Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([NH:22][C@H:23]([CH3:27])[C:24](O)=[O:25])=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:27][C@@H:23]([NH:22][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:29]=[CH:28][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21])[C:24]([N:34]1[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]1)=[O:25]
Reactant: CN1CCNCC1
Reactant: C[C@@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C)C(=O)N1CCN(C)CC1
Yield: 33.6 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [(R)-1-methyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]amide (20 mg) was prepared by following General Procedure F starting from (R)-2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid (50 mg), 1-methyl-piperazine (50 mg), HBTU (150 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 511.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.82-8.67 (m, 1H), 8.12 (m, 1H), 7.97 (s, 1H), 7.85-7.83 (m, 1H), 7.56-7.52 (m, 2H), 7.44-7.41 (m, 1H), 5.02-4.96 (m, 1H), 4.50-4.43 (m, 1H), 4.35-4.19 (m, 1H), 3.69 (s, 3H), 3.62-3.51 (m, 2H), 3.45 (m, 1H), 3.28 (m, 1H), 3.10 (m, 1H), 2.78-2.77 (d, 3H), 1.44-1.35 (m, 3H)—NH proton signal was not observed.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[N:7]=2)[CH:3]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([O-:30])=O)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[O:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:1][C:2]3[CH:10]=[CH:9][C:8]4[C:4](=[CH:5][N:6]([C:11]5[CH:16]=[CH:15][C:14]([N:17]6[CH2:22][CH2:23][O:18][CH2:19][CH2:20]6)=[CH:13][CH:12]=5)[N:7]=4)[CH:3]=3)=[O:30])=[CH:31][CH:32]=2)[CH2:22][CH2:23]1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Reactant: Nc1ccc(-n2cc3cc(N)ccc3n2)cc1
Product: O=C(Nc1ccc2nn(-c3ccc(N4CCOCC4)cc3)cc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 538 was prepared according to the procedure described in Scheme IV from 5-amino-2-(4-aminophenyl)indazole and 4-morpholinobenzoate. [M+H]+ calcd for C28H29N5O3: 484.23; found: 484.13.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:23])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:24][C:25]1([CH3:65])[C:51]2[C:46](=[C:47](P(C3C=CC=CC=3)C3C=CC=CC=3)[CH:48]=[CH:49][CH:50]=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=C[C:26]1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[N:18]1([CH2:17][CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:5]3[N:4]=[C:3]([NH:23][C:5]4[N:4]=[C:3]([NH:23][C:47]5[CH:48]=[CH:49][CH:50]=[C:51]([C:25]([CH3:24])([CH3:26])[CH3:65])[CH:46]=5)[C:2]([CH3:1])=[CH:7][N:6]=4)[C:2]([CH3:1])=[CH:7][N:6]=3)=[CH:14][CH:13]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: Cc1cnc(Nc2ccc(OCCN3CCCC3)cc2)nc1N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cnc(Nc2nc(Nc3ccc(OCCN4CCCC4)cc3)ncc2C)nc1Nc1cccc(C(C)(C)C)c1
Yield: 94.5 %

Procedure:
A mixture of intermediate 41 (210 mg, 0.67 mmol), intermediate 38 (185 mg, 0.67 mmol), Pd2(dba)3 (55 mg, 0.06 mmol). Xantphos (104 mg, 0.18 mmol) and cesium carbonate (782 g, 2.4 mmol) were suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (94 mg of HCl salt, 24%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([N:13]=[C:14]=O)([CH3:12])[CH3:11])[CH:5]=1)=[CH2:3].[CH:16]1([N:22]=C=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([N:22]=[C:14]=[N:13][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([CH3:1])=[CH2:3])[CH:5]=2)([CH3:12])[CH3:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Reactant: O=C=NC1CCCCC1
Product: C=C(C)c1cccc(C(C)(C)N=C=NC2CCCCC2)c1
Temperature: 150 °C

Procedure:
