Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:36][N:37]([CH3:42])[CH:38]1[CH2:41][NH:40][CH2:39]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:40]3[CH2:41][CH:38]([N:37]([CH3:42])[CH3:36])[CH2:39]3)=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN(C)C1CNC1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)C1
Temperature: 80 °C
Yield: 87 %

Procedure:
A solution of ethyl 5{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (360 mg, 0.91 mmol) and triethylamine (370 mg, 3.65 mmol) in ethanol (5 ml) was treated with N,N-dimethyl-3-azetidinamine (J.Med.Chem.;36; 801; 1993) (300 mg, 0.91 mmol) and the resulting mixture was heated at 80° C. under a nitrogen atmosphere for 16 hours. The mixture was partitioned between ethyl acetate (150 ml) and saturated aqueous ammonium chloride solution (150 ml). The organic layer was washed with saturated ammonium chloride solution (150 ml), water (150 ml) and brine (150 ml), dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate:diethylamine (87.5:12.5:0.25) gradually changing to pentane:ethyl acetate: diethylamine (50:50:1) to afford the title compound as a colourless oil (355 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17]([OH:19])=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.Cl>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([C:17](=[O:19])[NH:26][C:25]3[CH:27]=[CH:28][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:23][CH:24]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cc(C(=O)O)nn1-c1ncccc1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)Nc2ccc(C(F)(F)F)cc2)nn1-c1ncccc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 1.00 g (3.55 mmol) of 1-(3-chloropyridin-2-yl)-5-(methoxycarbonyl)-1H-pyrazole-3-carboxylic acid in 13 ml of dichloromethane and 1.3 ml of N,N-dimethylformamide was cooled to 0° C., a solution of 0.86 g (5.33 mmol) of 4-(trifluoromethyl)aniline in 3 ml of dichloromethane was added dropwise and 0.68 g (3.55 mmol) of N-ethyl-N′-3-(dimethylaminopropyl)carbodiimide×HCl and 87 mg (710 μmol) of 4-dimethylaminopyridine were added a little at a time. The mixture was stirred at 0° C. for 2 hours and at 20° C. for 16 hours. The mixture was then diluted with dichloromethane and washed successively with 1 N aqueous hydrochloric acid and water. The organic phase was dried over sodium sulphate, the solvent was removed under reduced pressure and the residue was purified on silica gel using cyclohexane/ethyl acetate=3:1→2:1. (logP: 3.54).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]#[N:11])([CH3:4])([CH3:3])[CH3:2].[CH:17](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C>CO.C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([O:13][CH3:17])=[C:9]([CH:12]=1)[C:10]#[N:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C#N)c(O)c([N+](=O)[O-])c1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: COc1c(C#N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Yield: 99.9 %

Procedure:
The above nitrile (0.5 g, 2.27 mmol) was taken up in 1:9 methanol/acetonitrile (20 mL). N,N-diisopropylethylamine (1.1 mL, 6.35 mmol) was added dropwise followed by (trimethylsilyl)diazomethane (3.2 mL, 6.35 mmol). The reaction was stirred until the bubbling stopped (20 min) and the reaction was quenched with water. The water was extracted 3× with methylene chloride, dried over Na2SO4, filtered, and concentrated in vacuo to give 5-tert-butyl-2-methoxy-3-nitro-benzonitrile (0.531 g, 99%) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.CO.O.[NH2:16][NH2:17]>O>[OH:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[OH:10])[C:3]([NH:16][NH2:17])=[O:2]
Reactant: NN
Reactant: COC(=O)c1ccc(O)c(O)c1
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc(O)c(O)c1

