Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:13]=[C:12]([S:14][CH3:15])[C:8]([C:9]([OH:11])=O)=[C:7]([S:16][CH3:17])[CH:6]=2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)(=[O:23])=[O:22])[CH3:20].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([S:16][CH3:17])[C:8]([C:9]([N:37]3[CH2:38][CH2:39][CH:34]([C:19]([CH3:20])([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)(=[O:22])=[O:23])[CH3:18])[CH2:35][CH2:36]3)=[O:11])=[C:12]([S:14][CH3:15])[CH:13]=2)[CH2:2][CH2:3]1
Reactant: CSc1cc(OC2CC2)cc(SC)c1C(=O)O
Reactant: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CSc1cc(OC2CC2)cc(SC)c1C(=O)N1CCC(C(C)(C)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 16 ml vial was added 4-(cyclopropyloxy)-2,6-bis(methylthio)benzoic acid (375 mg, 1.39 mmol), 4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperdine (465 mg, 1.39 mmol), Bop reagent (675 mg, 1.53 mmol), diisopropylethyl amine (1.21 ml, 6.93 mmol) and 4 ml dimethylformamide. The resulting solution was stirred at room temperature for 1 hour. It was diluted with 30 ml ethyl acetate, washed sequencially with 20 ml 1N HCl, 20 ml 5% KOH and 20 ml brine. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:2 to 1:1 ethyl acetate/hexane to give desired product as sticky material.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH2:8]Cl)=[O:7])(=[O:3])[CH3:2].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>COC(C)(C)C>[C:1]([O:4][CH2:5][C:6]([CH2:8][S:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: Cc1ccc(S)cc1
Reactant: CC(=O)OCC(=O)CCl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)CSc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a solution of 1-acetoxy-3-chloroacetone (5.0 g, 33.2 mmol) and 4-methylthiophenol (4.12 g, 33.2 mmol) in tert-butyl methyl ether (100 ml) was slowly added triethylamine (5.1 ml, 36.6 mmol) under ice-cooling. The solution was stirred at room temperature for 30 minutes. The reaction solution was washed with water, saturated aqueous sodium hydrogen carbonate solution, then saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 7.72 g of 1-acetoxy-3-(4-methylphenylthio)acetone (yield: 97%) as oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:12][C:11]1[C:2]([CH3:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2
Reactant: Cc1nc2ncccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cccnc4nc3C)c2cc1OC
Temperature: 140 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
2-Methyl-[1,8]naphthyridin-3-ol (20 mg), 4-chloro-6,7-dimethoxyquinoline (84 mg), and 4-dimethylaminopyridine (46 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 3 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (41 mg, yield 100%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19]>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[CH:18]=[O:19])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Yield: 35 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (300 mg), 130 mg of 3-formylbenzeneboronic acid and 55 mg of Bis(triphenylphosphine)palladium(II) dichloride in 0.6 mL of 1M Na2CO3 and 0.6 mL of acetonitrile was heated to 100° C. in the microwave reactor for 15 min. The reaction mixture was diluted with ethyl acetate (60 mL), and then washed with H2O (40 mL). The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by ISCO CombiFlash (0-40% ethyl acetate/hexane) to yield 99 mg of 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzaldehyde.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:22]([CH3:24])[CH3:23].[Cl:25][CH:26]([Cl:30])[C:27]([OH:29])=[O:28]>C(OCC)(=O)C.CCCCCCC>[Cl:25][C:26]([Cl:30])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:22]([CH3:24])[CH3:23])[C:27]([OH:29])=[O:28]
Reactant: CC(C)c1cccc(C(C)C)c1OCCCCCCCCCCBr
Reactant: O=C(O)C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)c1cccc(C(C)C)c1OCCCCCCCCCCC(Cl)(Cl)C(=O)O
Yield: 52.8 %