We combined 0.0830 g TPAO, 60.41 g of m-TMI, and 25.04 g cyclohexylisocyanate. After heating at 150° C. for 7 hours, IR showed nearly complete conversion of isocyanates to carbodiimides. 1H--NMR indicated the desired product contaminated with 1,3-dicyclohexylcarbodiimide, and 1,3-bis[2-(3-isopropenylphenyl)-2propyl]carbodiimide.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[CH2:30][N:31]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:32][CH3:33])[C:9](OS(C(F)(F)F)(=O)=O)=[CH:10][CH:11]=1)C.[C:45]1(B(O)O)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(=O)([O-])[O-].[K+].[K+].N#N>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.O.COCCOC>[CH2:37]([O:36][C:34]([N:31]([CH2:30][C:21]1[CH:22]=[C:23]([C:26]([F:29])([F:27])[F:28])[CH:24]=[CH:25][C:20]=1[C:8]1[C:9]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:44])[CH:7]=1)[CH2:32][CH3:33])=[O:35])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1-c1ccccc1)C(=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of {2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester (0.11 g, 0.17 mmol), phenylboronic acid (0.023 g, 0.19mmol), and potassium carbonate (0.070 g, 0.51 mmol) in 2:1 DME:H2O (5 mL) was purged with N2 for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.02 mmol) was added, and the reaction was purged with N2 for another 10 minutes, and then stirred at 90° C. overnight. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound. M+H is 548.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[S:13]([OH:16])(=[O:15])=[O:14])([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:21]O>CN(C=O)C>[CH3:21][O:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[S:13]([OH:16])(=[O:15])=[O:14])=[O:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reactant: CO
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of 190.0 g (0.77 mol) of 2-carboxy-5-nitrobenzenesulfonic acid, 10 ml of DMF and 250 ml (3.43 mol) of thionyl chloride is heated at boiling for 3 h. After separating off the insoluble constituents by filtration, the filtrate is concentrated. 200 ml (4.94 mol) of methanol are added to the residue which results. When addition is complete the reaction mixture is cooled to 0° C. The solid which precipitates is filtered off and dried. 70.9 g (35.3% of theory) of colorless, crystalline 2-methoxycarbonyl-5-nitrobenzenesulfonic acid (m.p.: 92°-94° C.) are thus obtained. By distilling off the volatile components from the mother liquor, a second fraction (62.5 g, 31.1% of theory) is obtained.
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[CH:8]1[S:13][CH2:12][CH2:11][CH2:10][S:9]1.[CH2:16]([N:23]1[C:31]2[C:30](=[O:32])[N:29]([CH2:33][CH2:34][CH3:35])[C:28](=[O:36])[N:27]([CH2:37][CH2:38][CH3:39])[C:26]=2[N:25]=[C:24]1[CH:40]1[CH2:44][CH2:43][C:42](=O)[CH2:41]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CCCCCC.O1CCCC1>[CH2:16]([N:23]1[C:31]2[C:30](=[O:32])[N:29]([CH2:33][CH2:34][CH3:35])[C:28](=[O:36])[N:27]([CH2:37][CH2:38][CH3:39])[C:26]=2[N:25]=[C:24]1[CH:40]1[CH2:41][CH2:42][C:43](=[C:8]2[S:13][CH2:12][CH2:11][CH2:10][S:9]2)[CH2:44]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCn1c(=O)c2c(nc(C3CCC(=O)C3)n2Cc2ccccc2)n(CCC)c1=O
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCn1c(=O)c2c(nc(C3CCC(=C4SCCCS4)C3)n2Cc2ccccc2)n(CCC)c1=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
