Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@@H:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N#N>C1(C)C=CC=CC=1>[C:16]1([CH:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc([C@@H]2[C@H](c3ccccc3)N2c2ccccc2)cc1
Agent: N#N
Solvent: Cc1ccccc1
Product: c1ccc(CC(Nc2ccccc2)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
In a glove box, tBu2PH(C6F4)BH(C6F5)2 (0.33 g, 0.05 mmol) and cis-1,2,3-triphenylaziridine (0.271 g, 1.0 mmol) were weighed into a 100 ml round bottomed glass flask equipped with a Kontes valve and a magnetic stirbar. Toluene (4 ml) is added, the reaction transferred to a vacuum/H2 line and the mixture is freeze-pump-thaw cycled three times. The mixture is cooled to −196° C. (liquid N2) and 1 atm. H2 is introduced. The flask is sealed, the reaction is placed in a 120° C. preheated bath and rapidly (500 rpm) stirred. The reaction is periodically monitored by 1H NMR spectroscopy and is complete in 2 hours. The reaction mixture is poured onto a small plug of silica and eluted with 2:1 hexanes/ethyl acetate (50 ml). The solvent is removed in vacuo and the product N-1,2-diphenylethyl-N-phenyl amine isolated. Yield: 0.269 g (98%)
Reaction SMILES: F[C:2]1[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[CH:23][C:3]=1[C:4]([C:6](=[CH:12][NH:13][N:14](C(OC(C)(C)C)=O)[CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F-].[K+]>CN(C)C=O>[F:27][C:26]1[CH:2]=[C:3]2[C:23](=[C:24]([F:29])[C:25]=1[F:28])[N:13]([NH:14][CH3:15])[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]2=[O:5]
Reactant: CCOC(=O)C(=CNN(C)C(=O)OC(C)(C)C)C(=O)c1cc(F)c(F)c(F)c1F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(NC)c2c(F)c(F)c(F)cc2c1=O
Temperature: 0 °C
Yield: 87.5 %

Procedure:
A mixture of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-(2-tert-butoxycarbonyl-2-methylhydrazino)acrylate (2.00 g) and potassium fluoride (0.31 g) in dimethylformamide(5 ml) was heated at 60°~65° C. for one hour, and refluxed for 5 hours. The mixture was poured into ice-water (60 ml) to give a solid. The solid was collected by filtration and dried over phosphorus pentaoxide under reduced pressure to give ethyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.25 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[CH:4]=[C:5]([C:7]#[N:8])[CH:6]=1.[I:21]N1C(=O)CCC1=O>C(#N)C.O>[NH2:1][C:2]1[N:3]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:11][C:10]=2[Cl:20])[CH:4]=[C:5]([C:7]#[N:8])[C:6]=1[I:21]
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O
Product: N#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-1-(2,6-dichloro4-trifluoromethylphenyl)4-cyanopyrrole (EP-372982 A2) in acetonitrile (20 ml) was added N-iodosuccinimide (703 mg). The reaction was stirred at room temperature for 30 minutes, diluted with water (100 ml) and extracted with ether (100 ml). The organic fraction was separated, dried over MgSO4, filtered and evaporated to dryness, the residue was purified by column chromatography (silica, 20 g) eluted with dichloromethane:hexane (7:3) to give the title compound as a yellow crystaline material, m.p. 130-132° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[C:9]([CH3:17])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12].IC>CC(C)=O>[CH3:1][O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([Br:7])[C:9]=1[CH3:17]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)cccc1C(=O)O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cccc(Br)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Potassium carbonate (5.46 g, 39.53 mmol) is added to a solution of 3-bromo-2-methyl-benzoic acid (5 g, 23.25 mmol) in acetone (50 mL). The suspension is stirred for 15 minutes at room temperature, then iodomethane (1.74 mL, 27.90 mmol) is added and the mixture is heated to 70° C. for 2.5 hours. The reaction mixture is filtered and evaporated to dryness. The crude product is purified by chromatography on a 50 g Isolute Flash Si II column, eluting with ethyl acetate/cyclohexane (5:95) to yield the title compound.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:17]([CH2:19][C:20]([NH2:22])=[O:21])#[N:18].N1CCCCC1>C(O)C>[C:17]([C:19]1[C:20](=[O:21])[NH:22][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:9]2)#[N:18]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C1CC(c2ccccc2)CCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(=O)c(C#N)c2c1CC(c1ccccc1)CC2