Procedure:
7.95 g (20.0 mmol) 81 was reacted with 10.3 g (80.0 mmol) dichloroacetic acid as in example 9. Flash chromatography (ethyl acetate/heptane 1:10) yielded 4.7 g (53%) 29 as a light coloured oil.
Reaction SMILES: [OH-].[Li+].O.C([O:6][P:7]([CH2:16][C@@H:17]([OH:29])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[O:8])C.P(=O)(O)(O)O>C(O)C>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[CH2:20][NH:19][CH2:18][C@H:17]([OH:29])[CH2:16][P:7]([CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])(=[O:6])[OH:8]
Reactant: CCOC(OCC)P(=O)(C[C@@H](O)CNCc1ccc(Cl)c(Cl)c1)OCC
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(OCC)P(=O)(O)C[C@@H](O)CNCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.254 g of lithium hydroxide and 6 ml of water are added to a solution of 2.26 g of 3-[N-(3,4-dichlorobenzyl)amino]-2(S)-hydroxy-propyl(diethoxymethyl)phosphinic acid ethyl ester in 3 ml of ethanol and the mixture is stirred at 60° for 24 hours. The mixture is allowed to cool to room temperature, adjusted to pH 7 with aqueous phosphoric acid and concentrated to dryness by evaporation. The evaporation residue is made into a slurry in hot methanol and filtered. The filtrate is concentrated to dryness by evaporation and the glassy evaporation residue is taken up in a small amount of ethanol. The pH value is adjusted to pH 1 with ethanolic hydrochloric acid and the solvent is removed. Crystallisation from acetonitrile yields 3-[N-(3,4-dichlorobenzyl)amino]-2(S)-hydroxy-propyl(diethoxymethyl)phosphinic acid; [α]20D =-10.8°±1.7° (c=0.595 in methanol); 1H-NMR (CD3OD): δ=7.76 (1H, m), 7.61 (1H, m), 7.45 (1H, m), 4.47 (1H, d), 4.29 (1H, m), 4.20 (2H, m), 3.80 (2H, m), 3.69 (2H, m), 3.25 (1H, dd), 3.02 (1H, d, d), 2.04 (1H, dd), 1.87 (1H, d, d); 1.20 (6H, t).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:23](OCC)=[O:24].[O-]CC.[Na+].Cl>C(O)C>[OH:24][CH:23]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3)cc1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Temperature: 78 °C
Yield: 67.7 %

Procedure:
N-[4-(2-Oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (1.15 g, 3.90 mmol) and ethyl formate (0.95 mL, 11.70 mmol) were dissolved in anhydrous ethanol (8.00 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (4.40 mL, 11.70 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 3 with dropwise addition of 1M HCl(aq). The dark orange precipitate that formed was filtered then re-dissolved in EtOH (25 mL). The ethanolic solution was made basic with the addition of 1 M NaOH(aq) (4 mL). The basic solution then was re-acidified to pH 1 with 1 M HCl(aq) (10 mL) causing the formation of a pale orange precipitate. This suspension was filtered yielding an orange solid as the pure N-[4-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (0.852 g, 2.64 mmol, 68%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]#[N:14])=[N:6]1.C[O-].[Na+].C(O)(=O)C.[Cl-].[NH4+:27]>CO>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:27])[NH2:14])=[N:6]1
Reactant: N#Cc1nn(Cc2ccccc2F)c2c1CCC2
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nn(Cc2ccccc2F)c2c1CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen atmosphere, 3.600 g (14.92 mmol) of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile was dissolved in 37 ml of absolute methanol. 1.306 g (24.17 mmol) of sodium methylate was added and it was stirred for 4 h at RT. 1.452 g (24.17 mmol) of acetic acid and 1.197 g (22.38 mmol) of ammonium chloride were added and the suspension was stirred overnight at 50° C. The reaction mixture was concentrated by evaporation and the residue was suspended in 100 ml water and 25 ml 1N hydrochloric acid. The mixture was extracted with dichloromethane. The aqueous phase was made basic (pH=12) with 2N sodium hydroxide solution and extracted three times with a mixture of dichloromethane/methanol (v/v=8:2). The combined organic phases were dried over sodium sulphate, concentrated by evaporation, toluene was added and again evaporated to dryness. 1.94 g (50% of theor.) of the target compound was obtained.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[NH2:10][C:11]1[NH:12][C:13]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17].N.CO>O1CCCC1.O>[NH2:5][C:3]([NH:10][C:11]1[NH:12][C:13]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])=[O:4]
Reactant: NC(=O)c1cc(-c2ccc(Br)cc2)[nH]c1N
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: N
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)Nc1[nH]c(-c2ccc(Br)cc2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 36 %