Procedure:
120 g of 3,4-dihydroxybenzoic acid methyl ester was subjected to reaction with 340 ml of methanol and 340 ml of hydrazine hydrate over 3 days at room temperature. Then 340 ml of water was added thereto and the solvent was evaporated in vacuum. Addition of water and evaporation were repeated twice. Subsequently the product was crystallized from 340 ml of water. m.p. 260° C. (decomposed).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:36]>[Cu]I.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:34][C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(=O)N3CCOCC3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
The title compound was prepared by following general procedure 7. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.43 mmol), was taken into DMF. To the above solution CuI (8 mg, 0.043 mmol), L-proline (9 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol) were added and stirred for 10 min. at RT. 2-Chloro-1-morpholinoethanone (84 mg, 0.51 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 21 mg of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-morpholinoethanone as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[NH:18][C:19]1[NH:20][CH2:21][CH2:22][N:23]=1>O1CCCC1.CS(C)=O>[CH3:1][C:2]1[S:3][C:4]([C:7]([N:23]2[CH2:22][CH2:21][N:20]=[C:19]2[NH:18][C:12]2[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])=[O:9])=[CH:5][N:6]=1
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Reactant: Cc1ncc(C(=O)O)s1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ncc(C(=O)N2CCN=C2Nc2c(Cl)cccc2Cl)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.6 %

Procedure:
3.15 g (22.0 millimoles) of 2-methyl-thiazole-5-carboxylic acid are dissolved in 500 ml of absolute tetrahydrofuran and 50 ml of absolute dimethylsulfoxide, 3.6 g (22.2 millimoles) of N,N'-carbonyldiimidazole are added and the mixture is stirred for 45 minutes at room temperature. A solution of 5.0 g (21.7 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 100 ml of absolute tetrahydrofuran is then added dropwise and the mixture is stirred overnight at room temperature. The solvents are stripped off under reduced pressure on a rotary evaporator and the residue is stirred thoroughly with 100 ml of 0.5 percent strength sodium bicarbonate solution, whereupon crystallization occurs. The crystals are filtered off, washed with water and dried under reduced pressure, over a phosphorus pentoxide desiccant. 5.6 g of crude 1-(2-methylthiazol-5-oyl)-2-(2',6'-dichlorophenylamino)-2-imidazoline are obtained and are recrystallized from isopropanol, giving 2.7 g of pure product, of melting point 183°-185° C.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[CH:9]=[N:8][CH:7]=[C:6]([N:11]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Cl:20])[CH:17]=4)[C:12]3=[O:21])[C:5]=2[CH2:4][CH2:3]1.CCN(CC)CC.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[Cl:20][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:21])[N:11]([C:6]1[C:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:29](=[O:31])[CH3:30])[C:10]=3[CH:9]=[N:8][CH:7]=1)[CH2:19]2
Reactant: CC(=O)Cl
Reactant: NC1CCc2c1cncc2N1Cc2cc(Cl)ccc2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCc2c1cncc2N1Cc2cc(Cl)ccc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a stirred solution of 2-(7-amino-6,7-dihydro-5H-[2]pyrindin-4-yl)-5-chloro-2,3-dihydro-isoindol-1-one (126 mg, 0.42 mmol) and Et3N (1.0 mL) in DCM (10 mL) was added acetyl chloride (0.032 mL, 0.44 mmol) at 0° C. and stirred at 0° C. for 1 hour. The resulting mixture was extracted with EtOAc (2×100 mL) and the combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 50% EtOAc-heptane gradient to give a racemic mixture of title compound (121 mg, 85%) as light yellow solid. MS: 342.1 (M+H+). This racemic mixture was then separated by chiral HPLC to afford (−)-N-[(S or R)-4-(5-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H-[2]pyrindin-7-yl]-acetamide (33 mg, example 318), MS: 342.1 (M+H+) and (+)-N—[(R or S)-4-(5-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H-[2]pyrindin-7-yl]-acetamide (27 mg, example 319). MS: 342.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:24]12([CH2:34][NH2:35])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([NH:35][CH2:34][C:24]12[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2)=[O:6]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cc(O)ccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(O)ccc1Cl
Reaction time: 2.5 h
Yield: 2.6 %