At -75° C. 14.37 ml (0.023 mol) of a 1.6M solution of butyl lithium in n-hexane is added dropwise to 4.0 g of 2-trimethylsilyl-1,3-dithiane (0.021 mol) in 15 ml of absolute tetrahydrofuran and the mixture is stirred for a further 30 minutes at -70° C. Then at the same temperature a solution of 8.0 g (0.020 mol) of 7-benzyl-8-(3-oxocyclopentyl)-1,3-dipropylpurine-2,6-dione in 70 ml of absolute tetrahydrofuran is added dropwise. The mixture is stirred for 2 hours at -70° C. and then for 2 hours at -30° C., then water is carefully added at -30° C. The phases are separated, the organic phase is evaporated down, the residue is taken up in dichloromethane, washed with water and the solution is dried and evaporated down. Purification is carried out by chromatography on silica gel using a mixture of cyclohexane/ethyl acetate as eluant in the ratio 3:1. 3.55 g (35.5% of theory) of the title compound are obtained in the form of a yellowish oil which crystallises when left to stand.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:30]([S:33]([N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:66])[C:51]3[CH:56]=[CH:55][C:54](B4OC(C)(C)C(C)(C)O4)=[CH:53][CH:52]=3)=[CH:45][CH:44]=2)[CH2:38][CH2:37]1)(=[O:35])=[O:34])[CH2:31][CH3:32].C([O-])(O)=O.[Na+]>COCCOC.O>[CH2:25]([S:22]([N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([C:54]4[CH:55]=[CH:56][C:51]([C:50]([NH:49][C:46]5[CH:47]=[CH:48][C:43]([CH2:42][N:39]6[CH2:40][CH2:41][N:36]([S:33]([CH2:30][CH2:31][CH3:32])(=[O:34])=[O:35])[CH2:37][CH2:38]6)=[CH:44][CH:45]=5)=[O:66])=[CH:52][CH:53]=4)=[CH:3][CH:4]=3)=[O:7])=[CH:10][CH:11]=2)[CH2:17][CH2:18]1)(=[O:24])=[O:23])[CH2:26][CH3:27]
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(Br)cc3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4ccc(C(=O)Nc5ccc(CN6CCN(S(=O)(=O)CCC)CC6)cc5)cc4)cc3)cc2)CC1
Temperature: 80 °C
Yield: 15.2 %

Procedure:
A mixture containing 5 (88.8 mg, 0.18 mmol), 6 (101.4 mg, 0.19 mmol), Pd(TPP)4 (9.1 mg, 0.008 mmol), and NaHCO3 (57.1 mg, 0.68 mmol) in DME/H2O (4.5:1 v/v, 7 mL) was heated at 80° C. for 19 h, allowed to cool to rt, and evaporated to dryness. The remaining crude product was washed with H2O (3×10 mL) and dried, then a portion (60.5 mg of the 178.1 mg isolated) was purified by PTLC to give the title product (21.9 mg). Rf 0.38 (100:10:1 v/v CHCl3/MeOH/NH4OH (28%)). HPLC: tR 1.68 min (method 1). LC-MS m/z calcd for C42H52N6O6S2 ([M]+), 800. found, 801 ([M+H]+). 1H NMR (DMSO-d6): δ 0.92 (t, J=7.5 Hz, 3H), 1.62 (m, 2H), 2.38 (m, 4H), 2.95 (m, 2H), 3.10 (m, 4H), 3.44 (br s, 2H), 7.23 (m, 2H), 7.70 (m, 2H), 7.87 (m, 2H), 8.03 (m, 2H), 10.25 (s, 1H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[N:30]([CH3:31])[C:19]2=[N:20][CH:21]=[C:22]([S:24]([C:26]([F:29])([F:28])[F:27])=[O:25])[CH:23]=[C:18]2[N:17]=1)(=[O:5])=[O:4])[CH3:2].[OH:32]O.C(#N)C>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].O>[CH2:1]([S:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[N:30]([CH3:31])[C:19]2=[N:20][CH:21]=[C:22]([S:24]([C:26]([F:29])([F:27])[F:28])(=[O:32])=[O:25])[CH:23]=[C:18]2[N:17]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: OO
Reactant: CCS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1nc2cc(S(=O)C(F)(F)F)cnc2n1C
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1nc2cc(S(=O)(=O)C(F)(F)F)cnc2n1C
Temperature: 25 °C

Procedure:
A mixture of 2-(2-ethylsulfonyl-4-trifluoromethylphenyl)-3-methyl-6-trifluoromethylsulfinyl-3H-imidazo[4,5-b]pyridine (0.26 g), sodium tungstate dihydrate (36 mg), 30% of aqueous hydrogen peroxide solution (1 ml) and acetonitrile (5 ml) was stirred under reflux for 4.5 hours. The mixture was cooled to room temperature. Into the reaction mixture, water was poured, and extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.24 g of 2-(2-ethylsulfonyl-4-trifluoromethylphenyl)-3-methyl-6-trifluoromethylsulfonyl-3H-imidazo[4,5-b]pyridine (hereinafter, Present Compound 302).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19](=[O:22])[CH2:20]Cl)=[N:17][C:12]3=[CH:11][CH:10]=2)=[CH:6][C:5]([NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=2)=[C:4]([F:37])[CH:3]=1.C(N(CC)CC)C.[CH2:45]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH3:46]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19](=[O:22])[CH2:20][N:50]4[CH2:51][CH2:52][N:47]([CH2:45][CH3:46])[CH2:48][CH2:49]4)=[N:17][C:12]3=[CH:11][CH:10]=2)=[CH:6][C:5]([NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:32])[CH3:33])[CH:26]=2)=[C:4]([F:37])[CH:3]=1
