Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.II.Cl.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1.O>[N:4]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[C:1]=[S:3]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: S=C=S
Agent: Cl
Agent: II
Agent: O=S([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(N=C=S)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
Carbon disulfide (0.66 mL, 11 mmol) was added to a mixture comprising 4-aminobenzoic acid (0.50 g, 3.6 mmol), tetrahydrofuran (2.5 mL), water (2.5 mL) and triethylamine (1.3 mL, 9.1 mmol), followed by stirring at room temperature for 24 hours. To the obtained reaction mixture, a tetrahydrofuran (2.5 mL) solution of iodine (1.0 g, 4.0 mmol) was dropwise added over a period of 5 minutes at 0° C., followed by stirring at 0° C. for further two hours. Thereafter, 1M hydrochloric acid (3.6 mL) and sodium sulfite (91 mg, 0.72 mmol) were added and stirred. Then, ethyl acetate (15 mL) was added, and the organic layer was separated and concentrated under reduced pressure to dryness. To the residue, ethyl acetate (5 mL) and hexane (5 mL) were added and thoroughly mixed, and then, the insoluble matter was collected by filtration to obtain 4-isothiocyanatobenzoic acid as a colorless solid (0.65 g, yield: 100%, HPLC purity: 92%, HPLC retention time: 3.7 min). LC-MS ES-178 (retention time: 4.0 min, condition 1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5].B.C1COCC1>C1COCC1>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1c(Cl)ccc(F)c1Cl
Agent: B
Solvent: C1CCOC1
Product: OCc1c(Cl)ccc(F)c1Cl

Procedure:
To a solution of 2,6-Dichloro-3-fluorobenzoic acid (125 g, 0.59 mol) in THF (200 mL) was added BH3.THF (592 mL, 592 mmol, 1M solution in THF) dropwise at room temperature. The reaction mixture was heated to reflux for 12 h. The borane was quenched with methanol (200 mL) and the resulting solution was concentrated to dryness. The residue was again co-evaporated with methanol to remove most of the trimethylborate. To the residue was added aq. sodium carbonate (50 g in 500 mL). The mixture was cooled and a white fine precipitate was filtered off to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=2.10 (t, 1H, J=6.9 Hz), 4.96 (d, 2H, J=6.9 Hz), 7.09 (dd, 1H, J=8.1, 9.0 Hz), 7.29 (dd, 1H, J=4.8, 9.0 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[CH:16]=[C:17]([C:22]([O:24]C)=[O:23])[N:18]([CH2:19][CH2:20][OH:21])[C:14]=3[CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[F:26][C:27]([F:36])([F:35])[C:28]1[N:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[CH:16]=[C:17]([C:22]([OH:24])=[O:23])[N:18]([CH2:19][CH2:20][O:21][C:31]4[CH:32]=[N:33][C:28]([C:27]([F:36])([F:35])[F:26])=[CH:29][CH:30]=4)[C:14]=3[CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(-c2nccc3c2cc(C(=O)OC)n3CCO)c1
Reactant: Oc1ccc(C(F)(F)F)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cccc(-c2nccc3c2cc(C(=O)O)n3CCOc2ccc(C(F)(F)F)nc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Methyl 4-(3-ethoxyphenyl)-1-(2-hydroxyethyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (30 mg, 0.088 mmole), 6-(trifluoromethyl)pyridine-3-ol (19 mg, 0.116 mmole), and PS-triphenylphosphine resin (116 mg, 0.264 mmole) were combined in a screw cap vial. To this was added THF (1 mL) and DIAD (0.022 mL, 0.115 mmole) at RT. After stirring overnight the mixture was filtered washing with CH2Cl2 and concentrated. The residue was taken up in THF (1 mL). To this was added 2M NaOH (0.132 mL, 0.264 mmole) then the mixture was heated to 60° C. After 3 hr the mixture was cooled to RT and concentrated. The crude material was taken up in DMSO and acidified with TFA. The resulting solution was purified by preparative reversed-phase HPLC (21×100 mm Phenomenex AXIA-Gemini-NX, 15%-40% CH3CN/water containing 0.1% TFA over 18 min at 20 mL/min) to give the title compound (39 mg, 76%) as a white solid. 1H NMR (499 MHz, DMSO): δ 8.57 (d, J=6.7 Hz, 1 H); 8.46 (s, 1 H); 8.19 (s, 1H); 7.99 (d, J=8.8 Hz, 1 H); 7.63-7.55 (m, 2 H); 7.48-7.44 (m, 2 H); 7.27 (d, J=8.2 Hz, 1 H); 6.79 (d, J=8.7 Hz, 1 H); 5.18 (m, 2 H); 4.80 (m, 2 H); 4.16 (q, J=7.0 Hz, 2 H); 1.38 (t, J=6.9 Hz, 3 H). HRMS (ESI) calc (M+H)+=472.1479. found 472.1459.