Procedure:
To a solution of 2-chloro-5-hydroxybenzoic acid (3.12 g) in N,N-dimethylformamide (50 ml) was added 1,1′-carbonyldiimidazole (3.0 g). The resulting reaction mixture was stirred for 2.5 h and then 1-adamantanemethylamine (3.0 g) was added. Stirring was continued for 14 h. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was separated, washed with water and brine and then dried over sodium sulphate (Na2SO4). The organic layer was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (eluting with 3-10% methanol in dichloromethane) to yield the subtitle compound as a white solid (0.15 g).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:25][S:24][C@@H:9]2[C@H:10]([NH:13][C:14]([C@H:16]([NH2:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:26]([OH:28])=[O:27])=O.[CH2:29]([N:31]1[C:36](=[O:37])[C:35](=[O:38])[NH:34][N:33]=[C:32]1[SH:39])[CH3:30]>>[NH2:23][C@H:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:14]([NH:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C:7]([C:26]([OH:28])=[O:27])=[C:6]([CH2:5][S:39][C:32]3[N:31]([CH2:29][CH3:30])[C:36](=[O:37])[C:35](=[O:38])[NH:34][N:33]=3)[CH2:25][S:24][C@H:9]12)=[O:15]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1
Reactant: CCn1c(S)n[nH]c(=O)c1=O
Product: CCn1c(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)[C@H](N)c4ccccc4)[C@H]3SC2)n[nH]c(=O)c1=O

Procedure:
In a manner analogous to that described in Example 1 8.1 g of cephaloglycine and 3.78 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine were reacted to yield 4.19 g (40.5%); of (7R)-7-[(R)-2-amino-2-phenylacetamido]-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-3-cephem-4-carboxylic acid which was isolated as a Zwitter ion; yield 4.19 g (40.5% melting point>180° (decomposition); [α]D20 =-86.3) (c=0.276 in dimethylformamide).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=1)=[CH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=1.Cl.NO>C(#N)C>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:22][N:6]=[C:7]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:28]=3)[CH:8]=2)=[CH:11][CH:12]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCOc1ccc(C(=O)C=C(N)c2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
Dimethylformamide (44 ml), 1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene (5.5 g) and hydroxylamine hydrochloride (2.0 g) were charged in 300-ml three-necked flask at room temperature and heated, and the reaction was carried out at the inner temperature of 55 to 60° C. for 4 hours. After completion of the reaction, the mixture was cooled down to room temperature, and acetonitrile (110 ml) was added to separate the crystals. The inner temperature was made 0 to 5° C., and the crystals were filtered and washed with acetonitrile (28 ml) and water (110 ml) The crystals were dried overnight in vacuo to give methyl 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate (5.21 g).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([O:13][CH3:14])[N:3]=1.C([OH:22])C1C=CC=CC=1.[H-].[Na+]>CN(C=O)C>[CH:8]([C:7]1[C:2]([OH:22])=[N:3][C:4]([O:13][CH3:14])=[N:5][C:6]=1[O:11][CH3:12])([CH3:10])[CH3:9]
Reactant: COc1nc(Cl)c(C(C)C)c(OC)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(O)c(C(C)C)c(OC)n1
Temperature: 0 °C

Procedure:
To a mixture of 4-chloro-5-isopropyl-2,6-dimethoxy-pyrimidine (1.4 g, 6.51 mmol, 1 eq) and benzyl alcohol (704 mg, 1.0 eq.) in 10 mL DMF, NaH (60% in mineral oil, 273 mg, 1.05 eq.) was added at 0° C. The reaction mixture was stirred at 0° C. then warmed up to room temperature. LC-MS showed that the desired product formed. The reaction mixture was then diluted with ethyl acetate, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give the crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16]O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]1[O:6][CH2:16][C:15]([CH3:19])([CH3:18])[N:14]=1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: COc1ccc(C2=NC(C)(C)CO2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A solution of 27.4 g of 2,4-dimethoxybenzoyl chloride in 30 ml of methylene chloride was added dropwise to a solution of 26.2 g of 2-amino-2-methyl-1-propanol in methylene chloride at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered and the filtrate washed twice with 1N hydrochloric acid, once with water, dried, and concentrated in vacuo. Excess thionyl chloride was added to the oily residue. After stirring one hour the mixture was poured into diethyl ether. The resulting solid was recovered by filtration and washed with diethyl ether. The solid was added to 1N sodium hydroxide and stirred. The aqueous mixture was extracted with ethyl acetate and the organic layer separated, dried, and concentrated in vacuo. Distillation of the resulting yellow oil at 165°-170° C. at 0.02 mm pressure provided 17.8 g of the desired subtitled intermediate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[C:19]([F:26])[CH:18]=3)[C:10]2=S)=[CH:5][C:4]=1[C:28]([F:31])([F:30])[F:29])#[N:2].[OH:32]O>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[C:19]([F:26])[CH:18]=3)[C:10]2=[O:32])=[CH:5][C:4]=1[C:28]([F:31])([F:30])[F:29])#[N:2]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(C(N)=O)c(F)c1
Reactant: OO
Solvent: CCO
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1c1ccc(C(N)=O)c(F)c1