Reactant: CCN1CCNCC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CCl)sc4n3)c(Cl)cc2F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN1CCN(CC(=O)Nc2nc3ccc(Oc4cc(NC(=O)c5cccc(C(C)(C)C#N)c5)c(F)cc4Cl)nc3s2)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
N-[4-Chloro-5-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]-3-(1-cyano-1-methylethyl)benzamide synthesized above was dissolved in tetrahydrofuran (3.0 mL), triethylamine (128 μL, 0.933 mmol) and N-ethylpiperazine (118 μL, 0.933 mmol) were added, and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), washed with water (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→85/15), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/hexane to give the title compound (133 mg, 67%) as a colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4](OCC)(OCC)[CH3:5])[CH3:2].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13]>C(OC(=O)C)(=O)C>[C:12](/[C:14](=[C:1](\[O:3][CH2:4][CH3:5])/[CH3:2])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)/C(C#N)=C(\C)OCC
Temperature: 95 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
A mixture of 1,1,1-triethoxyethane (25 g, 154.11 mmol, 1.00 equiv), ethyl 2-cyanoacetate (15 g, 132.61 mmol, 0.86 equiv) in acetic anhydride (100 mL) was stirred at 95° C. for 8 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. The solid was collected by filtration to give 4.4 g (16%) of (E)-ethyl 2-cyano-3-ethoxybut-2-enoate as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 4.31-4.19 (m, 4H), 2.61 (s, 3H), 1.46 (t, J=6.3 Hz, 3H), 1.32 (t, J=6.3 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.31 min, m/z=184.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[S:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[N:6]=[C:7]([S:19][CH3:23])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CI
Reactant: CCN1c2ncccc2C(=S)Nc2c(C)cc(C)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1c2ncccc2C(SC)=Nc2c(C)cc(C)nc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution of 5,11-dihydro-2,4-dimethyl-11-ethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-thione (0.2 g, 0.7 mmol) in dimethylformamide (10 mL) was added NaH (50% in mineral oil, 0.04 g, 0.8 mmol). The mixture was stirred under argon at 40° C. for 1 hr. After cooling to 30° C. methyl iodide (0.12 g, 0.8 mmol) was added, and the mix was stirred for 1 hr. The reaction was quenched with water, and the mixture was concentrated in vacuo. The residue was treated with ethyl acetate, washed, dried, and concentrated. Chromatography over silica gel (eluted with 20% EtOAc/Hex) gave 0.2 g of the title compound, m.p. 130°-132° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: C1CNCCN1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 1.0 g (3.35 mmole) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.15 g (13.4 mmole) of piperazine, 1.36 g (13.35 mmole) of triethylamine and 60 ml of acetonitrile is refluxed for three hours and then stirred at room temperature for 16 hours. The precipitate is removed by filtration, washed with acetonitrile and dried in vacuo at 60° C. to give 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid, mp 257°-259° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[F:37])[C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:22][CH2:23][CH3:24])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[Li+].