Reaction SMILES: [CH2:1]([CH2:8][N:9]=[C:10]([NH2:12])[NH2:11])[CH2:2][C@H:3]([NH2:7])[C:4]([OH:6])=[O:5].O.[CH2:14]([O:18][CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]1[O:17][CH2:16]1.[ClH:27]>C(O)C>[ClH:27].[OH:17][CH:15]([CH2:14][O:18][CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][NH:7][C@H:3]([C:4]([OH:6])=[O:5])[CH2:2][CH2:1][CH2:8][NH:9][C:10](=[NH:12])[NH2:11]
Reactant: CCCCC(CC)COCC1CO1
Reactant: NC(N)=NCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCC(CC)COCC(O)CN[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 78 °C
Reaction time: 4 h

Procedure:
In a four-necked 200-mL flask equipped with a reflux cooling tube, a dropping funnel, a thermometer and a stirring blade, 9.4 g (53.7 mmol) of L(+)-arginine, 50.0 g of water and 50.0 g of ethanol were placed, and the mixture was heated to 78° C. while being stirred under a nitrogen atmosphere. Subsequently, the inside of the reaction system was maintained at 78 to 80° C., 10.0 g (53.7 mmol) of 2-ethylhexyl glycidyl ether was added dropwise thereto. Thereafter, the mixture was aged for 4 hours at 78 to 80° C., and then was returned to room temperature. Subsequently, 9.8 g (53.7 mmol) of a 6 mol/L aqueous solution of hydrochloric acid was added thereto to neutralize the mixture. Water and ethanol were completely distilled off from the reaction solution under reduced pressure, and thus 21.6 g of N-[2-hydroxy-3-(2-ethylhexyl)oxypropyl]-L-arginine hydrochloride was obtained as a white solid. This compound corresponds to the compound 2 of Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([O:24][CH:25]2[CH2:28][O:27][CH2:26]2)[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([O:24][CH:25]3[CH2:26][O:27][CH2:28]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(OC2COC2)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2nc(C)cc(OC3COC3)n2)ccc1-n1cnc(C)c1
Yield: 27 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-chloro-4-methyl-6-(oxetan-3-yloxy)-pyrimidine, using potassium carbonate as a base. The title compound was isolated in a yield of 27%. MS ISP (m/e): 368.1 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=9.62 (s broad, 1H), 7.67 (d, 2H), 7.41 (dxd, 1H), 7.26 (d, 1H), 7.04 (s, 1H), 6.28 (s, 1H), 5.65 (m, 1H), 4.90 (t, 2H), 4.58 (m, 2H), 3.81 (s, 3H), 2.31 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [NH:1]([CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C:2]([NH2:4])=[S:3].C(N(CC)C(C)C)(C)C.Br[CH:23]([CH:26]=O)[CH:24]=[O:25]>C1COCC1>[CH:24]([C:23]1[S:3][C:2]([NH:1][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[N:4][CH:26]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)CNC(N)=S
Reactant: O=CC(Br)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNc1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the crude product from Example 1 in anhydrous THF (200 mL) is added N,N-diisopropylethylamine (25 mL, 143 mmol) followed by 2-bromomalonaldehyde (18.5 g, 123 mmol). The resulting mixture is allowed to stir at room temperature for 18 h, heated to 70° C. for 6 h, and then stirred at room temperature for an additional 18 h. The solvent is removed in vacuo and the residue is partitioned between EtOAc (400 mL) and water (350 mL). The water layer is back extracted with EtOAC (300 mL), the organic layers are combined, washed with brine (1×200 mL), dried over Na2SO4, filtered and the solvent removed in vacuo. The residue is purified by BIOTAGE® Silica gel chromatography on a 300 g Thompson Single Step silica cartridge using a linear gradient from 100% CH2Cl2 to 45% EtOAc/CH2Cl2 over 8 column volumes to give 3.5 g (17%, 2 steps) of the title compound as a tan solid. LC/MS (Condition A): ret. T=2.66 min, (M+Na) 265.09. 1H NMR (500 MHz, chloroform-d) δ ppm 9.73 (1 H, s), 7.86 (1 H, s), 4.05 (2 H, s), 1.49 (9 H, s).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[O:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([C:32](O)=[O:33])=[CH:31][C:25]=3[N:24]=2)=[CH:19][CH:18]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(NC(C)C)(C)C>CN(C)C=O>[NH2:16][C:14]1[O:15][C:11]([CH:2]([NH:1][C:32]([C:30]2[CH:29]=[CH:28][C:26]3[NH:27][C:23]([C:20]4[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=4)=[N:24][C:25]=3[CH:31]=2)=[O:33])[CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:12][N:13]=1