Procedure:
2-Acetyl-4-phenylcyclohexanone, 1.68 g, 0.73 g of cyanoacetamide and a small quantity of piperidine were mixed with 10 ml of ethanol followed by heating to reflux for 2 hours. After cooling, the precipitated crystals were taken out by filtration and purified to give 1.5 g of 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-7-phenylisoquinoline.
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[C:9]([C:14](OC)=[O:15])[N:8]=2)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[CH:1]([NH:4][C:5]1[S:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[C:9]([CH2:14][OH:15])[N:8]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(NC(C)C)sc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Nc1nc2ccc(CO)nc2s1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 84.3 %

Procedure:
To a solution of methyl 2-(isopropylamino)thiazolo[5,4-b]pyridine-5-carboxylate (1.67 g, 6.64 mmol, 1.0 eq.) in THF (17 mL) under nitrogen at 0° C. was added LAH (1M, THF; 10 mL, 10 mmol, 1.5 eq.). After 2.25 hr, ice and EtOAc were added, the cold bath was removed, and the solution was stirred to room temperature. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography using CH2Cl2:MeOH (10:0.4) as eluent afforded (2-(isopropylamino)thiazolo[5,4-b]pyridin-5-yl)methanol as a white solid (1.25 g, 84% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22](C)=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].ClC1C2C=CC([F:39])=CC=2SC=1C(O)=O>>[Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22]([F:39])=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8]
Reactant: O=C(O)c1sc2cc(F)ccc2c1Cl
Reactant: Cc1ccc2c(Cl)c(C(=O)N[C@H](Cc3ccccc3)C(=O)O)sc2c1
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(F)ccc2c1Cl

Procedure:
Following the 2a synthetic method, using 3-chloro-6-fluorobenzo[b]thiophene-2-carboxylic acid (115.32 mg, 0.5 mmol) instead of 3-chloro-6-methylbenzo[b]thiophene-2-carboxylic acid gave 4a as a white powder; (177.01 mg, 93.7%). [α]D25: −21.9 (c=0.37, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 7.95-7.76 (m, 3H), 7.44-7.22 (m, 6H), 5.04-4.97 (m, 1H), 3.45-3.26 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.48, 163.90, 160.62, 159.50, 139.15, 136.67, 133.50, 129.50, 128.40, 126.89, 124.94, 118.57, 115.15, 114.82, 109.30, 108.95, 53.95, 36.78; HRMS (ESI): calcd for: C18H13ClFNO3S [M+H]+=378.0361, obsd [M+H]+=378.0347.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.C([C:20]([O:22][CH3:23])=[O:21])#N>ClCCl>[CH3:23][O:22][C:20]([C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1)=[O:21]
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Reactant: COC(=O)C#N
Solvent: ClCCl
Product: COC(=O)c1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 21 h
Yield: 88.9 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (4.0 g, 16.2 mmole) and methyl cyanoformate (2.75 g, 32.4 mmole) in 30 mL of dichloromethane was stirred at room temperature for 21 h. The precipitate was filtered and washed with dichloromethane to give 3.36 g (84%) of 3-(methoxycarbonyl)-1,2,4-thiadiazolo [4,5-a]benzimidazole as a colourless solid: mp 208-209° C.; 1H NMR (CDCl3)δ 8.61 (d, 1H), 7.82 (d, 1H), 7.51 (t, 1H), 7.31 (t, 1H), 4.17 (s, 3H) ppm; 13C NMR (CDCl3)δ 164.02, 156.51, 150.67, 140.89, 129.34, 125.93, 122.41, 119.48, 115.41, 54.04 ppm; IR (KBr)ν 1733 cm-1 ; HRMS calcd for C10H7N3O2S 233.0259, found 233.0262. Anal. Calcd. for C10H7N3O2S: C, 51.50;H, 3.02; N, 18.02. Found: C, 51.41;H. 2.89; N, 18.16.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@@H:23]3O)=[N:6][C:7]([CH:18]3[CH2:20][CH2:19]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:51]=[N+:52]=[N-:53].CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1.C1COCC1>[N:51]([C@@H:23]1[CH2:24][C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:22]1[NH:21][C:5]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[C:7]([CH:18]2[CH2:19][CH2:20]2)[N:6]=1)=[N+:52]=[N-:53]
Reactant: [N-]=[N+]=N
Reactant: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of (1R,2S)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol (0.76 g, 1.7 mmol) in toluene (10 mL) and THF (10 mL) was added PPh3 (1.14 g, 4.57 mmol). The solution was cooled to 0° C. and HN3 (5.6 mL, 6.38 mmol) and a solution of diethylazodicarboxylate (0.69 mL, 4.37 mmol) in toluene (10 mL) were added. The reaction was stirred at rt overnight. The precipitates were removed by filtration and the filtrate was concentrated. Dissolve residue in 1 N HCl and EtOAc. Extract with EtOAc (3×30 mL). The aqueous phase was neutralized with sat. aq. NaHCO3 to pH 7.5 followed by a small amount of 6 N NaOH to pH 9. The aqueous phase was extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purify by biotage MPLC (90 g column, 29–39% ethyl acetate/hexanes) to afford 0.8 g (78%) of N-[(1R,2R)-2-azido-2,3-dihydro-1H-inden-1-yl]-3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-amine as a solid: 1H NMR (CDCl3) δ 0.74–1.10, 1.63–1.71, 2.97–3.03, 3.36–3.42, 4.09–4.13, 4.26–4.29, 5.05, 5.57, 7.25–7.53; MS (ESI+) for C25H22Cl2N6 m/z 477 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:5]([N+:22]([O-])=O)=[C:4]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[H][H]>C1(C)C=CC=CC=1.[Pt]>[CH3:8][C:7]1[C:6]([NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:5]([NH2:22])[C:4]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:3][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCCCc2cccnc2)c1C
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCOCCCc2cccnc2)c1C

