Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[C:13](=O)([O-])[O-:14].[K+].[K+]>CO.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:14][CH3:13])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCc1cccc(C(=O)OC)c1
Temperature: 55 °C
Yield: 100.8 %

Procedure:
A mixture of 3-bromomethyl-benzoic acid methyl ester (556 mg, 2.4 mmol) and potassium carbonate (670 mg, 4.9 mmol) in methanol (10 ml) and tetrathydrofuran (10 ml) was heated at 55° C. for 2 h. After cooling, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. After drying in vacuo, 3-methoxymethyl-benzoic acid methyl ester (436 mg, quantitative) was isolated as a white solid. 1H NMR (CDCl3), δ (ppm): 8.01 (s, 1H), 7.98 (d, 1H), 7.55 (d, 1H), 7.43 (t, 1H), 4.50 (s, 2H), 3.92 (s, 3H), 3.41 (s, 3H).
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]([C:16]2[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=2)[C:19]([N:21]=[C:22]([NH2:24])[NH2:23])=[O:20])[CH:13]=[CH:14][CH:15]=1)=[O:10])C1C=CC=CC=1.O.C(=O)([O-])[O-].[K+].[K+]>CO.[C].[Pd]>[C:9]([C:11]1[N:12]([C:16]2[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=2)[C:19]([N:21]=[C:22]([NH2:23])[NH2:24])=[O:20])[CH:13]=[CH:14][CH:15]=1)([OH:10])=[O:8]
Reactant: NC(N)=NC(=O)c1cccc(-n2cccc2C(=O)OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(N)=NC(=O)c1cccc(-n2cccc2C(=O)O)c1
Yield: 45.5 %

Procedure:
10% Palladium-carbon (0.2 g) was added to a mixture of 2-[3-(2-benzyloxycarbonylpyrrol-1-yl)benzoyl]guanidine (1.2 g) in methanol and the mixture was hydrogenated at ambient temperature under an atmospheric pressure. After the mixture was added to water, and the mixture was adjusted to pH 10 with potassium carbonate. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in a mixture of water and ethyl acetate and the separated aqueous layer was adjusted to pH 5 with 6N-hydrochloric acid. The isolated precipitate was collected by filtration and the precipitate was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-[3-(2-carboxypyrrol-1-yl) benzoyl]guanidine (0.41 g).
Reaction SMILES: CCN([CH2:6][CH3:7])CC.S(Cl)(C1C=CC(C)=CC=1)(=O)=[O:9].[OH:19][CH2:20][CH2:21][N:22]1[C:31]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=3[C:38](=[O:39])[C:30]=2[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:40]>C(Cl)Cl>[C:6]([O:19][CH2:20][CH2:21][N:22]1[C:31]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=3[C:38](=[O:39])[C:30]=2[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:40])(=[O:9])[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Reactant: O=C1c2ccccc2-c2c1c1ccccc1c(=O)n2CCO
Solvent: ClCCl
Product: CC(=O)OCCn1c2c(c3ccccc3c1=O)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
Et3N (34.7 mg, 0.343 mmol), CH3COOAg (57.2 mg, 0.343 mmol), and TsCl (65.4 mg, 0.343 mmol) were added to the solution of 18 (50 mg, 0.172 mmol) in CH2Cl2 (50 mL). The reaction mixture was stirred at room temperature for 16 h, and then washed with sat. NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated, adsorbed onto SiO2, and purified by flash column chromatography (SiO2), eluting with EtOAc—CHCl3 (2:8) to afford the desired product as a red solid (38.5 mg, 67%): mp 221-224° C. IR (film) 1738, 1693, 1655, and 1506 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.75 (d, J=8.0 Hz, 1H), 8.37 (d, J=7.9 Hz, 1H), 7.75 (t, J=5.8 Hz, 2H), 7.67 (dd, J=1.1 and 5.8 Hz, 1H), 7.51-7.41 (m, 3H), 4.84 (t, J=6.2 Hz, 2H), 4.57 (t, J=6.1 Hz, 2H), 1.94 (s, 3H); probe-EI/CI-MS m/z (rel intensity) 334 (MH+, 100); HRMS (+EI/CI) calcd for M+: 333.1001. found: 333.1005; HPLC purity: 97.3% (MeOH, 100%), 98.0% (MeOH—H2O, 90:10).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:25])[C:20]([O:22]CC)=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.[F:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:25])[C:20]([NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:27]([F:26])[CH:28]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: Nc1cccc(F)c1
Product: O=C(Nc1cccc(F)c1)C(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Temperature: 100 °C
Yield: 16.5 %

