.641 mmol) in EtOH (2 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (132 mg, 0.641 mmol). The mixture was stirred at 120° C. for 30 minutes under microwave mediated heating. After evaporation of the solvent, the reaction mixture was purified by prep-HPLC to afford the desired product (64 mg, Yield 25%). 1H NMR (400 MHz, METHANOL-d4) δ=8.41-8.31 (m, 1H), 7.90-7.80 (m, 1H), 7.58-7.46 (m, 3H), 7.44-7.35 (m, 1H), 7.18-6.95 (m, 5H), 6.91 (d, J=7.8 Hz, 1H), 4.76 (s, 2H), 4.05 (quin, J=6.0 Hz, 1H), 3.72-3.59 (m, 2H), 3.56-3.48 (m, 1H), 3.41 (dd, J=6.5, 13.6 Hz, 1H), 2.93-2.83 (m, 2H), 2.80-2.72 (m, 2H), 2.59-2.52 (m, 2H). LCMS (m/z): 391.2 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:15]1[C:24]2[C:19](=[C:20]([N:25]3[C:29]([NH2:30])=[C:28]4[CH2:31][CH2:32][CH2:33][C:27]4=[N:26]3)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1.Cl>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:30][C:29]2[N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:19]=3[CH:18]=[CH:17][N:16]=[CH:15]4)[N:26]=[C:27]3[CH2:33][CH2:32][CH2:31][C:28]=23)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1c2c(nn1-c1cccc3cnccc13)CCC2
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2c3c(nn2-c2cccc4cnccc24)CCC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
A mixture of 4-t-butylbenzenesulfonyl chloride (0.075 g, 0.32 mmol) and 2-(isoquinolin-5-yl)-2,4,5,6-tetrahydrocyclopentapyrazol-3-amine (0.050 g, 0.20 mmol) in pyridine (1 mL) was stirred at room temperature for 1 h. The reaction mixture was added 1 N aqueous hydrochloric acid and extracted with in 2:1 CH2Cl2/iPrOH (2×10 mL). The combine organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting material was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.025 g, 0.056 mmol, 28%). 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.35 (s, 1H), 8.42 (d, J=6.0 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.41-7.37 (m, 3H), 7.18 (d, J=4.8 Hz, 1H), 2.64 (t, J=7.2 Hz, 2H), 2.21 (pent, J=7.2 Hz, 2H), 2.06 (t, J=7.5 Hz, 2H), 1.25 (s, 9H); MS: (ES) m/z calculated for C25H27N4O2S [M+H]+ 447.2. found 447.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:34])([CH3:33])[CH2:15][C:16]([N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH:20]([NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:19]2)=[O:17])[CH2:11][O:10]C1(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[NH:28][CH:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]([C:16](=[O:17])[CH2:15][C:14]([CH3:34])([CH3:33])[CH2:13][C@H:12]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:11][OH:10])[CH2:19]1
Reactant: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3.1 g of 4(S)-[4-(3(R,S)-methoxycarbonylamino-3,4-dihydro-2H-quinolin-1-yl)-2,2-dimethyl-4-oxo-butyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and 104 mg of p-toluenesulfonic acid monohydrate in 49 ml of methylene chloride under argon is stirred at room temperature for 3.5 hours. More p-toluenesulfonic acid monohydrate (200 mg) is added and the mixture is stirred at room temperature for 1.5 hours The solution is concentrated. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60 F). Rf=0.14 (3:1 EtOAc-heptane); Rt=3.91 (gradient I).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[N:11][C:4]=2[NH:3]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([NH:36][C:12]([C:10]4[CH:9]=[CH:8][C:5]5[S:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=5[N:11]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4ccc5c(n4)NC(=O)CS5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow solid (7 mg, 10% yield) following Scheme 3 and in analogy to Example 35 using 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (26 mg, 0.12 mmol, 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (40 mg, 0.12 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH2:29])[CH3:28].C(N(CC)CC)C>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH:29][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[CH3:28]
Reactant: CC(N)c1ccccc1-c1cc(F)ccc1F
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Product: COc1cccc(S(=O)(=O)NC(C)c2ccccc2-c2cc(F)ccc2F)c1
Yield: 94.2 %