Reactant: Nc1nnc(C(N)CCc2ccccc2)o1
Reactant: O=C(O)c1ccc2[nH]c(-c3ccncc3)nc2c1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Nc1nnc(C(CCc2ccccc2)NC(=O)c2ccc3[nH]c(-c4ccncc4)nc3c2)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.18 g of 5-(1-amino-3-phenylpropyl)-[1,3,4]oxadiazol-2-ylamine was dissolved in 10 ml of dry dimethylformamide at RT, treated with 200 mg of 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid, 270 mg of TOTU, and 0.12 ml of diisopropylamine, and stirred at RT for 4 h. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate and washed successively with water, saturated sodium hydrogencarbonate solution, water, and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The residue was stirred with methyl tert-butyl ether, filtered off, and dried under high vacuum. 2-Pyridin4-yl-1H-benzimidazole-5-carboxylic acid [1-(5-amino-[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]amide, which melts at 160° C. with decomposition, is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([C@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([O:24]C)=[O:23])[CH:20]=2)[CH2:15][CH2:14]1)[CH3:12])(=[O:10])=[O:9].O[Li].O>CO.C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([C@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=2)[CH2:15][CH2:14]1)[CH3:12])(=[O:9])=[O:10]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N(C)S(=O)(=O)c1ccccc1Cl)CC2
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN([C@@H]1CCc2ccc(C(=O)O)cc21)S(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a cooled (0° C.) solution of (R)-methyl 3-(2-chloro-N-methylphenylsulfonamido)-2,3-dihydro-1H-indene-5-carboxylate (C-16) (840 mg, 2.216 mmol, 1.0 eq.) in MeOH:THF (1:1, 20 ml) was added dropwise a solution of LiOH.H2O (185 mg, 4.433 mmol, 2.0 eq.) in water (10 ml) and the reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness and diluted with water (20 ml) and washed with ethyl acetate (20 ml). The aqueous layer was acidified to pH≈3 using 1N HCl and then extracted with methylene chloride (2×50 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to afford the desired product as an off-white solid. Yield: 58% (470 mg, 1.2876 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.Br[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22]>CO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1CCNc1ccc(Cl)nc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-5-aminopyridine (12.85 g, 0.1 mol) and N-(2-bromoethyl)phthalimide (25.4 g, 0.1 mol) were stirred together at ambient temperature (20° C.). The resulting mixture was heated to 120° C. and held at that temperature for 30 minutes whilst vigorous stirring was maintained. The mixture was allowed to cool, and when the temperature had reduced to 60° C., methanol (250 ml) was added and stirring was maintained until a homogeneous solution was obtained. The solution was then cooled to ambient temperature (20° C.), silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm) (50 g) was added and the mixture was evaporated to dryness. The title product, (N-(N-(6-chloro-3-pyridyl)-2-aminoethyl)phthalimide, was isolated from the dried mixture by flash chromatography on a silica column using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), and with 2% w methanol in dichloromethane as eluent, as a buff solid (7 g, 46%).