Procedure:
Prepared from ethyl 2-(3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylamino)-2-oxoacetate (Example 2; 36 mg, 0.10 mmol) and 3-fluoroaniline (139 mg, 1.25 mmol) according to the procedure for Example 3, except the reaction was heated to 100° C. for 18 hours. The product was purified by preparative TLC (1:1 EtOAc/hexanes). The product was obtained as a white powder (7 mg, 6%). 1H NMR (400 MHz, CDCl3+MeOD-d3) δ 8.48 (d, J=6 Hz, 1H), 7.92 (m, 1H), 7.83 (d, J=6 Hz, 1H), 7.67 (m, 1H), 7.57 (d, J=6 Hz, 1H), 7.51 (m, 1H), 7.35 (m, 3H), 6.94 (m, 1H), 6.57 (d, J=6 Hz, 1H). LRMS (ESI pos) m/e 426 (M+1). HPLC: 97% purity (220 nm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([OH:15])=[O:14].CO[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.[CH3:26][O-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[C:22](\[O:23][CH3:26])/[C:21]1[CH:24]=[CH:25][CH:18]=[CH:19][CH:20]=1)/[C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COc1ccc(C=O)cc1
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2C1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CO/C(=C1/C(C)=C(CC(=O)O)c2cc(F)ccc21)c1ccccc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5-fluoro-2-methyl-3-indenylacetic acid (15 g, 0.072 mol), p-methoxybenzaldehyde (12.39 g, 0.091 mol) and sodium methoxide (13.0 g, 0.24 mol) are heated in methanol (200 ml) at 60° C. under nitrogen with stirring for 6 hours. After cooling, the reaction mixture is poured into 750 ml of ice-water, and is acidified with 2.5 N hydrochloric acid. The collected solid is triturated with a little ether to produce (Z)-5-fluoro-2-methyl-1-(-methoxybenzylidene)-3-indenylacetic acid (m.p. 184-186° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:20][N+:21]1[CH:26]=[C:25]([Cl:27])[N:24]=[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=1.[C:36]([O:40][CH3:41])(=[O:39])[C:37]#[CH:38].O>CN(C=O)C>[CH2:29]([O:28][C:23]1[C:22]2[N:21]([N:20]=[CH:38][C:37]=2[C:36]([O:40][CH3:41])=[O:39])[CH:26]=[C:25]([Cl:27])[N:24]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C#CC(=O)OC
Reactant: N[n+]1cc(Cl)nc(OCc2ccccc2)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnn2cc(Cl)nc(OCc3ccccc3)c12
Reaction time: 8 h
Yield: 44.2 %

Procedure:
Potassium carbonate (457 mg, 3.31 mmol) was added to a mixture of 1-amino-3-(benzyloxy)-5-chloropyrazin-1-ium 2,4,6-trimethylbenzenesulfonate 5.34 (992 mg, 2.28 mmol) and methyl propiolate (0.24 mL, 2.66 mmol) in DMF (11 mL) at room temperature. After stifling overnight, reaction mixture was poured into water and extracted with ethyl acetate. Combined organics were washed with 50% brine, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-30% ethyl acetate/hexanes) to yield methyl 4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyrazine-3-carboxylate 5.35 (320 mg).
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[C:7]([O:11][C:12]([N:14]1[CH2:21][C:20]2[C:19]([NH2:22])=[N:18][NH:17][C:16]=2[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C>C1COCC1>[CH2:3]([O:2][C:1]([N:17]1[C:16]2[CH2:15][N:14]([C:12]([O:11][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:13])[CH2:21][C:20]=2[C:19]([NH2:22])=[N:18]1)=[O:5])[CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]nc(N)c2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(N)c2c1CN(C(=O)OC(C)(C)C)C2
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of ethyl chlorocarbonate (8.9 ml, 93 mmol) in THF (250 ml) was added slowly to a mixture of 3-amino-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (20 g, 89 mmol) and DIEA (92 ml, 528 mmol) in THF (500 ml) at 0-5° C. The reaction was kept at the same temperature for two hours then allowed to reach r.t. and stirred overnight. The obtained mixture was evaporated to dryness under vacuum. The resulting residue was extracted with AcOEt and water. The organic phase was separated, dried over sodium sulfate and evaporated to dryness. The mixture was purified by flash-chromatography (eluent: ethyl acetate/cyclohexane 4/6 to 7/3) to give 19 g (72% yield) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].[Cl:9]N1C(=O)CCC1=O>C1COCC1.O>[Br:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: OCc1ccsc1Br
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(Cl)sc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-bromo-3-hydroxymethylthiophene from Example 1, Step 1 (13.0 g, 67.3 mmol) in THF (100 mL) and water (10 mL) was added N-chlorosuccinimide (9.88 g, 74.0 mmol) and the mixture was stirred at r.t. for 5 h and concentrated in vacuo. The residue was worked up as above to afford the desired product. The crude product was used directly.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.N1C=CC=CC=1.[S:36](N)([NH2:39])(=[O:38])=[O:37].O>C(Cl)(Cl)Cl>[ClH:1].[NH2:39][S:36]([N:26]1[CH2:27][CH2:28][CH2:29][C@H:24]([NH:23][C:21]([C:17]2[N:13]3[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[C:12]3=[N:19][C:18]=2[CH3:20])=[O:22])[CH2:25]1)(=[O:38])=[O:37]
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCCNC1
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCCN(S(N)(=O)=O)C1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
To 200 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-piperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride were added 5 ml of pyridine and 217 mg of sulfamide, followed by heating to reflux for 4 hours. After leaving to be cooled at room temperature, to the reaction mixture were added water and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The obtained solid was suspended in ethyl acetate, and 120 μl of a 4 M hydrogen chloride/ethyl acetate solution was added thereto. The resulting solid was collected by filtration and dried to obtain 151 mg of N-[(3S)-1-(aminosulfonyl)piperidin-3-yl]-8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxamide hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[C:19]([O:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CN(C=O)C.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>[NH2:1][C:2]1[C:7]2=[C:8]([C:30]3[CH:29]=[CH:28][C:27]([NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[CH:32][CH:31]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCCCOC(=O)c1cc(Br)c2c(N)ncnn12
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
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: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CCCCOC(=O)c1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)c2c(N)ncnn12
Temperature: 80 °C
Yield: 26.3 %

