Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].[NH2:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH:26]=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[N:28]=2)[N:25]=1>C(#N)C>[C:1]1([CH2:7][C:8]([NH:13][C:12]([NH:15][C:16]2[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=2)[O:19][C:20]2[CH:21]=[CH:22][C:23]3[N:24]([CH:26]=[C:27]([NH:29][C:30]([CH:32]4[CH2:34][CH2:33]4)=[O:31])[N:28]=3)[N:25]=2)=[S:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#C[S-]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: O=C(Cc1ccccc1)NC(=S)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
To a solution of phenylacetyl chloride (155 mg, 1.0 mmol) in acetonitrile (20 mL) was added potassium thiocyanate (292 mg, 3.0 mmol), and the mixture was stirred at 60° C. for 3 hr and concentrated under reduced pressure. The residue was diluted with tetrahydrofuran (20 mL). N-[6-(3-Aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (155 mg, 0.50 mmol) was added to the mixture, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) and precipitated from diisopropyl ether to give the title compound (142 mg, yield 58%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:33])[CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: C1CNCCN1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCNCC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazine (Aldrich) to give the title compound. LC-MS: 581.2 [(M+H)+]
Reaction SMILES: C[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3](Cl)=[O:4].[F:11][C:12]([F:42])([F:41])[C:13]1[CH:26]=[CH:25][C:24]2[S:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][C:33]([O:37][CH2:38][CH2:39][OH:40])([CH3:36])[CH2:32][CH2:31]3)[C:15]=2[CH:14]=1.[CH2:43](N(CC)CC)C>C1C=CC=CC=1>[F:42][C:12]([F:41])([F:11])[C:13]1[CH:26]=[CH:25][C:24]2[S:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][C:33]([O:37][CH2:38][CH:39]([CH3:43])[O:40][C:3](=[O:4])[CH2:2][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH3:36])[CH2:34][CH2:35]3)[C:15]=2[CH:14]=1
Reactant: CC1(OCCO)CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Reactant: CCN(CC)CC
Reactant: CCCCCC(C)C(=O)Cl
Solvent: c1ccccc1
Product: CCCCCCC(=O)OC(C)COC1(C)CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2.7 g of 2-methylheptanoic acid chloride in 10ml of anhydrous benzene was added dropwise at 10° C to a solution of 6.05 g of 2-trifluoromethyl-10-[3-(4-{2-hydroxyethoxy}-4-methyl-piperidino)-propyl]-phenothiazine in 50 ml of anhydrous benzene containing 1.7 g of triethylamine and the mixture was stirred at room temperature for 20 hours. After washing the benzene solution with water, the mixture was stirred for 4 hours with an aqueous solution saturated with sodium bicarbonate and the organic phase was decanted and concentrated.. The oily residue was purified by chromatography over silica gel with a 99-1 cyclohexane-triethylamine mixture as eluant to obtain 6.5 g of 2-trifluoromethyl-10-[3-(4-{2-methyl -2-heptanoyloxyethoxy}-4-methyl-piperidino)-propyl]-phenothiazine in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Br.[CH3:13][CH:14]1[CH2:19][CH:18]([CH3:20])[CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][CH:14]1[CH2:19][CH:18]([CH3:20])[CH2:17][N:16]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=2)[CH2:15]1
Reactant: CC1CNCC(C)C1
Reactant: Cc1cc(CBr)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(CN2CC(C)CC(C)C2)ccc1[N+](=O)[O-]
Yield: 61 %

Procedure:
3-Methyl-4-nitrobenzyl bromide (1.00 g), 3,5-dimethylpiperidine (0.60 ml) and potassium carbonate (0.90 g) were dissolved in acetone (20 ml), followed by heating under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, dissolved in chloroform (10 ml), poured into water (100 ml) and extracted with chloroform (50 ml). The organic layer was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate and, after filtration, concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (developing solvent: n-hexane/ethyl acetate=10:1) to obtain the subject compound (NCR-7) (0.70 g, yield 61%) as a yellow oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:18]>CCOCC>[Br:18][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccccc1SCc1ccccc1
Solvent: CCOCC
Product: BrCc1ccccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