Procedure:
The title compound was prepared from 3-methoxybenzenesulfonyl chloride (326 mg, 1.6 mmol), 1-(-2′,5′-difluoro-biphenyl-2-yl)ethylamine (350 mg, 1.5 mmol), and triethylamine (418 μL, 3 mmol) according to the procedure and in the same manner as described in Example 112, step c. The product was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the desired compound (570 mg, 94%) as a clear glass;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1.[C:27]([O-:30])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CO.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:23]([C:4]1[C:5]([O:21][CH3:22])=[C:6]([CH:20]=[C:2]([C:9]2[C:27](=[O:30])[NH:15][CH:12]=[CH:11][CH:10]=2)[CH:3]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C([O-])[O-]
Reactant: COc1c(COc2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1c(COc2ccc(NS(C)(=O)=O)cc2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C

Procedure:
step 5—A mixture of 120 (0.20 g, 0.46 mmol), 112 (0.095 g, 0.69 mmol), Pd(PPh3)4 (0.053 g, 0.046 mmol) and Na2CO3 (0.15 g, 1.4 mmol) in DCM/MeOH (3:1, 8 mL) was irradiated in microwave synthesizer at 115° C. for 35 min. The reaction mixture was filtered and the filtrate concentrated. The crude residue was purified by SiO2 chromatography eluting with DCM/MeOH/NH4OH and the recovered product triturated with ether to afford I-71 as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH:15][S:16]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([O:26]C)=[O:25])(=[O:18])=[O:17])=[O:4].O.O.[OH-].[Li+].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH:15][S:16]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([OH:26])=[O:25])(=[O:18])=[O:17])=[O:4]
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(NS(=O)(=O)c2ccsc2C(=O)O)ccc2c1CCCC2
Temperature: 60 °C

Procedure:
A solution of Example 463A (1.37 g, 3.36 mmol) in methanol (31 mL) and distilled water (3.5 mL) was treated with lithium hydroxide monohydrate (0.704 g, 16.78 mmol), heated to 60° C. for 30 minutes, cooled to room temperature, treated with 1N HCl, and concentrated. The aqueous layer was extracted with dichloromethane twice and the combined organic fractions were dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 396 (M+H)+; (ESI(−)) m/e 394 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.98 (br s, 1H), 7.89 (d, 1H), 7.33 (d, 1H), 7.12 (s, 2H), 3.77 (s, 3H), 2.67 (br s, 2H), 2.53 (br s, 2H), 1.65 (quint, 4H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([CH2:12]Br)[CH:10]=2)[C:5]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([CH3:12])[CH:10]=2)[C:5]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: COc1cc(CBr)cc2c(Br)ccc(OC(C)C)c12
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: ClCCl
Product: COc1cc(C)cc2c(Br)ccc(OC(C)C)c12
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a 0° C. cold solution of 7.60 g (19.6 mmol) 1-bromo-7-bromomethyl-4-isopropoxy-5-methoxy-naphthalene in 150 mL dry dichloromethane, 20.0 mL (20.0 mmol) of a 1M L-selectride-solution was added under Ar. After 2 h, further 2.50 mL (2.50 mmol) 1M L-selectride-solution was added. After that the solvent was removed in vacuo and the residue was filtered over a short silica gel column (petroleum/acetone, 30:1). After removal of the solvent in vacuo, the residue was recrystallized from acetone to give 5.90 g (98%) of 4 as colorless needles (m.p. 78° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34]4[O:38][CH:37]=[N:36][C:35]=4[C:39]([O:41]CC)=[O:40])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[OH-].[Na+].O1CCCC1.Cl>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:29][CH2:30][C@H:31]([C:34]4[O:38][CH:37]=[N:36][C:35]=4[C:39]([OH:41])=[O:40])[CH2:32][CH2:33]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3ocnc3C(=O)OCC)CC2)c2ncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3ocnc3C(=O)O)CC2)c2ncnn12
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 5-(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)-1,3-oxazole-4-carboxylate (1.3 g), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (10 mL) and methanol (10 mL) was stirred at 50° C. for 16 hr. 1N Aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.94 g, 76%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:11][S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([CH3:27])[CH:4]=1)#[N:2].[OH-:28].[Na+].OO>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:11][S:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:5]([CH3:27])[CH:4]=1)(=[O:28])[NH2:2]
Reactant: COc1ccc(-c2scc(CCC(=O)O)c2-c2ccc(C#N)cc2C)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(-c2scc(CCC(=O)O)c2-c2ccc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
To a solution of 3-(4-(4-cyano-2-methylphenyl)-5-(4-methoxyphenyl)thiophen-3-yl)propanoic acid (30 mg, 0.08 mmol) in DMSO (5 mL) was added NaOH (6 mg, 0.16 mmol), and 30% H2O2 (9 mg, 0.08 mmol). The mixture was stirred at room temperature for 2 h, and purified by preparative HPLC to give 16 mg of the title compound, Example 14 (Scheme III, 17, X1=4-carbamoyl-2-methylphenyl, X2=4-methoxyphenyl) (yield 52%) as a white solid. 1H NMR (CD3OD 400 MHz TMS): δ7.72 (s, 2H), 7.26 (d, J=8.4 Hz, 1H), 7.14 (s, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 3.70 (s, 3H), 2.57 (t, J=7.2 Hz, 2H), 2.38 (t, J=8.0 Hz, 2H), 1.96 (s, 3H); MS (ESI): m/z 317.9 [M+23]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:38].[H][H]>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([CH2:24][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[CH:19][CH:18]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:38]
Reactant: COCC#Cc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCCCc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 96 %