Reaction SMILES: [S:1]([CH2:4][S:5][C:6]1[S:7][C:8](=C)[C:9]([CH2:13][CH3:14])([CH2:11][CH3:12])[N:10]=1)[C:2]#[N:3].ClCl.[Cl:18][CH2:19][Cl:20]>>[S:1]([CH2:4][S:5][C:6]1[S:7][C:8](=[C:19]([Cl:20])[Cl:18])[C:9]([CH2:13][CH3:14])([CH2:11][CH3:12])[N:10]=1)[C:2]#[N:3]
Reactant: C=C1SC(SCSC#N)=NC1(CC)CC
Reactant: ClCCl
Agent: ClCl
Product: CCC1(CC)N=C(SCSC#N)SC1=C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Thiocyanomethylthio-4,4-diethyl-5-methylenethiazoline, 23. gm, is added to 75 ml of dichloromethane. 0.72 gm of chlorine in 20 ml of dichloromethane is then added to the system. The system is stirred at room temperature for 1 hour. The system is then washed with saturated sodium bicarbonate solution, filtered and the organic solution dried over magnesium sulfate. The dichloromethane is removed by stripping to give the 2-thiocyanomethylthio-4,4-diethyl-5-dichloromethylenethiazoline.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]([N:18]1[C:22]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:21][N:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CS(O)(=O)=O.[OH-].[Na+]>O>[CH2:11]([N:18]1[C:22]([CH:23]2[C:5]3[C:6](=[C:7]([CH3:8])[C:2]([CH3:1])=[C:3]([O:9][CH3:10])[CH:4]=3)[C:25](=[O:26])[CH2:24]2)=[CH:21][N:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(C)c1C
Reactant: O=C(O)C=Cc1cncn1Cc1ccccc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(c(C)c1C)C(=O)CC2c1cncn1Cc1ccccc1
Temperature: 92.5 °C

Procedure:
A mixture of 2,3-dimethylanisole (2.0 g), 3-(3-benzyl-3H-imidazol-4-yl)-acrylic acid (3.4 g) and methanesulfonic acid (60 ml) is heated at 90-95° C. for 45 minutes. The cooled reaction mixture is poured into water and is made alkaline with sodium hydroxide solution. The product is extracted into ethyl acetate which is washed with water, dried with sodium sulfate and evaporated in reduced pressure. The crude product is purified by flash chromatography by eluting with methylene chloride-methanol solution. The yield is 1.1 g.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([F:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:31])[N:17]=2)[CH2:9]1.[OH:33][C:34]1([C:41]2[S:45][CH:44]=[N:43][CH:42]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[OH:33][C:34]1([C:41]2[S:45][CH:44]=[N:43][CH:42]=2)[CH2:35][CH2:36][CH:37]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([F:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=4)[N:18]([CH3:31])[N:17]=3)[CH2:9]2)[CH2:38][CH2:39]1
Reactant: O=C1CCC(O)(c2cncs2)CC1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(O)(c4cncs4)CC3)C2)c2cc(C(F)C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-methyl-5-(1,2,2,2-tetrafluoro-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in the previous step) and 4-hydroxy-4-thiazol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH:11]2O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O>[CH2:17]([N:13]1[CH2:14][C:15](=[O:16])[N:10]2[CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH:11]2[CH2:12]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CN(Cc2ccccc2)CC(O)N1CCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CN(Cc2ccccc2)CC2c3ccccc3CCCN12
Temperature: 180 °C
Yield: 31.8 %

Procedure:
1-(3-Phenylpropyl)-4-benzyl-2-hydroxy-6-oxopiperazine (2.6 g) and polyphosphoric acid (53 g) were mixed, heated at 180° C. and maintained at this temperature for 3/4 h. The mixture was cooled to 60° C. and water (200 ml) added. The mixture was cooled, basified with sodium hydroxide solution, and extracted with chloroform (3×50 ml). The solvent was evaporated and the product crystallised from diethyl ether to give the title compound (0.78 g, 32%) m.p. 125°-8° C.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[C:11]1[CH:15]=[CH:14][NH:13][N:12]=1)C.[OH-].[Na+:18]>CO.O>[Na+:18].[NH:13]1[CH:14]=[CH:15][C:11]([C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([O-:16])=[O:3])=[N:12]1
Reactant: CCOC(=O)c1cccnc1-c1cc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C([O-])c1cccnc1-c1cc[nH]n1
Reaction time: 1 h

Procedure:
