Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].ClC[C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][N:18]([CH2:23][C:34]3([C:35]#[N:36])[CH:33]=[CH:32][CH:31]=[CH:38][CH2:37]3)[C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: N#Cc1ccc(CCl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(CC3(C#N)C=CC=CC3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To a solution of N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide (0.20 g, 0.63 mmol) in anhydrous N,N-dimethylformamide (8 mL) was added potassium carbonate (0.10 g, 0.69 mmol), followed by the addition of 4-(chloromethyl)benzonitrile (0.11 g, 0.69 mmol). The reaction mixture was stirred at 80° C. for 4 hours. The solvent was concentrated in vacuo to one-fourth, then diluted with ethyl acetate (150 mL) and washed with water (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane to afford the title compound as a colorless solid in 40% yield (0.11 g): mp 176-178° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.65-7.63 (m, 2H), 7.40-7.24 (m, 7H), 5.88 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 4.51 (s, 2H), 4.13-4.07 (m, 2H), 3.50-3.44 (m, 2H), 2.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.2, 157.0, 155.5, 152.8, 141.1, 137.8, 132.7, 129.0, 128.8, 128.7, 127.8, 118.3, 117.6, 112.1, 47.7, 44.1, 42.0, 17.2; MS (ES+) m/z 432.3 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]2[CH2:16][N:17](CCC3C=CC=CC=3)[CH2:18][CH2:19][CH2:20][C@@H:14]2[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)OC(Cl)C>ClCCCl>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]2[CH2:16][NH:17][CH2:18][CH2:19][CH2:20][C@@H:14]2[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@H]2CCCN(CCc3ccccc3)C[C@H]21
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)N1CC[C@H]2CCCNC[C@H]21
Temperature: 23 °C

Procedure:
To a solution of (3aR,8aS)-7-Phenethyl-octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acid benzyl ester (1.0 g, 2.64 mmol) in 1,2-dichloroethane (20 mL) was added 1-chloroethyl carbonochloridate (0.286 mL, 2.64 mmol, 1.0 eq) at 0° C. The reaction was stirred with warming to 23° C. over 1 hr, then refluxed for 3 hr. The solvent was removed in vacuo then 20 mL methanol added and the reaction mixture heated to 50° C. for 1 hr. The reaction was concentrated and purified using chromatography (1:2 Ethyl Acetate/Heptane to 100% Ethyl Acetate followed by 12:1 CH2Cl21-Methanol) giving (3aR,8aS)-Octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acid benzyl ester.
Reaction SMILES: F[C:2](F)(F)C(O)=O.ICI.[F:11][C:12]([F:21])([CH2:18][CH:19]=[CH2:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl>ClCCl.[Cu].[Zn]>[CH:19]1([CH2:18][C:12]([F:21])([F:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2][CH2:20]1
Reactant: C=CCC(F)(F)C(=O)OCC
Reactant: O=C(O)C(F)(F)F
Agent: [Cu]
Agent: Cl
Agent: [Zn]
Solvent: ICI
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)CC1CC1
Temperature: 2.5 °C