Procedure:
To a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamide (Compound (MII)) (1.48 g, 3.4 mmol) in ethanol (60 mL) was added 30% aqueous H2O2 (30 mL) at room temperature. The solution was heated to reflux for 1 h. After removal of ethanol, brine (100 mL) was added and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product that was purified by silica gel chromatography. MS (m/z): 435 (M+1). HPLC: Column, YMC ODS A, 4.6×150 mm, 5 μm, Mobile Phase A:10 mM Ammonium acetate, Mobile Phase B: Acetonitrile, Gradient, 10% B up to 2 min, 10% to 90% B in 6 min, hold for 10 min, 90% to 10% B in 4 min, Retention time, 9.548 min, HPLC Purity, 98.08%, Flow Rate, 1 mL/min. 1H NMR (CDCl3, Freebase): δ (ppm) 8.3 (t, 1H), 8.18 (s, 1H), 8.2 (d, 1H), 7.96 (d, 1H), 7.25 (m, 2H), 6.65 (bd, 1H), 5.9 (bs, 1H) 1.65 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.S(C)C.[OH-].[Na+].[ClH:33]>C1COCC1.CCOCC>[ClH:33].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:17][CH:18]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Agent: FB(F)F
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(CNCc2ccc(F)cc2)cc1
Temperature: -30 °C
Yield: 93 %

Procedure:
4-Fluoro-N-(4-fluoro-benzyl)-benzamide (40.0 grams, 0.16 mole) was dissolved in 240 mL of THF. To this was added BF3.Et2O (7.4 mL. 0.06 mole) and the resulting mixture heated to reflux for 15 min. After cooling to −30° C., BH3.SMe2 (22.3 mL, 0.24 mole) was added using a dropping funnel. The reaction was allowed to warm to room temperature. The reaction flask was fitted with a distillation condenser and solvent removed under reflux for 25 min. The distillation apparatus was replaced with a reflux condenser and the reaction heated to 110° C. for 2 h. After cooling to 0° C., 100 mL of 6N HCl was added and the mixture heated to reflux for 1 hr to yield a thick slurry. 300 mL of 6N NaOH was slowly added at room temperature with intermittent cooling using an ice bath. After all the solid has dissolved Et2O was added and the mixture transferred to a separatory funnel. The organic layer was separated, dried over Na2SO4, filtered and the solvent removed under vacuum to yield an oil. The oil was dissolved in 50 mL of Et2O and 4N HCl (dioxane) added resulting in the formation of a white precipitate which was isolated by filtration to yield 40 grams (93% yield) of bis-(4-fluoro-benzyl)-amine hydrochloride. MS (M+H) calcd for C14H14F2N, 234.1. found: 234.0. Anal. calcd for C14H14F2NCl: C, 62.34; H, 5.23; N, 5.19. found: C, 61.89; H, 5.15; N, 5.27. 1H NMR (500 MHz, DMSO) δ: 4.12 (br s, 4), 7.26 (m, 4), 7.65 (m, 4), 9.91 (br s, 2).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][CH2:13][C@:14]2([F:27])[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[N:3]=1.[CH2:28]([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:28]([N:30]1[CH:34]=[C:33]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[C:4]([O:12][CH2:13][C@:14]3([F:27])[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)[N:3]=2)[CH:32]=[N:31]1)[CH3:29]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(COc2nc(Cl)cc3ncccc23)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCn1cc(-c2cc3ncccc3c(OC[C@]3(F)CCCN(C(=O)OC(C)(C)C)C3)n2)cn1
Yield: 86.9 %

