Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2.O>C(O)(=O)C>[Br:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([N:6]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])=[C:4]([F:13])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CC(C)Oc1cc(N)c(F)cc1Br
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Br
Temperature: 25 °C
Yield: 51.9 %

Procedure:
4-Bromo-2-fluoro-5-isopropoxyaniline (2.0 g) and 3,4,5,6-tetrahydrophthalic anhydride (1.23 g) were dissolved in acetic acid (10 ml) and refluxed for 3 hours. The resultant mixture was allowed to cool to room temperature and poured into water, followed by extraction with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and subjected to filtration. The filtrate was concentrated under reduded pressure, and the residue was purified by silica gel chromatography to obtain 1.6 g of N-(4-bromo-2-fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (Compound No. 2). M.P., 116.5°-117.5° C.
Reaction SMILES: NC(N)=[S:3].Cl[C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=2[N:7]=1>C(O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=3[N:7]=[C:6]2[SH:3])=[CH:13][CH:14]=1
Reactant: Fc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: Fc1ccc(Cn2c(S)nc3ccccc32)cc1

Procedure:
A mixture of 8.35 parts of thiourea, 26 parts of 2-chloro-1-[(4-fluorophenyl)methyl]-1H-benzimidazole and 400 parts of ethanol was stirred and refluxed for 5 hours. The reaction mixture was evaporated. The residue was suspended in 2,2'-oxybispropane. The precipitated product was filtered off and crystallized from ethanol, yielding 6.1 parts of 1-[(4-fluorophenyl)methyl]-1H-benzimidazole-2-thiol; mp. 194.7° C. (62).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@:4]([CH2:7][CH2:8][C:9]#[N:10])([CH3:6])[NH2:5].C(N(CC)CC)C.C([O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32]C(=O)C)[C:26](Cl)=[O:27])(=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C@:4]([CH2:7][CH2:8][C:9]#[N:10])([CH3:6])[NH:5][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([OH:32])=[C:23]([OH:22])[CH:24]=1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Reactant: COC(=O)[C@](C)(N)CCC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@](C)(CCC#N)NC(=O)c1ccc(O)c(O)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
1.56 g of 2-(2-cyanoethyl)alanine methyl ester and 1.4 ml of triethylamine were added to a solution of crude 3,4-diacetoxybenzoyl chloride (prepared from 1.96 g of 3,4-diacetoxybenzoic acid and 2.08 g of phosphorus pentachloride) in 30 ml of dichloromethane, at 5° C. The reaction mixture was stirred at 0°-5° C. for one hour and then washed with 30 ml of water. The organic layer was separated off and dried over magnesium sulphate, and the solvent was distilled off. The resulting residue was dissolved in 10 ml of methanol, 8.3 ml of 28% aqueous ammonia solution were added, and the solution was stirred at room temperature for 23 hours. The mixture was then cooled to 5° C., adjusted to pH 2.0 with concentrated hydrochloric acid, diluted with 50 ml of water, and extracted with two 50 ml portions of dichloromethane. The organic extract was dried over magnesium sulphate, the solvent was distilled off, and the resulting residue was purified by silica gel chromatography (eluent: 2:1 mixture of cyclohexane and ethyl acetate), to give 1.60 g of the desired product as a colourless glass.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[N:3]=1.[F:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[F:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[N:3]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(-c5ccccc5F)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Yield: 72.8 %

Procedure:
To a solution of 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (500 mg, 0.85 mmol) and 2-fluorophenylboronic acid (143.5 mg, 1.02 mmol) in p-dioxane/H2O (3:1, 15 mL) was added K2CO3 (235.5 mg, 1.71 mmol) and Pd(PPh3)4 (49 mg, 0.0427 mmol). The reaction was heated at reflux for 24 h, quenched with H2O and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 50% EtOAc in Hex) to give to 5-(3-(4-(2-fluorophenyl)pyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (400 mg, 72.8%). MS (ESI, pos. ion) m/z: 647.1 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.06-8.97 (m, 2H), 8.42-8.17 (m, 2H), 8.12-8.03 (m, 3H), 7.91 (dd, J=8, 1.6 Hz, 1H), 7.65-7.53 (m, 5H), 7.46-7.40 (m, 4H), 7.28 (m, 2H), 6.88 (d, J=8 Hz, 2H), 4.35 (d, J=8 Hz, 2H), 3.72 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[C:17](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:16]=[C:15]([NH:27][C:28]3[NH:32][N:31]=[C:30]([CH3:33])[CH:29]=3)[C:14]=2[N+:34]([O-])=O)[CH2:9][CH2:8]1>Cl.CO.C(OCC)(=O)C.[OH-].[Na+]>[CH3:6][N:7]1[CH2:8][CH2:9][N:10]([C:13]2[N:18]=[C:17](/[CH:19]=[CH:20]/[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:16]=[C:15]([NH:27][C:28]3[NH:32][N:31]=[C:30]([CH3:33])[CH:29]=3)[C:14]=2[NH2:34])[CH2:11][CH2:12]1
Reactant: Cc1cc(Nc2nc(/C=C/c3ccccc3)nc(N3CCN(C)CC3)c2[N+](=O)[O-])[nH]n1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Nc2nc(/C=C/c3ccccc3)nc(N3CCN(C)CC3)c2N)[nH]n1
Temperature: 60 °C
Yield: 53.9 %