A solution of (2-Benzylsulfanyl)methanol 4 (120 mg, 0.522 mmol) in anhydrous Et2O was cooled to 4° C. A solution of PBr3 (49 μL, 0.52 mmol) in anhydrous Et2O was added dropwise, keeping the temperature below 10° C. The reaction was allowed to warm to ambient temperature and stirred for one hour. The reaction was filtered through silica gel (2.0 g) and washed with Et2O. The filtrate was washed with H2O saturated aqueous sodium bicarbonate and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give 95 mg of the named product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4](=[N:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5](=[O:11])[CH2:6][C:7](OC)=[O:8]>ClC1C=CC=CC=1Cl>[CH3:1][O:2][C:3]([C:4]1[C:5]([OH:11])=[CH:6][C:7](=[O:8])[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:12]=1)=[O:20]
Reactant: COC(=O)CC(=O)C(=NNc1ccccc1)C(=O)OC
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1nn(-c2ccccc2)c(=O)cc1O
Reaction time: 20 h
Yield: 99.1 %

Procedure:
A mixture of 3-oxo-2-(phenylhydrazono)-pentanedioic acid dimethyl ester (4.38 g, 15.7 mmol) in 1,2-dichlorobenzene (15 mL) was refluxed. After 20 hours, the reaction mixture was concentrated under reduced pressure to give 3.83 g (99%) of the desired product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([NH:7][NH:8][C:9](=[O:12])[CH2:10][CH3:11])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(#N)C>[CH2:10]([C:9]1[O:12][C:5]([C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([I:1])[CH:3]=2)=[N:7][N:8]=1)[CH3:11]
Reactant: CCC(=O)NNC(=O)c1cccc(I)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1nnc(-c2cccc(I)c2)o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
3-Iodo-N′-propionylbenzohydrazide (382 mg, 1.20 mmol) obtained in Step 2 was dissolved in acetonitrile (21 mL), and the mixture was stirred at 60° C. for 2 hours after adding triphenylphosphine (629 mg, 2.40 mmol), carbon tetrachloride (0.46 mL, 4.80 mmol), and triethylamine (0.33 mL, 1.54 mmol). After concentrating the mixture under reduced pressure, the residue was purified by silica gel column chromatography to give 2-ethyl-5-(3-iodophenyl)-1,3,4-oxadiazole (331 mg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:38][C:39](=[O:44])[CH2:40][C:41](O)=[O:42])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:41](=[O:42])[CH2:40][C:39]([NH:38][C:32]1[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:30]([O:29][CH3:28])[CH:31]=1)=[O:44]
Reactant: COc1ccc(NC(=O)CC(=O)O)cc1OC
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (30 mg, 0.071 mmol), 3-(3,4-dimethoxyphenylamino)-3-oxopropanoic acid (34.2 mg, 0.143 mmol), DMAP (17.44 mg, 0.143 mmol), and EDC (41.1 mg, 0.214 mmol) were dissolved in DMF (1.5 ml). The reaction was stirred at RT overnight to achieve completion. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with HCl 1N, Na2CO3 sat. sol. and brine, dried over Na2SO4 and concentrated under vacuum. The crude product was purified by Preparative reverse-phase HPLC to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(3,4-dimethoxyphenylamino)-3-oxopropanoyloxy)-ethyl)pyridine 1-oxide (20 mg, 43.7% yield).
Reaction SMILES: Br.Br[CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH3:9].[SH:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([C:18]([F:21])([F:20])[F:19])[N:12]=1.C(N(CC)CC)C>C(O)C>[CH3:9][C:5]1[N:6]=[CH:7][S:8][C:4]=1[CH2:3][S:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([C:18]([F:21])([F:19])[F:20])[N:12]=1
Reactant: Cc1ncsc1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.5 %

Procedure:
To a 0° C. mixture of 5-(bromomethyl)-4-methyl-1,3-thiazole hydrobromide (19.4 mmol) and 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (2.47 g, 12.6 mmol) in absolute ethanol (100 mL) was added triethylamine (8.00 mL, 57.4 mmol). The mixture was stirred at room temperature for 2 days. The solid material was removed by filtration and washed with diethyl ether (100 mL). The filtrate was evaporated to dryness and then co-evaporated with ethyl acetate (1×50 mL). The solid residue was treated with water (100 mL), and the mixture was stirred for 30 minutes. The solid product was recovered by filtration, washed with water (2×25 mL), diethyl ether (2×25 mL), and hexanes (2×25 mL), and then dried in vacuo to afford 2-{[(4-methyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (1.76 g, 45%); 1H NMR (500 MHz, DMSO-d6): δ 2.39 (s, 3H), 4.61 (s, 2H), 6.65 (s, 1H), 8.86 (s, 1H); M+308.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][N:25]=2)=O)[CH:15]=[CH:16][C:17]=1[Cl:18].O>C1COCC1>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:22][NH:21][CH2:20][CH2:19][C:14]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=2)=[N:25][CH:26]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(C(=O)NCCc2ccc(Cl)c(Cl)c2)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)nc1
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