Procedure:
Under a nitrogen atmosphere, a solution of 2,3-dimethyl-5-nitro-6-phenoxy-N-[2-(3-pyridin-3-ylpropoxy)ethyl]pyridin-4-amine (27.1 g) in toluene (300 ml) was added to a Parr hydrogenation flask containing 5% platinum on carbon (10 g). After 4 hours at a hydrogen pressure of 207 kPa, the reaction was judged complete by HPLC and TLC analysis. The molecular weight and structure of the product were confirmed by LC/MS and NMR analysis, respectively. The reaction mixture was filtered through filter paper, Celite™, and magnesium sulfate. The filtrate was used in the next step.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([OH:29])[C:27]=1[I:28])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:29][C:26]1[CH:25]=[C:19]([CH:18]=[C:17]([O:16][CH2:14][CH3:15])[C:27]=1[I:28])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(O)c(I)c(OCC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC)c(I)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Benzyl bromide (2.95 mL) was added to a DMF (200 mL) suspension of ethyl 3-ethoxy-5-hydroxy-4-iodobenzoate (7.59 g) and potassium carbonate (4.68 g), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (7.09 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:14])([C:6](=[O:13])[CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)[CH3:5].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.O>CN(C)C=O>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][CH:7]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[C:6](=[O:13])[C:4]([CH3:14])([CH3:3])[CH3:5])=[CH:18][CH:17]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)C(=O)Cn1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)C(Cc1ccc(Cl)cc1)n1cncn1
Temperature: 20 °C
Reaction time: 5 h
Yield: 63.5 %

Procedure:
7.5 g (0.25 mol) of sodium hydride (80% strength suspension in oil) are slowly introduced, at 10° C., into a solution of 50.1 g (0.3 mol) of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one in 150 ml of absolute N,N-dimethylformamide, and the mixture is stirred at 20° C. until the evolution of gas has ended. A solution of 62 g (0.3 mol) of 4-chlorobenzyl bromide in 50 ml of N,N-dimethylformamide is then added dropwise, while stirring. After 5 hours, the reaction mixture is stirred into 900 ml of water, and the solid product which separates out is filtered off and recrystallized from 175 ml of ethanol. 55.6 g (76.3% of theory) of 5-(4-chlorophenyl)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-pentan-3-one are obtained in the form of colorless crystals of melting point 124° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[C:17]([O:22][CH3:23])[CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=2)=[C:17]([O:22][CH3:23])[CH:16]=1
Reactant: COc1cc(Cl)ncc1N
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2cnc(Cl)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 137.5 %

Procedure:
A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (211 mg, 1 mmol), 6-chloro-4-methoxypyridin-3-amine (150 mg, 0.95 mmol) and para-toluenesulphonic acid (190 mg, 1 mmol) in 1,4-dioxane (2 mL) was heated at 100° C. for 1 h. The mixture was cooled and filtered, the solid was washed with dioxane and dried in vacuo to give the product as a cream coloured solid (436 mg, >100%). 1H NMR (400 MHz, DMSO): δ 9.82 (s, 1H); 8.76 (s, 1H); 8.44 (s, 2H); 7.38 (s, 1H); 4.00 (s, 3H); 2.99-2.92 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[S:10])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[S:10])=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(NC(=S)NCc2ccncc2)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(NC(=S)NCc2ccncc2)cc1
Reaction time: 0.5 h