Procedure:
Zinc-copper (Zn—Cu) couple (1.6 Kg, 800 mol %) and dichloromethane (7.5 L) was charged into a dry 20.0 L, 4-neck round bottomed flask, fitted with an over head stirrer, a thermo socket and a condenser under a nitrogen atmosphere. Trifluoroacetic acid (235 mL, 100 mol %) was added to the above Zn—Cu couple at ambient temperature via addition funnel over 30 minutes. Diiodomethane (860 mL; 2.86 Kg; 10.7 mol; 352 mol %) was added to above the Zn—Cu couple at ambient temperature via addition funnel over 1.5 hours. The reaction temperature was raised to reflux and then ethyl 2,2-difluoropent-4-enoate (500 g; 3.05 mol) in dichloromethane (500 mL) was added slowly via addition funnel over 30 minutes at reflux. The reaction temperature was maintained for 40-60 hours at reflux. Progress of the reaction was monitored by GC analysis which showed about 93% conversion to product based on relative area % of the peaks corresponding to product and starting material. The reaction mass was cooled to 0-5° C. and 5% dilute hydrochloric acid (500 mL) was added then the solution was filtered and washed with dichloromethane (1500 mL). The filtrate was washed with a solution of 5% aqueous hydrochloric acid (500 mL), water (1000 mL) followed by a solution of brine (1000 mL). The organic layer was concentrated under vacuum at 35° C./260-360 mm Hg to provide crude ethyl 3-cyclopropyl-2,2-difluoropropanoate (740 g), which was 79% pure by GC analysis. The crude product was then subjected to an oxidative work-up as described below to remove residual starting material (5% by area as determined by GC analysis).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[OH:13])[CH:2]=[CH2:3].[CH3:14][C:15]([CH3:17])=O.C(=O)([O-])[O-].[K+].[K+].ICC=C>C(OCC)(=O)C>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[O:13][CH2:17][CH:15]=[CH2:14])[CH:2]=[CH2:3]
Reactant: C=CCc1cccc([N+](=O)[O-])c1O
Reactant: CC(C)=O
Agent: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: C=CCOc1c(CC=C)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
Into a microwave vial was placed 1-allyloxy-2-nitrobenzene (0.5 g, 0.003 mol). The yellow-green oil was heated neat in the microwave at 180° C. for 30 min producing a black solid. 1H NMR of the crude solid showed desired product plus impurities. The reaction mixture was purified by ISCO chromatography on silica gel using 5-20% ethyl acetate-hexane. Product, 2-allyl-6-nitrophenol, was isolated as a yellow oil (0.1 g, 20%). 1H NMR (CDCl3, 400 MHz) δ 10.95 (s, 1H), 8.00 (d, 1H, J=8.59 Hz), 7.47 (d, 1H, J=7.58 Hz), 6.93 (t, 2H, J=8.59, 7.58 Hz), 5.97 (m, 1H), 5.12 (m, 2H), 3.49 (d, 2H, J=6.31 Hz), 861c) To a stirred solution of 2-allyl-6-nitrophenol (100 mg, 0.0006 mol) in acetone (4 mL, 0.06 mol) at 0° C. in an ice bath was added potassium carbonate (0.092 g, 0.00067 mol) followed by 3-iodo-1-propene (0.11 g, 0.00067 mol) under an atmosphere of nitrogen. The reaction mixture was stirred for 1 h at 0° C. then warmed to room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% HCl, water, dried over magnesium sulfate and concentrated in vacuo. The reaction mixture was purified by ISCO chromatography on silica gel (12 g) using ethyl acetate-hexane (10%-50%) to give 1-allyl-2-allyloxy-3-nitrobenzene as a yellow oil (93 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, 1H, J=8.0 Hz), 7.44 (d, 1H, J=7.8 Hz), 7.16 (t, 1H, J=8.08, 7.8 Hz), 5.90-6.13 (m, 2H), 5.40 (d, 1H, J=17 Hz), 5.29 (d, 1H, J=10 Hz), 5.15 (d, 1H, J=10 Hz), 5.09 (d, 1H, J=17 Hz), 4.50 (d, 2H, J=5.8 Hz), 3.49 (d, 2H, J=6.3 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:24]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][C:28]1=[O:37])[C:25]#[CH:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:28]3=[O:37])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCN1C(=O)CCc2ccccc21
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nnc2n1-c1ccc(C#CCN3C(=O)CCc4ccccc43)cc1C(c1ccccc1F)=NC2
Reaction time: 0.17 h