Diisobutylaluminum hydride (1 M solution in THF, 0.40 mL, 0.40 mmol) was added dropwise to a solution of 5-tert-butyl-pyridine-2-carboxylic acid [2-(3,4-dichloro-phenyl)-ethyl]-amide (195 mg, 0.555 mmol) in THF (2 mL) at 0° C., then after 15 min, the reaction was stopped by careful addition of water. The reaction mixture was partitioned between ethyl acetate and 1 M aq. potassium sodium tartrate solution, the organic layer was washed with brine, dried (MgSO4), and concentrated. Chromatography (SiO2, heptane/ethyl acetate 1:1, then dichloromethane/methanol 9:1) afforded (5-tert-butyl-pyridin-2-ylmethyl)-[2-(3,4-dichloro-phenyl)-ethyl]-amine (128 mg, 68%). Yellow oil, MS (ISP): 337.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:28])=[CH:4][C:5]([F:27])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22](OCC)=[O:23])=[CH:9]2)[CH:7]=1.[NH3:29].C[N:31](C)C=O>>[NH2:29][C:15]1[C:16]([Cl:18])=[C:17]2[C:12]([C:11](=[O:21])[C:10]([C:22]([NH2:31])=[O:23])=[CH:9][N:8]2[C:6]2[CH:7]=[C:2]([NH2:1])[C:3]([F:28])=[CH:4][C:5]=2[F:27])=[CH:13][C:14]=1[F:20]
Reactant: CCOC(=O)c1cn(-c2cc(N)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CN(C)C=O
Reactant: N
Product: NC(=O)c1cn(-c2cc(N)c(F)cc2F)c2c(Cl)c(N)c(F)cc2c1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Ethyl 1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (200 mg) was dissolved in N,N-dimethylformamide (4 ml). 28% Aqueous ammonia (1 ml) was added to this solution, and the mixture was stirred overnight at 50° C. in a closed state. Additional 28% aqueous ammonia (2 ml) was added, and the mixture was stirred overnight in the same manner as described above. After the temperature of the reaction mixture was given back to room temperature, it was concentrated to two-thirds under reduced pressure. Red solids deposited were collected by filtration, washed with water and then dried to obtain the title compound (90 mg) as a reddish brown powder.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH:9]=O)=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[NH2:18].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:23][O:22][C:20]1[CH:19]=[C:17]([NH:18][CH2:9][C:8]2[C:3]([NH:2][CH3:1])=[N:4][C:5]([S:11][CH3:12])=[N:6][CH:7]=2)[CH:16]=[C:15]([O:14][CH3:13])[CH:21]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CNc1nc(SC)ncc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNc1nc(SC)ncc1CNc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (1.0 g, 5.46 mmol) and 3,5-dimethoxyaniline (840 mg, 5.46 mmol) in methanol (60 mL) was stirred at RT for 3 h, followed by the addition of sodium cyanoborohydride (520 mg, 8.20 mmol) and 1 mL of acetic acid. The reaction mixture was then stirred at RT for another 4 h. LCMS showed the reaction was completed. The reaction was quenched by 30 mL of 1N HCl, then stirred for 0.5 h and extracted with ethyl acetate (3×50 mL). The organic layers were separated, combined, washed with saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to afford the title compound (crude 1.2 g, 69%) as a white solid, which was directly used in the next step without further purification. MS (ES+) C15H20N4O2S requires: 320. found: 321 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)C.[OH-].[K+].C(O)C>O>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:25])=[O:3])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Yield: 74.5 %

Procedure:
A solution of 2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester (17.7 g, 0.051 mole), potassium hydroxide pellets (4.5 g, 0.080 mole), 95% ethanol (150 ml), and water (10 ml) was refluxed to 2-1/2 hrs. The ethanol was evaporated in vacuo, the residue acidified with glacial acetic acid, and the mixture filtered. The filter cake was suspended in water (300 ml) and filtered. The filter cake was air dried (17 g) and recrystallized from ethanol-water to give 12.21 g (75%) of a white solid, mp 240°-241° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[H][H]>[Pt].O>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1cccnc1-c1ccccc1
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: O
Product: NC1CCCNC1c1ccccc1

Procedure:
A 500 ml Parr bottle was charged with 5 grams of 5% platinum/carbon (50% water wet), 5 grams (0.0293 mol.) 3-amino-2-phenylpyridine (1 equivalent), 75 ml of water (15 vol.) and 25 ml of concentrated hydrochloric acid (5 vol.). The reaction was hydrogenated (maintaining the hydrogen pressure between 36 psi and 50 psi) until high pressure liquid chromatography (HPLC) indicated complete reaction. The catalyst was removed by filtration and the pH of the filtrate was adjusted from 0 to a stable 11.2 using 25% sodium hydroxide (NaOH). The aqueous layer was extracted twice with 50 ml of methylene chloride (CH2Cl2). The organic extracts were combined, dried with magnesium sulfate (MgSO4) and the filtrate was atmospherically distilled to an oil, 4.34 grams (84.1%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:18]([NH:20][C@H:21]([C:34]([O:36]CC1C=CC=CC=1)=[O:35])[CH2:22][CH2:23][C:24](=[O:33])[O:25]CC1C=CC=CC=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].O>CO.C(O)(=O)C.[Pd]>[NH2:1][C@H:2]([C:18]([NH:20][C@H:21]([C:34]([OH:36])=[O:35])[CH2:22][CH2:23][C:24](=[O:25])[OH:33])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:9])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CCC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reaction time: 8 h