[OH-].Cl>C(#N)C>[CH2:1]([N:5]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:28]=1[F:37])[C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:22][CH2:23][CH3:24])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(C(F)(F)F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCN(Cc1ccc(C(F)(F)F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of ethyl(2S)-3-[4-(2-{butyl[2-fluoro-4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-ethoxypropanoate (0.748 g, 1.42 mmol) in acetonitrile (70 mL) was added aqueous 0.10 M LiOH (35 mL) and the reaction mixture was stirred at room temperature overnight. After neutralisation with 5% HCl, the solvent volume was reduced in vacuo and the remaining aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.688 g (97%) of a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl-].[NH4+:14].[OH-].[NH4+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:7]([C:8]([NH2:14])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: [NH4+]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Product: NC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.8 %

Procedure:
To a mixture of ethyl 2-chloro-3-pyridinecarboxylate (1.85 g, 10 mmol), ammonium chloride (0.53 g, 10 mmol) and 15 mL of ammonium hydroxide (150 mmol) was added tetrabutylammonium bromide (0.32 g, 1 mmol). The mixture was stirred at ambient temperature for 18 hours, concentrated, washed with water and methanol, and dried to give 0.78 g (50%) of the title compound (m.p. 164°-166° C., uncorrected).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9]C(C)=[N:7][C:6]=2[CH:11]=1.Cl>C(O)CO.[OH-].[Na+]>[NH2:7][C:6]1[CH:11]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[SH:9]
Reactant: Cc1nc2cc(F)ccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: Nc1cc(F)ccc1S
Temperature: 129 °C

Procedure:
A solution of 5-fluoro-2-methylbenzo[d]thiazole (1.2 g, 7.18 mmol) in ethylene glycol and NaOH (5N, 2 ml) was degassed under N2 for 10 min, then refluxed at 129° C. for 3 hours. The solution was cooled to 0° C. and then acidified to pH 3˜4 using c. HCl. The mixture was extracted with EtOAc (2×50 ml). The organic layer was washed with brine and dried with Na2SO4 and concentrated in vacuo. The crude residue (1.01 g, 98%) was used directly in the next step without purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][CH3:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Yield: 96.4 %

Procedure:
Potassium carbonate (1.65 gm; 12 mmol) was added to a solution of 2-methoxy-5-nitro phenol (1.69 g; 10 mmol) and benzyl bromide (1.71 gm; 10 mmol) in acetone (60 ml). The reaction mixture was refluxed for 12 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The ethyl acetate layer was separated, washed with water (2×50 ml), dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 2.5 g of 1-Benzyloxy-2-methoxy-5-nitrobenzene (Yield=96.5%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][OH:48])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:49][S:50](Cl)(=[O:52])=[O:51]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][O:48][S:50]([CH3:49])(=[O:52])=[O:51])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCO)CCC3)cc1
Reactant: CS(=O)(=O)Cl
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCOS(C)(=O)=O)CCC3)cc1

Procedure:
In analogy to the procedure described in example 8(b), the (3R,4R)-3-[1-(2-hydroxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 5(a)] was treated with methanesulfonyl chloride to yield the (3R,4R)-3-[1-(2-methanesulfonyloxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil; MS: 739 (M+H)+.