Procedure:
A mixture of 0.84 g (2 mmol) of 6-(2-fluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine, 0.48 g (2.6 mmol) of 3,4-dihydro-1-(2-propynyl)-2(1H)quinolinone, 80 mg of triphenylphosphine, 20 mg of cuprous iodide, 1.5 ml of triethylamine and 50 ml of dimethylformamide was deqassed with argon for 10 minutes. Palladium acetate, 25 mg, was then added and stirring was continued for 18 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was separated. dried and evaporated and the residue was chromatographed over 50 g of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. Crystallization of the combined clean fractions from ethyl acetate gave colorless crystals of 1-{3-[6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][ 1,4]benzodiazepin 8-yl]-2-propynyl}3,4 dihydro-2(1H)-quinolinone with m.p. 236°-239°.
Reaction SMILES: [N+](C1C=C([O:10][C:11](=O)[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)C=CC=1)([O-])=O.[N+](C1C=C(C=CC=1)C=CC(O)=O)([O-])=O.S(Cl)([Cl:40])=O.Cl>CN(C=O)C.C(OCC)(=O)C>[N+:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH:13]=[CH:12][C:11]([Cl:40])=[O:10])([O-:22])=[O:21]
Reactant: O=S(Cl)Cl
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)Oc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1
Yield: 96.9 %

Procedure:
Synthesis of (3′-nitrophenyl)-3-nitrocinnamate 193.2 g (1 mole) of 3-nitrocinnamic acid and 650 g of ethyl acetate were placed in a reaction vessel. While 200 g of thionyl chloride with some drops of DMF was dropped into the reaction mixtures, the reaction mixtures were refluxed with stirring until the generation of hydrogen chloride gas stopped. The reacted solution was concentrated until a solid could be precipitated and poured into hexane. The precipitate was separated by filtration and dried. 205 g of 3-nitrocinnamoyl chloride was yielded.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:8][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cccc(Br)c2)cc1
Yield: 65.1 %

Procedure:
A suspension of 1,3-dibromobenzene (25.3 g), 4-fluorophenylboronic acid (5.00 g) and 2M aqueous sodium carbonate solution (35.7 ml) in DMF (250 ml) was degassed. Tetrakis(triphenylphosphine)palladium(0) (2.06 g) was added under an argon atmosphere and the mixture was refluxed under heating for 21 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed twice with water and washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and distilled under reduced pressure to give the title compound (5.84 g) as a colorless oil.
Reaction SMILES: [C:1]([NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(OCC)C.[Cl:26][CH2:27][C:28]([O:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29].ClCC([O-])=O>CCCCCC>[Cl-:26].[CH3:20][N+:18]([CH3:19])([CH2:27][C:28]([O:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29])[CH2:17][CH2:16][CH2:15][NH:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)NCCCN(C)C
Reactant: O=C(CCl)OCCc1ccccc1
Agent: O=C([O-])CCl
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC(=O)OCCc1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.2 %