Procedure:
Trichloroacetyl isocyanate (60 μL, 0.50 mmol) was added dropwise to a solution of 2-amino-5-(4-bromophenyl)pyrrole-3-carboxamide (Reference compound No. 1-1, 0.17 g, 0.60 mmol) in anhydrous tetrahydrofuran (3.0 mL) at −40° C. and the mixture was stirred for 1 hour. Furthermore, ammonia solution 2.0 M in methanol (3.0 mL, 6.0 mmol) was added thereto, and the whole was stirred at room temperature for 3 days. Water (20 mL) was added to the reaction solution, then the precipitated solid was filtered off. The obtained solid was dried under reduced pressure to give the target compound (0.070 g) as a brown solid (Yield 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]([NH:25][CH:26]([CH:34]1[O:36][CH2:35]1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOC(C)=O>CN(C=O)C>[CH2:15]([O:22][C:23]([NH:25][CH:26]([CH:34]([OH:36])[CH2:35][N:12]1[CH2:11][CH2:10][CH:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:14][CH2:13]1)[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(NC(Cc1ccccc1)C1CO1)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccccc1)C(O)CN1CCC(Cc2ccc(F)cc2)CC1)OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 4-(4-fluorophenyl)methyl-piperidine (0.515 g, 2.314 mmoles) and 2-benzyloxycarbonylamino-1-phenyl-3,4-epoxy-butane (0.688 g, 2.314 mmoles) in 5 mL of DMF was stirred for 4 hours at 100° C. and cooled to room temperature. After addition of EtOAc (30 mL), the mixture was washed with water (2×) and brine. The oranic solution was dried over Na2SO4, and evaporated to give an oily residue. It was then purified by passing through a plug of silica gel with elution by EtOAc to give pure product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=[C:4]([N:17]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>CC(C)=O>[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]([CH3:15])([CH3:16])[CH2:10][C:11]([CH3:12])([CH3:14])[CH3:13])[N:5]=[C:4]([N:17]3[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[N:3]=2)=[CH:29][CH:28]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Solvent: CC(C)=O
Product: CC(C)(C)CC(C)(C)Nc1nc(Nc2ccc(F)cc2)nc(N2CC3CCC(CC3)C2)n1

Procedure:
Eight grams (0.022 mole) of 3-[4-chloro-6-(1,1,3,3-tetramethylbutylamino)-s-triazin-2-yl]-3-azabicyclo[3.2.2]nonane and 21 ml. (0.22 mole) of p-fluoroaniline is placed in a glass liner in a bomb and then heated in an oil bath maintained at 190°-205° C. for about 40 hours. After cooling, the indigo contents of the bomb are rinsed with chloroform and water into a flask and 50 ml. of 10 N NaOH is added. The solution is then evaporated in vacuo and the aqueous solution remaining is extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered through Magnesol® and the Magnesol® washed with chloroform. Removal of solvent in vacuo, addition of toluene and re-evaporation in vacuo several times gives an orange solid which on slurrying with acetone gives white crystals. Recrystallization from acetone gives 7.1 g. of colorless crystals m.p. 173.5°-174.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([NH2:23])[CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:23][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCC1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NC1CCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(cyclobutyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.34 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.42 mmol of cyclobutylamine.LC/MS [9.86 min; 412 (M+1)]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:18])([F:20])[F:19])[N:16]=[C:10]2[CH:9]1[CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1COS(C)(=O)=O
Temperature: 0 °C

Procedure:
To a 0° C. solution of 100 mg (0.31 mmol) of 7-N-(tert-butoxycarbonyl)-8-(hydroxymethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine in 1.0 mL of dichloromethane was added sequentially 0.047 mL (0.341 mmol) of triethylamine and 0.029 mL (0.372 mmol) of methanesulfonyl chloride. The reaction mixture was stirred at 0° C. and allowed to warm to room temperature for 4 h. Aqueous sodium bicarbonate solution was added, and the resultant mixture was extracted with three portions of dichloromethane. The combined organics were washed with brine, dried over magnesium sulfate, and concentrated to give a yellow oil which was used without further purification. LC/MS 401 (M+1).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].C([N:13]=[C:14]([NH2:28])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[N:17]=1)(C)(C)C.[OH-:29].[Na+]>S(=O)(=O)(O)O>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH2:23][CH2:24][CH2:25][C:26]([NH2:27])=[O:29])[N:17]=1)[C:14]([NH2:28])=[NH:13]
Reactant: CC(C)(C)N=C(N)Nc1cccc(SCCCC#N)n1
Reactant: [OH-]
Agent: O=C(O)/C=C\C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N=C(N)Nc1cccc(SCCCC(N)=O)n1