Procedure:
In a similar manner to Step 1 of Example 328, 4-(3-methoxy-1-propinyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (157 mg, 0.306 mmol) was dissolved in methanol (6.3 mL), and the solution was added with 10% Pd—C (46 mg) to react hydrogen. The reaction mixture was filtered using Celite. The solvent of the filtrate was evaporated under reduced pressure to obtain 4-(3-methoxypropyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (152 mg, yield 96%).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][O:5][CH2:20][CH:19]=[CH2:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
To a solution of Boc-L-HomoSer-OH (10.0 g, 45.6 mmol) in DMF was added sodium hydride (2.74 g, 114 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 mins, and then allyl bromide (6.90 g, 57.0 mmol) was added. The mixture was warmed to 20° C. and stirred for 2 hrs. The mixture was quenched with saturated NH4Cl solution and then concentrated in vacuum. The residue was diluted with water, and sequentially washed with hexane and ether. The organic layers were discarded, and the aqueous layer was carefully adjusted to pH=3 with 1 N HCl. The acidic aqueous solution was extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated in vacuum to give Boc-L-HomoSer(O-allyl)-OH (8.00 g, 67.8%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C1COCC1>[CH3:5][O:4][N:3]([CH3:2])[C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([CH3:6])=[CH:8][CH:9]=1
Reactant: CNOC
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100.9 %

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (8.20 g) in THF (dry) (75 mL) was added TEA (23.4 mL) at 0° C. After being stirred at 0° C. for 20 min, 4-methylbenzoyl chloride (10 g) in THF (dry) (20 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 2 days. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give N-methoxy-N,4-dimethylbenzamide (11.7 g) as a yellow oil. n-Butyllithium (1.6 M in hexane) (25.1 mL) was added dropwise to a mixture of 1,4-dibromobenzene (8.29 g) in THF (dry) (105 mL) at −78° C. for 10 min. The mixture was stirred at the same temperature under nitrogen for 30 min to form white precipitates. A solution of N-methoxy-N,4-dimethylbenzamide (6 g) in THF (dry) (20 mL) was added to the reaction mixture at −78° C. and the mixture was stirred at the same temperature under nitrogen for 30 min and then at room temperature under a dry atmosphere with anhydrous calcium chloride tube overnight. The mixture was quenched with sat. NH4Cl aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (7.18 g) as a pale yellow solid.
Reaction SMILES: [C:1](=[NH:24])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=2)=[C:8]([F:23])[CH:7]=1)[NH2:2].[OH:25]/[CH:26]=[C:27](\[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=1)/[C:28](OC)=O.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:23][C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][O:3][C:1]2[NH:2][CH:28]=[C:27]([CH2:32][C:33]3[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=3)[C:26](=[O:25])[N:24]=2)[CH:11]=[CH:10][C:9]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]=1
Reactant: N=C(N)OCCc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Reactant: COC(=O)/C(=C/O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4cccc(C(F)(F)F)n4)c(F)c3)nc2=O)cn1
Temperature: 160 °C
Yield: 21.7 %

Procedure:
A mixture of 2-(3-fluoro-4-{[6-(trifluoromethyl)-2-pyridinyl]oxy}phenyl)ethyl imidocarbamate (44 mg, 0.089 mmol), methyl (2E)-3-hydroxy-2-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-propenoate (30.1 mg, 0.134 mmol), and K2CO3 (37.1 mg, 0.268 mmol) in NMP (15 mL) was heated with a microwave reactor at 160° C. for 1 h. Purification via reverse phase flash chromatography then afforded the title compound (10 mg, 21.63% yield). LCMS: rt=3.13 min, [M+H]=518