Procedure:
5.21 Grams of Z-Lys(Tos)-Glu(OBzl)-OBzl was dissolved in a mixture of 80 ml of methanol with 20 ml of 10% acetic acid, and a small amount of palladium black was added thereto and stirred overnight under introducing hydrogen gas. After the reaction was completed, the catalyst was removed by vacuum filtration, and the filtrate was distilled under a reduced pressure to obtain the rresidue. To the residue was poured water and was lyophilized to obtain the desired product.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].N1C=CC=C[CH:34]=1>>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][S:29]([CH2:28][CH3:34])(=[O:31])=[O:30])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: c1ccncc1
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCN)c2n1
Agent: Cl
Product: CCS(=O)(=O)NCCOc1cccc2c(NCc3ccc(Cl)c(Cl)c3)cc(C)nc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
[8-(2-Aminoethoxy)-2-methylquinolin-4-yl]-(3,4-dichlorobenzyl)-amine dihydrochloride (example 20, 60 mg, 0.160 mmole) and methanesulfonyl chloride (33.8 mg, 0.30 mmole) were dissolved in pyridine and stirred at RT for 12 hrs. The content of the flask was concentrated, mixed with 1N NaOH and extracted with dichloromethane. The organic layer was washed with water and saturated NaCl solution and concentrated. The residue thus obtained was purified using silica gel chromatography, eluting with dichloromethane:methanol 95:5. After precipitation in ethyl acetate a white solid was obtained (12 mg, 17%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[NH:7][C:8]2[CH:14]=[C:13]([O:15][S:16]([C:19]3[CH:29]=[CH:28][C:22]([O:23][CH2:24][C:25](O)=[O:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].[CH:30]([N:33]([CH:36]([CH3:38])C)CC)([CH3:32])C.N1CCCC1>CN(C)C=O>[CH3:1][O:2][C:3]([NH:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][C:13]([O:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25](=[O:26])[N:33]4[CH2:30][CH2:32][CH2:38][CH2:36]4)=[CH:28][CH:29]=3)(=[O:18])=[O:17])=[CH:14][C:8]=2[N:7]=1)=[O:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(OCC(=O)O)cc3)cc2[nH]1
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: COC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(OCC(=O)N4CCCC4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of [4-(2-methoxycarbonylamino-3H-benzoimidazol-5-yloxysulfonyl)-phenoxy]-acetic acid (40 mg, example 64-e) in dry dimethylformamide (3 ml) was treated with N-{(dimethylamino)(1H-1,2,3-triazolo[4,5-b]pyridin-1-yl)methylene}-N-methylmethanaminium hexafluorophosphate N-oxide (39 mg) and diisopropylethylamine (50 μl). After stirring at ambient temperature for 30 minutes, pyrrolidine (21 μl) was added and the mixture stirred at room temperature for a further 3 hours. The solvent was removed in vacuo and the residue was purified by triggered LC/MS to give 4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl-ester as an off-white solid. Mass spectrum: 475[M+H]+; retention time=8.39 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:34][CH2:35][C:36]([NH2:38])=[O:37].C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[F:32][C:28]1[CH:27]=[C:26]([S:23]([NH:22][C:18]2[CH:17]=[C:16]([C:9]3[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=3[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][CH2:35][C:36]([NH2:38])=[O:37])[N:7]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: NCC(N)=O
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(NCC(N)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 86, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide (100 mg, 0.20 mmol) and glycinamide hydrochloride (225 mg, 2.0 mmol) and K2CO3 (566 mg, 4.0 mmol) in 1-butanol (5 mL) the title compound was obtained as a white powder (29 mg, 27.6% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.51 (s, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.57-7.65 (m, 2H), 7.48-7.53 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 7.19-7.22 (m, 4H), 6.04 (s, 1H), 3.23-3.30 (m, 1H), 2.76 (s, 3H), 1.36 (d, J=6.7 Hz, 6H). MS (ESI): 527.1 [M+H]+.