Procedure:
A solution of tin (II) chloride dihydrate (600 mg, 4.43 mmol) in concentrated hydrochloric acid (1 mL), 9.04 mmol) was cooled below 10° C. A solution of 6-(4-methylpiperazin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-5-nitro-2-[(E)-2-phenylvinyl]pyrimidin-4-amine (Example 4, 400 mg, 0.95 mmol) in methanol (20 mL) was added dropwise to the reaction mixture. The reaction was allowed to come to ambient temperature and was then heated to 60° C. for 3 hours. Progress of the reaction was monitored by TLC. The reaction mixture was reduced to ⅓rd volume of the original volume under vacuum. The residue was diluted with ethyl acetate (40 mL) and 1N NaOH (20 mL) was added to the reaction mixture. The organic layer was separated, dried and the solvent evaporated under reduced pressure. The residue was then triturated with ethyl acetate and hexane to afford 6-(4-methylpiperazin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-[(E)-2-phenylvinyl]pyrimidin-4,5-diamine as a yellow solid (200 mg). 1H NMR (400 MHz, DMSO-d6): δ 7.94 (br, 1H), 7.70 (d, 1H, J=16 Hz), 7.59 (m, 2H) 7.38 (m, 2H), 7.29 (m, 1H), 7.05 (d, 1H, J=16 Hz), 6.36 (br, 1H), 3.44 (br, 2H), 3.3 (br, 4H), 2.59 (br, 4H), 2.36 (s, 3H), 2.33 (s, 3H). MS (m/z) 391 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[C:14]([CH3:25])[C:13]=2[CH:26]=1)C1C=CC=CC=1>C(O)C.O1CCCC1>[CH:19]1([C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:26][C:13]=3[C:14]=2[CH3:25])=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(OCc3ccccc3)cc12
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc(O)cc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl](cyclohexyl)methanone (7.3 g) synthesized in the above-mentioned (2) was dissolved in a ethanol (150 mL) and tetrahydrofuran (30 mL), and palladium carbon-ethylenediamine complex (1.0 g) was added at room temperature. The reaction mixture was stirred at 60° C. for 3 hr under hydrogen atmosphere (1 atm), allowed to cool to room temperature, and the catalyst was filtered. The filtrate was concentrated under reduced pressure to give a crude product (5.2 g, quantitative) of the title object compound as a colorless solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.O[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]CC)=[O:14]>>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([OH:15])=[O:14])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: OCC1CCOCC1
Product: O=C(O)c1cccc(OCC2CCOCC2)c1

Procedure:
Prepared from tetrahydro-2H-pyran-4-yl-methanol and ethyl 3-hydroxybenzoate.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:26].CSC.C(Cl)(=O)C>[Cl-].[Zn+2].[Cl-]>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:26]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@H](CCC(N)=O)OC3=O)cc2)CC1F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CSC
Solvent: CC(=O)Cl
Product: NC(=O)CC[C@H]1CN(c2ccc(N3CCC(=O)C(F)C3)cc2)C(=O)O1
Yield: 65 %

Procedure:
The compound was prepared by reacting (S)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with zinc chloride, dimethyl sulphide and acetyl chloride as per procedure described in Example E in 65% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:6]([O:8]CC)=[O:7].OS(O)(=O)=O.CC(O)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(OCCS(C)(=O)=O)c(OC)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(=O)O)ccc1OCCS(C)(=O)=O
Temperature: 90 °C