Procedure:
A solution of 4-[2-(2-t-butylguanidino)pyrid-6-ylthio]butyronitrile hydrogen maleate (0.1 g.) in concentrated sulphuric acid (0.5 ml.) was kept at room temperature for 72 hours. The solution was added to crushed ice and then basified with 10N aqueous NaOH and the mixture extracted three times with EtOAc. The combined extracts were dried and evaporated to dryness. A solution of the residue in acetone was added to a solution of maleic acid in acetone, and the crystalline precipitate was collected to give 4-(2-guanidinopyrid-6-ylthio)butyramide hydrogen maleate (0.04 g.), m.p. 169°-170°.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[NH2:15][CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH:29]=O>>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:29][NH:1][C:4]1[C:5]2[CH:6]=[CH:7][C:8]([NH:15][CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[N:9][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: NC1Cc2ccccc2C1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: Fc1cc(F)cc(CNc2cccc3nc(NC4Cc5ccccc5C4)ccc23)c1

Procedure:
The title compound, MS: m/e=402.4 (M+H+), was prepared in accordance with the general method of example 43 from 5-nitro-2-chloroquinoline, 2-aminoindane and 3,5-difluorobenzaldehyde.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:19](=[O:34])[N:20]([CH3:33])[C@@H:21]([C:29](=[O:32])[NH:30][CH3:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:12]([O:11][CH2:10][C@@H:9]([NH:7][CH3:6])[C:19]([N:20]([CH3:33])[C@@H:21]([C:29](=[O:32])[NH:30][CH3:31])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:34])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)NC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
N-((1R)-2-Benzyloxy-1-(N-methyl-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-carbamoyl)ethyl)N-methylcarbamic acid tert-butyl ester (0.23 g; 0.476 mmol) was dissolved in methylene chloride (3 mL) and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred for 10 min at room temperature. Methylene chloride (50 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9) and sodium hydrogen carbonate (solid) were added to the reaction mixture until pH 9. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 0.182 g of (2R)-3-Benzyloxy-N-methyl-2-(methylamino)-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)propionamide.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[C:11](=[O:18])[C:12]([Cl:17])=[CH:13][C:14](=[O:16])[CH:15]=1.Cl.C(OCC)(=O)C>C1COCC1>[Cl:9][C:10]1[C:11](=[O:18])[C:12]([Cl:17])=[CH:13][C:14]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([OH:16])[CH:15]=1
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C1C=C(Cl)C(=O)C(Cl)=C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)C=C(Cl)C(=O)C(Cl)=C1
Yield: 74 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. A solution of 0.59 g (3.33 mmol) of 2,6-dichloro-p-benzoquinone in 3 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3) afforded 0.76 g of the desired product (NMR yield 74%; internal standard trioxane). As a purified product, 0.48 g of the desired product was obtained (yield 54%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[CH3:13][CH2:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1)=[O:17].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([C:16]([O:15][CH2:14][CH3:13])=[O:17])=[CH:23][CH:22]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCC(=O)Cl)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)CCc2ccc(C)cc2)cc1

Procedure:
A solution of 15 g. of 3-(4-methylphenyl)propionyl chloride in 100 ml. of dichloromethane is created with stirring with a solution of 15 g. of benzocaine and 9.13 g. of triethylamine in 100 ml. of dichloromethane. The mixture is stirred overnight, then washed with 100 ml. each of 10% hydrochloric acid, water, and brine, then dried with magnesium sulfate, and evaporated to yield a solid. This solid is crystallized from 200 ml. of acetonitrile and dried in vacuo, giving 22.08 g. of the desired product, m.p. 154°-155° C.