Procedure:
A mixture of 1,1-dimethylethyl (3S)-3-{[(7-chloro-1,6-naphthyridin-5-yl)oxy]methyl}-3-fluoro-1-piperidinecarboxylate (1.1 g, 2.78 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.679 g, 3.06 mmol) and caesium carbonate (2.263 g, 6.95 mmol) in 1,4-dioxane (16 ml) and water (3 ml) was degassed with nitrogen before adding tetrakis(triphenylphosphine)palladium (0) (0.096 g, 0.083 mmol). This was heated under reflux for 18 h. The reaction was partitioned between ethyl acetate and aqueous ammonium chloride. The aqueous was re-extracted with ethyl acetate and the combined organics were washed with brine, passed through a hydrophobic frit and concentrated in vacuo to give crude product. This was dissolved in DCM and purified through silica (20 g) eluting with a gradient of ethyl acetate in DCM. The product eluted in neat ethyl acetate. Appropriate fractions were combined and concentrated in vacuo to yield the title compound as a pinkish cream foam (1.10 g).
Reaction SMILES: [I:1][C:2]([C:5]([O:11][C:12]([C:15]([C:18]([NH2:20])=O)([F:17])[F:16])([F:14])[F:13])([C:7]([F:10])([F:9])[F:8])[F:6])([F:4])[F:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[I:1][C:2]([C:5]([O:11][C:12]([C:15]([C:18]#[N:20])([F:16])[F:17])([F:13])[F:14])([C:7]([F:10])([F:9])[F:8])[F:6])([F:4])[F:3]
Reactant: NC(=O)C(F)(F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)I
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: N#CC(F)(F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)I
Temperature: 175 °C

Procedure:
A mixture of 17.5 g of fine powder of ICF2CF(CF3)OCF2CF2CONH2 and 17 g of P2O5 was heated at 150 to 200° C., during which volatiles were distilled out. Final volatiles were collected in a -78° C. trap at 13.3 kPa. A total of 13.8 g of ICF2CF(CF3)OCF2CF2CN were obtained, 95% pure by GC. 19F NMR: -58.6 (dm J=212.4 Hz, 1F), -60.1 (dm J=212 Hz, 1F), -76.7 (m, 3F), -83.3 (dm, J=135 Hz, 1F), -84.8 (dm, J=135 Hz, 1F), -108.6 (t, j=6.3 Hz, 2F), -133.6 (m, 1F). IR(neat): 2268 (m), 1113 (s).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=O.[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1>C(O)C>[CH2:14]([S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:16]=[C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][N:18]2[CH:2]=1)(=[O:13])=[O:12])[CH3:15]
Reactant: CCS(=O)(=O)c1ccccc1C(=O)CBr
Reactant: Nc1cc(C(F)(F)F)ccn1
Solvent: CCO
Product: CCS(=O)(=O)c1ccccc1-c1cn2ccc(C(F)(F)F)cc2n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A mixture of 1.0 g of 2-bromo-2′-ethylsulfonylacetophenone, 334 mg of 2-amino-4-trifluoromethylpyridine and 4 ml of ethanol was refluxed for 1 hour and concentrated under reduced pressure. A mixture of the residue, 250 mg of sodium bicarbonate and 1.5 ml of DMF was stirred at 130° C. for 1 hour. Water was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 190 mg of 2-(2-ethylsulfonylphenyl)-7-trifluoromethyl-imidazo[1,2-a]pyridine (hereinafter, referred to as Compound of Present Invention 8).