Procedure:
A mixture of butyl 4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (456.0 mg, 1.46 mmol), {4-[(tert-butoxycarbonyl)amino]phenyl}boronic acid (517.8 mg, 2.18 mmol), 2 M aqueous sodium carbonate solution (2.2 mL, 4.40 mmol), and tetrakis(triphenylphosphine)palladium(0) (168.3 mg, 0.15 mmol) in 1,2-dimethoxyethane (11 mL) was heated (80° C.) overnight. The reaction mixture was diluted with DMF and purified by HPLC using a gradient of 30-95% of MeCN in water to give 163.2 mg (26%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.52 (s, 1 H), 8.08 (bs, 1 H), 8.06 (s, 1 H), 7.56 (d, J=8.6 Hz, 2 H), 7.35 (d, J=8.6 Hz, 2 H), 7.18 (s, 1 H), 5.67 (bs, 1 H), 4.25 (t, J=6.5 Hz, 2 H), 1.71-1.64 (m, 2 H), 1.47-1.37 (m, 2 H), 0.93 (t, J=7.4, 3 H); MS [M+H]+=426.2; LCMS RT=3.43 min.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br)#[N:16].[H-].[Na+].C(O)(=O)C>CN(C=O)C>[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C:10]1=[O:14])#[N:16]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C#N)c2)C(=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a stirred solution of 4-Boc-2-piperazinone (2.0 g, 10 mmol), 3-cyanobenzyl bromide (1.8 g, 10 mmol) in DMF (35 mL) at 0° C. was added sodium hydride (480 mg of a 60% suspension in mineral oil, 12 mmol) in several portions over a period of 15 min. The mixture was stirred a 0° C. for 1 h and then at ambient temperature for 1 h. Acetic acid (1 mL) was added and the solvent was removed in vacuo. The residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The EtOAc layer was separated, dried (MgSO4), filtered, and the solvent was removed in vacuo. The residue was triturated in ether and the white solid was collected by filtration to give 1-(3-cyanobenzyl)4-Boc-2-piperazinone (2.6 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1.C1CCN2C(=NCCC2)CC1.C1N=[CH:27][N:26]([C:29](N2C=NC=C2)=[O:30])[CH:25]=1.CNC>CC#N>[CH3:25][N:26]([CH3:27])[C:29]([NH:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1)=[O:30]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1CC(=O)c2sc(N)nc2C1
Agent: CNC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1CC(=O)c2sc(NC(=O)N(C)C)nc2C1
Temperature: 110 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 2-amino-5-methyl-5,6-dihydro-4H-benzothiazol-7-one (30.0 g, 0.165 mol) in MeCN (750 mL) are added DBU (75.2 g, 0.495 mol) and CDI (80.1 g, 0.495 mol) at RT. The reaction mixture is stirred at 110° C. overnight. Dimethylamine (93.5 g, 1.15 mol) and another portion of DBU (175 g, 1.15 mol) are added to the mixture at RT and the stirring is continued overnight at 110° C. After cooling to RT, the reaction mixture is evaporated in vacuo and the residue is poured into ice water. The reaction mixture is treated with HCl (6 M) to pH to 5. The aqueous mixture is extracted with EtOAc (3×300 mL). The combined organic phase is washed with brine and dried over anhydrous Na2SO4. The solvent is evaporated and the residue is recrystallized from hexane to give 1,1-dimethyl-3-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-urea (32.1 g, 77% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]#[N:36]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]#[N:36])=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:28])[F:29])[CH:3]=1
Reactant: CNCCC#N
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(CCC#N)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
3-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-propionitrile was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and 3-methylamino-propionitrile following General Procedure B.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:20])=[CH:5][C:6]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:7][C:8]=1[O:9][CH3:10].[Br:21][C:22]1[CH:23]=[C:24]([C:35](O)=[O:36])[C:25]2[C:26]([CH3:34])=[CH:27][N:28]([CH:31]([CH3:33])[CH3:32])[C:29]=2[CH:30]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl.CN(C=O)C>[Br:21][C:22]1[CH:23]=[C:24]([C:35]([NH:1][CH2:2][C:3]2[C:4]([CH3:20])=[CH:5][C:6]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[N:7][C:8]=2[O:9][CH3:10])=[O:36])[C:25]2[C:26]([CH3:34])=[CH:27][N:28]([CH:31]([CH3:32])[CH3:33])[C:29]=2[CH:30]=1
Reactant: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Reactant: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1CN
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a stirred solution of tert-butyl ((5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (0.55 g, 1.955 mmol), 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid (0.63 g, 2.127 mmol), and HOAt (0.27 g, 1.984 mmol) in Dichloromethane (20 mL) and DMF (5 mL) was added EDC free base (0.34 g, 2.190 mmol). The reaction was stirred at RT for 2 hr then evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 40% EtOAc in hexanes) to give the product tert-butyl ((5-((6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamido)methyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (1.07 g, 1.912 mmol, 98% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.47 (t, J=4.8 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.35 (t, 1H), 7.33 (d, J=1.0 Hz, 1H), 6.99 (d, J=1.5 Hz, 1H), 6.67 (s, 1H), 4.74 (quin, J=6.6 Hz, 1H), 4.44 (d, J=4.8 Hz, 2H), 4.08 (d, J=6.3 Hz, 2H), 3.85 (s, 3H), 2.37 (s, 3H), 2.10 (s, 3H), 1.41 (s, 9H), 1.38 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 559.3 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)=[CH:26][CH:25]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: O=C(O)c1ccnc(-c2cn(CCNCc3ccc(F)cc3)cn2)c1
Yield: 20 %