2.61 g of 2-(pyrazol-3-yl)-nicotinic acid ethyl ester are dissolved in 20 ml of methanol and 0.5 g of NaOH in 5 ml of water added. After standing for 1 hr the methanol is removed under vacuum and an additional 0.07 g of NaOH added and dissolved by warming. After standing for 1 hr the mixture is diluted with H2O to 20 ml and divided into 4 aliquots of 5 ml. Each aliquot is chromatographed on Waters C18 sep. pak cartridge with 5 ml MeOH and 5 ml H2O each. The aqueous phases are combined, adjusted to pH 7.7 with HCl and freeze dried to give the title compound, m.p. 260°.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:39][C:40]1[N:41]([CH3:46])[CH2:42][C:43](=[O:45])[N:44]=1.C(N(CC)CC)C>C1COCC1>[CH3:46][N:41]1[CH2:42][C:43](=[O:45])[N:44]=[C:40]1[NH:39][C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[O:38])=[C:18]([CH2:26][CH2:27][CH3:28])[CH:19]=1)=[O:24]
Reactant: CCCc1cc(C(=O)O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Reactant: CN1CC(=O)N=C1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1cc(C(=O)NC2=NC(=O)CN2C)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Yield: 60.5 %

Procedure:
To a solution of 200 mg (0.370 mmol) of N-(4-isopropylbenzenesulfonyl)-α-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetamide (from Step D) in 1 mL of dry THF was added 90 mg (0.556 mmol) of 1,1-carbonyldiimidazole. The solution was stirred at reflux under N2 for 2 hours. The cooled solution was evaporated to dryness. The residue was dissolved in 1 mL of acetonitrile and treated with 63 mg (0.556 mmol) of 2-amino-4,5-dihydro-1-methyl-1H-imidazol-4-one (creatinine) and 129 μL (93.7 mg; 0.925 mmol) of triethylamine. The mixture was stirred at reflux overnight. The cooled reaction mixture was quenched by addition of 1N HCl and extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, and filtered. The filtrate was concentrated, and the residue was flash chromatographed (silica gel, 27×3.5 cm; elution with 500 mL of 99:1:1 CHCl3 -MeOH-concentrated NH4OH followed by 1 L of 85:15:1 CHCl3 -MeOH-concentrated NH4OH) to give 142 mg (60%) of the title compound as a yellow solid, mp 137°-139 ° C.; homogeneous by TLC in 85:15:1 CHCl3 -MeOH-concentrated NH4OH. ESI mass spectrum m/e 635 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:25]2[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:27][CH2:26]2)=[CH:32][CH:31]=1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: Clc1ccc(CBr)cc1
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccc(Cl)cc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and 4-chlorobenzyl bromide in the same manner as in Example 32.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[C:14]2[N:15]([N:19]=[C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:21]=2)[CH:16]=[CH:17][CH:18]=1.Cl[CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:11])([F:10])[F:12])=[CH:5][C:4]=1[C:13]1[C:14]2[N:15]([N:19]=[C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(C4CCNCC4)cc3)nc12
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(C4CCN(CC(=O)N(C)C)CC4)cc3)nc12

Procedure:
2-(4-{4-[8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine (0.150 g, 0.321 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.049 mL, 0.481 mmol) in a manner analogous to Example 313 to give product (0.060 g, 34%). MP=109-112° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.55 (s, 1H), 8.79 (d, 1H), 7.95 (s, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.55 (d, 2H), 7.35 (d, 1H), 7.05 (m, 3H), 3.85 (s, 3H), 3.15 (s, 2H), 3.05 (s, 3H), 2.95 (m, 2H), 2.82 (s, 3H), 2.40 (m, 1H), 2.10 (m, 2H), 1.65 (br m, 4H): MS=553 (MH)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:13]([S:14]([CH2:17][CH2:18]Cl)(=[O:16])=[O:15])=[C:12]([Cl:20])[C:11]([Cl:21])=[N:10]1>C(COC)OC>[CH3:8][N:9]1[C:13]([S:14]([CH:17]=[CH2:18])(=[O:16])=[O:15])=[C:12]([Cl:20])[C:11]([Cl:21])=[N:10]1
Reactant: Cn1nc(Cl)c(Cl)c1S(=O)(=O)CCCl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)c1c(Cl)c(Cl)nn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.2 g (0.022 moles) triethylamine in 75 ml dimethoxyethane, 5 g (0.018 moles) 1-methyl-3,4-dichloro-5-(2-chloroethylsulfonyl)pyrazole were added. The reaction mixture was stirred at ambient temperature for about one hour and then heated to reflux and refluxed about 2 hours. The reaction mixture was filtered, and the filtrate was stripped to give a yellow oil. The oil was chromatographed on silica gel eluting with methylene chloride yielding a thick oil which crystallized upon cooling with dry ice. Recrystallization from methylene chloride-hexane gave the product as a white solid, melting point 66°-69° C.