Procedure:
Ethyl 3-methoxy-4-(2-(methylsulfonyl)ethoxy)benzoate (30 mg, 0.099 mmol) was taken up in water (1.2 mL), H2SO4 (200 μL, 3.8 mmol), and AcOH (1300 μL, 23 mmol). The mixture was heated at 90° C. for 6 h before it was cooled to ambient temperature and was concentrated under vacuum. The residue was purified by column chromatography (1-40% MeOH/DCM) to give 3-methoxy-4-(2-(methylsulfonyl)ethoxy)benzoic acid. ESI-MS m/z calc. 274.1. found 275.1 (M+1)+; Retention time: 0.69 minutes (3 min run).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[Li]CCCC.[C:14]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:25][CH2:24]2)=[N:21][CH:22]=1)(=[O:16])[CH3:15]>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)([OH:16])[CH3:15])=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC(=O)c1cnc(N2CCN(C(=O)OCc3ccccc3)CC2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1cnc(N2CCN(C(=O)OCc3ccccc3)CC2)nc1)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of 2-bromo-5-fluoropyridine (1.3 g, 7.50 mmol) in anhydrous THF (30 mL) was added n-BuLi (2.76 mL, 6.62 mmol) at −78° C. dropwise, and the mixture was stirred at −78° C. for 2 h, followed by the addition of benzyl 4-(5-acetylpyrimidin-2-yl)piperazine-1-carboxylate (1.5 g, 4.41 mmol). The reaction mixture was allowed to warm to RT and stirred overnight. LCMS showed the reaction was completed. The solution was quenched with aqueous NH4Cl (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC to afford the title compound (0.4 g, 20%) as a white solid. MS (ES+) C23H24FN5O3 requires: 437. found: 438 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:20]=[N:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][O:14][CH2:15][CH3:16])=[O:12])=[C:4]([CH3:21])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:20]=[N+:19]([O-:30])[CH:18]=[CH:17][C:10]=2[C:11]([NH:13][O:14][CH2:15][CH3:16])=[O:12])=[C:4]([CH3:21])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCONC(=O)c1ccncc1Nc1ccc(Br)cc1C
Solvent: ClCCl
Product: CCONC(=O)c1cc[n+]([O-])cc1Nc1ccc(Br)cc1C
Yield: 44 %

Procedure:
3-[(4-Bromo-2-methylphenyl)amino]-N-ethoxyisonicotinamide 3b (80.0 mg, 0.228 mmol) was dissolved in 4 ml dry DCM and 3-chloroperbenzoic acid (73% pure, 60 mg) was added at ambient temperature. After 2 h the solvent was removed in vacuo and the crude material was purified by flash chromatography using silica gel and a gradient of 0-10% methanol in DCM as eluent to give 37 mg (101 μmol; 44% yield) of pure desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:23][C:24]([OH:26])=O.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH:36]([C:40]([NH2:42])=[O:41])[CH2:35]1.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:23][C:24]([N:37]1[CH2:38][CH2:39][N:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])[CH2:35][CH:36]1[C:40]([NH2:42])=[O:41])=[O:26]
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1CC(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-Methoxy-4-(1-Boc-4-piperidyloxy)phenylacetic acid (331 mg, 0.91 mmol), 4-(2-methylphenyl)piperazine-2-carboxamide (200 mg, 0.91 mmol), EDC (209 mg, 1.09 mmol), and HBT (141 mg, 1.04 mmol) were combined in DMF (7 ml) under nitrogen. The mixture was adjusted to pH ca. 9 (moistened E. Merck colorpHast indicator) by addition of triethylamine (0.4 ml) and stirred at ambient temperature for 72 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The ethyl acetate layer was washed with. sodium bicarbonate and with brine, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 3% methanol in methylene chloride. The combined product fractions were evaporated to dryness in vacuo to give 1-(2-methoxy-4-(1-Boc-4-piperdyloxy)phenylacetyl)-4-(2-methylphenyl)piperazine-2-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:24](=O)[CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[C:18]([CH3:36])[CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([NH:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[C:18]([CH3:36])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(NC(=O)CCOc4ccccc4C)cc3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3cc(C)c(NCCCOc4ccccc4C)cc3C)c2cc1OC
Temperature: 0 °C
Yield: 79.8 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-3-(2-methylphenoxy)propaneamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 473 (M++1)
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Br:43][C:44]1[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:46][C:45]=1I.[NH2:55][C:56]1[CH:61]=[CH:60][C:59]([S:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=[CH:58][C:57]=1/[CH:70]=[CH:71]/[C:72]([O:74]CC)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:63]([S:62][C:59]1[CH:58]=[C:57]2[C:56](=[CH:61][CH:60]=1)[N:55]([C:45]1[CH:46]=[CH:47][C:48]([C:50]([F:53])([F:52])[F:51])=[CH:49][C:44]=1[Br:43])[C:72](=[O:74])[CH:71]=[CH:70]2)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Reactant: FC(F)(F)c1ccc(I)c(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1ccc(C(F)(F)F)cc1Br