Procedure:
The title compound was prepared in 20% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 4-fluorobenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.86 (2H, t, J=6.0 Hz), 3.70 (2H, s), 4.09 (2H, t, J=6.0 Hz), 7.08 (2H, t, J=8.9 Hz), 7.33 (2H, dd, J=7.1 Hz and 2.6 Hz), 7.55 (1H, dd, J=3.2 Hz and 1.5 Hz), 7.75 (1H, d, J=1.0 Hz), 7.81 (1H, s), 8.27 (1H, s), 8.59 (1H, d, J=4.9 Hz). [M+H] Calc'd for C18H17FN4O2, 341. Found, 341.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH3:16][O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[CH2:18][O:17][CH3:16])=[O:15]
Reactant: COC[C@@H]1CCCN1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Product: COC[C@@H]1CCCN1C(=O)c1cnoc1-c1ccccc1Cl

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and (S)-2-methoxymethyl-pyrrolidine (6.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (11.9 mg). Calcd for C16H17ClN2O3: 320.0928, found 320.0932.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[CH2:11]1)=[O:7])(C)(C)C.[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32](C(O)=O)=[C:31]([O:39][CH3:40])[CH:30]=1>>[NH2:28][C:29]1[C:37]([Cl:38])=[CH:36][C:32]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:18](=[O:27])[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:25]3=[O:26])[CH2:11]2)=[O:7])=[C:31]([O:39][CH3:40])[CH:30]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN2C(=O)c3ccccc3C2=O)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCN2C(=O)c3ccccc3C2=O)C1

Procedure:
2-(2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethyl)-2,3-dihydro-1 H-isoindole-1,3-dione (1.5 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.81 g) to give 4-amino-5-chloro-N-(1-(2-(-2,3-dihydro-1 ,3-dioxo-1 H-isoindol-2-yl)ethyl)pyrrolidin-3-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].Cl>CN(C=O)C>[CH2:43]([O:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc2c(c1)C(=O)c1ccccc1-2
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
2-Hydroxy-9-fluorenone (196 mg, 2.04 mmol) was dissolved in DMF (8 ml), potassium carbonate (423 mg, 3.06 mmol), and docosyl bromide (96%, 785 mg, 1.93 mmol) were added. The mixture was heated to 80° C. and stirred overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and 1N hydrochloric acid (4 ml) was added dropwise thereto in a water bath to quench the reaction. The mixture was extracted with chloroform (23 ml), and washed once with 1N hydrochloric acid (7.5 ml) and 4 times with pure water (7.5 ml). The solvent of the organic layer was evaporated, and the residue was precipitated with methanol (10 ml) to give 2-docosyloxy-9-fluorenone (934 mg, 1.85 mmol, 96%).