Procedure:
To a chilled (circa 0° C.) solution of 5.16 gms. (0.02 mole) of 1-(p-aminophenyl)-3-(4-pyridylmethyl)-2-thiourea (Example 19, supra.) and 75 ml. of pyridine there is added dropwise 1.48 gms. (0.02 mole) of acetyl chloride with stirring, while maintaining the temperature at circa 0° C. Upon completion of the addition, the reaction mixture is stirred for an additional 30 minutes and then allowed to stand at room temperature for about 16 hours. Solvent is then removed in vacuo and the residue suspended in water. Water is then removed to give a residue of 1-(p-acetomidophenyl)-3-(4-pyridylmethyl)-2-thiourea.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCCCCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,5-dibromopentane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,5-dibromopentane. The crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a white solid. Yield: 1.01 g (60%). 1H-NMR (400 MHz, d6-DMSO) δ=1.40-1.52 (m, 2H), 1.75-1.85 (m, 2H), 3.52 (t, J=6.6 Hz, 2H), 3.78-3.89 (m, 2H), 6.64 (d, J=9.0 Hz, 2H), 7.72 (d, J=9.0 Hz, 2H), 8.97 (s, 2H). LRMS (FAB+): 334.1 (100, [M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[OH:33]>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[O:33][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: Oc1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(Oc2ccc(Cl)cc2Cl)n1
Yield: 81 %

Procedure:
This compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 2,4-dichlorophenol in analogy to example 3. Chromatography on silica gel using ethyl acetate as an eluent gave the title compound as a colorless solid in 81% yield.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:9]=[C:8]([CH:10]([CH3:24])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([F:23])[CH:12]=2)[O:7][N:6]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:30]O>>[CH3:30][O:2][C:1]([CH2:4][C:5]1[N:9]=[C:8]([CH:10]([CH3:24])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([F:23])[CH:12]=2)[O:7][N:6]=1)=[O:3]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CC(=O)O)no1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Reaction time: 8 h

Procedure:
To a solution of 1.27 g of 3-carboxymethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole obtained in Example 39 in 20 ml of dry methanol was added a drop of conc. sulfuric acid. The mixture was allowed to stand at room temperature overnight and then concentrated to dryness under reduced pressure. The solution of the residue in benzene was washed successively with a sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using benzene to give 0.95 g of 3-methoxycarbonylmethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole, nD25 1.5618.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH3:14])[O:12]C(=O)N2)[CH:5]=[CH:6][C:7]=1[F:8].FC1C=C(C[C:25]([OH:27])=[O:26])C=CC=1F.[Li+].CC([N-]C(C)C)C.C(=O)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]([CH3:14])[OH:12])[C:25]([OH:27])=[O:26])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@@H]1OC(=O)N[C@H]1c1ccc(F)c(F)c1
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: CC=O
Agent: [Li+]
Product: CC(O)C(C(=O)O)c1ccc(F)c(F)c1

Procedure:
4(S)-(3,4-difluorophenyl)-5(S)-methyloxazolidin-2-one precursor to Compound A can be prepared by treating 3,4-difluorophenylacetic acid with LDA, followed by reaction with acetaldehyde to form 2-(3,4-difluorophenyl)-3-methyl-3-hydroxypropionic acid, and then cyclizing the hydroxypropionic acid with diphenyldiphosphorylazide to form the oxazolidinone. The oxazolidinone can then be activated by treatment with p-nitrophenylchloroformate. The oxazolidinones can be resolved into their optical isomers via chromatography prior to activation, or the unresolved material can be activated directly. The activated oxazolidinone is then acylated to give Compound A by treatment with 3-[4-(4-fluorophenyl)piperidin-1-yl]propylamine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][N:38]([CH:41]2[CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42]2)[CH2:37][CH2:36]1.N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.N>ClCCl>[NH:43]1[CH2:44][CH:41]([N:38]2[CH2:39][CH2:40][N:35]([C:3]3[C:2]([Cl:1])=[C:7]([NH:8][C:9]4[N:14]=[C:13]([N:15]([CH:25]5[CH2:26][CH2:27]5)[CH2:16][C:17]5[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=5)[C:12]5=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]5[N:10]=4)[CH:6]=[C:5]([C:33]#[N:34])[CH:4]=3)[CH2:36][CH2:37]2)[CH2:42]1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5CN(C(=O)OC(C)(C)C)C5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: N
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5CNC5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl 3-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperazin-1-yl)azetidine-1-carboxylate (400 mg, 0.563 mmol) in dichloromethane (4.0 mL) at 0° C., was added 2,6-lutidine (0.197 mL, 1.690 mmol). After that TMS-OTf (0.305 mL, 1.690 mmol) was added drop wise. The reaction mixture was allowed to warm to room temperature and stirred for 5 h. The reaction mixture was diluted with dichloromethane (50 mL) and poured into a separating funnel containing liquor ammonia (5 mL). The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layer were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was washed with pentane (3×10 ml) and diethyl ether (3×5 mL). After the washing the resultant solid was dried under vacuum to get 2-((3-(4-(azetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (250 mg) as a off white solid.