Procedure:
A solution of xantphos (0.277 g, 0.479 mmol), Pd2(dba)3 (0.146 g, 0.160 mmol), 2-bromo-1-iodo-4-(trifluoromethyl)benzene (Oakwood Chemical, 1.232 g, 3.51 mmol), (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (1.000 g, 3.19 mmol), and potassium phosphate (2.032 g, 9.57 mmol) in 10 mL dioxane was heated to 90° C. for 5 hours. The reaction mixture was diluted with water and extracted with DCM. The organics were dried over MgSO4 and concentrated. The crude residue was used in the next step without purification. m/z (ESI) 536.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([OH:23])[CH3:22])[CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:25][NH:26][C:27](=O)OC(C)(C)C)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C.Cl>C(O)C>[CH3:27][NH:26][CH2:25][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]([S:12]([C:15]2[CH:16]=[C:17]([C:21]([OH:23])([CH3:24])[CH3:22])[CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(C)(C)O)c2)c1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(C)(C)O)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To a solution of tert-butyl [1-(5-phenyl-1-{[3-(1-methyl-1-hydroxyethyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]carbamate (334 mg) in ethanol (4 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (4.0 mL) and the mixture was stirred at room temperature for 3 hr. After the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate) to give the title compound as a white solid (yield 203 mg, 76%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1([C:8]([NH2:10])=[O:9])[CH2:7][NH:6][CH2:5]1)[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:21]1[N:26]2[C:27](=[O:30])[NH:28][N:29]=[C:25]2[C:24]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[C:23]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[N:22]=1>CCO>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C:23]2[N:22]=[C:21]([N:6]3[CH2:7][C:4]([NH:3][CH2:1][CH3:2])([C:8]([NH2:10])=[O:9])[CH2:5]3)[N:26]3[C:27](=[O:30])[NH:28][N:29]=[C:25]3[C:24]=2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:39][CH:40]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Reactant: CCNC1(C(N)=O)CNC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3n[nH]c(=O)n23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
To a stirred suspension of 3-(ethylamino)azetidine-3-carboxamide (25 mg, 0.17 mmol) in EtOH (1.0 mL) at room temperature under argon was added N,N-diisopropylethylamine (60 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 10 min to obtain a clear solution to which was added 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (60 mg, 0.15 mmol). The reaction mixture was stirred at 60° C. in a pre-heated oil bath for 5 min. The reaction mixture was then concentrated under reduced pressure, and the residue was dissolved in CH2Cl2 (5 mL). The resulting mixture was washed with water (2 mL×2), dried (MgSO4), and concentrated under reduced pressure to obtain the crude product. This crude product was purified by preparative reverse phase HPLC (without TFA) to obtain 35 mg of the title compound as a pale yellow solid. HPLC/MS: retention time=3.306 min, [M+H]30 =498.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][C:7]1[C:16]([CH3:17])=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:18])[NH:14]2)=[CH:9][C:8]=1[CH2:19][CH2:20]C(OCC)=O.[OH-:26].[Na+].Cl>CCO.C1COCC1>[CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][C:7]1[C:16]([CH3:17])=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:18])[NH:14]2)=[CH:9][C:8]=1[CH2:19][CH2:20][NH:14][C:13](=[O:18])[O:26][C:7]([CH3:16])([CH3:8])[CH3:6]
Reactant: CCOC(=O)CCc1cc2c(c(C)c1CCOCOC)NC(=O)CC2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COCOCCc1c(CCNC(=O)OC(C)(C)C)cc2c(c1C)NC(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10.81 g of ethyl 3-{7-[2-(methoxymethoxy)ethyl]-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}propanoate in 100 ml of EtOH and 100 ml of THF was added 100 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 1 hour. The reaction mixture was neutralized by the addition of hydrochloric acid and then concentrated under reduced pressure to one third of the liquid amount, and the residue was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. To a solution of the resulting residue in 300 ml of t-butanol were added 9.0 ml of triethylamine and 7.0 ml of DPPA, followed by heating and refluxing for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc), and then the resulting solid was washed with HEX to obtain 8.006 g of t-butyl (2-{7-[2-(methoxymethoxy)ethyl]-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}ethyl)carbamate as a milky white solid.