Procedure:
A 14.22 g (0.050 mol) portion of N-dodecanoyl-N′,N′-dimethyl-1,3-diaminopropane and 120 ml of diethyl ether were put into a flask, and 9.93 g (0.050 mol) of 2-phenylethyl chloroacetate was added thereto at 0 to 5° C. spending 5 minutes. The reaction mixture was further stirred at 25° C. for 24 hours, and disappearance of the most part of chloroacetate was confirmed by 1H-NMR. Next, the reaction mixture was slowly added dropwise to 600 ml of hexane which was ice-cooled and vigorously stirred, spending 10 minutes, to effect precipitation of the product as a white solid. Thereafter, in the same manner as described in Inventive Example 1, the title compound (to be referred to as betaine ester (11) hereinafter) was obtained as a white powder. Yield 20.10 g (0.0416 mol; yield 83.2%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:15]([C@@H:19]1[O:23][C:22](=[O:24])[C@:21]([CH2:26][CH3:27])([CH3:25])[O:20]1)([CH3:18])([CH3:17])[CH3:16]>C1COCC1.CCCCCC>[C:15]([C@@H:19]1[O:23][C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=2)([OH:24])[C@@:21]([CH2:26][CH3:27])([CH3:25])[O:20]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CSc1ccc(Br)cc1
Reactant: CC[C@@]1(C)O[C@H](C(C)(C)C)OC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[C@]1(C)O[C@H](C(C)(C)C)OC1(O)c1ccc(SC)cc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromothioanisole (48.5 g) in THF (600 mL) was cooled to -70° C. and a 2.5M solution of n-butyllithium in hexane (96 mL) was slowly added over 20 min. The resulting suspension was stirred for 1 h allowing the temperature of the cooling bath to raise to -50° C. It was then cooled back to -70° C. and a solution of dioxolanone from Step 2 (29.8 g) in TBF (100 mL) was added dropwise over 30 min. The reaction was allowed to proceed for another 30 min. and then quenched with AcOH (23 mL) always at -70° C. The reaction mixture was allowed to warm to r.t., diluted with a 25% aqueous solution of NH4OAc and extracted with EtOAc (2 L). The organic layer was dried over MgSO4 and concentrated. The resulting crude product was purified by flash chromatography (2→3→5→7% EtOAc in hexane) to give a light yellow solid. 1H NMR(CD3COCD3): mixture of diastereomers δ0.50 (0.5H, m), 0.68 (1.5H, s), 0.72 (1.5H, t), 0.97 (1.5H, t), 0.98 (9H, s), 1.38 (1.5H, s), 1.52 m), 1.68 (0.5H, m), 2.10 (0.5H, m), 2.48 (3H, 2s), 4.85 (1H, s, OH), 5.01 (0.5H, s), 5.32 (0.5H, s), 7.22-7.30 (2H, m), 7.50 (2H, dd).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18](I)[C:9]=2[C:8]1=[O:20].[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH3:30])[C:9]=2[C:8]1=[O:20]
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1ccnc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 99.4 %

Procedure:
In a similar manner to Reference Example 4, 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (300 mg) was reacted with 2-methylphenylboronic acid (116 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (278 mg, 99%).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12](/[CH:15]=[C:16]2/[C:17](=[O:31])[CH:18]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])[C:19](=[O:21])[CH2:20]/2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].O>ClCCl.C(N(CC)CC)C>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12](/[CH:15]=[C:16]2/[C:17](=[O:31])[CH:18]([C:22]3[C:23]([CH3:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=3[CH3:28])[CH:19]([O:21][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:20]/2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(C2C(=O)C/C(=C\C3CCC(OCc4ccccc4)CC3)C2=O)c(C)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C2C(=O)/C(=C/C3CCC(OCc4ccccc4)CC3)CC2OC(=O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a solution of the 4-[1-(4-benzyloxy-cyclohexyl)-meth-(E)-ylidene]-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (4.0 g, 9.6 mmol) in dichloromethane (60 ml) and triethylamine (2 ml) is added the pivaloyl chloride (1.73 g, 14.3 mmol) at 0° C. The reaction is allowed to warm to room temperature and then stirred for 3 hours. The reaction mixture is poured into water (50 ml) and extracted with dichloromethane (2×50 ml). The combined organic extracts are dried over magnesium sulphate, filtered and evaporated to give 2,2-dimethyl-propionic acid 4-[1-(4-benzyloxy-cyclohexyl)-meth-(E)-ylidene]-3-oxo-2-(2,4,6-trimethyl-phenyl)-cyclopentyl ester (4.5 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([OH:24])[N:17]=2)=[CH:12][CH:11]=1.C1COCC1>CO>[Br:1][C:23]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[N:17][C:18]([OH:24])=[C:19]([CH:22]=1)[C:20]#[N:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(-c2ccc(F)cc2)nc1O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(Br)c(-c2ccc(F)cc2)nc1O
Yield: 94.6 %

Procedure:
N-Bromosuccinimide (3.66 g) was added to a mixture of 6-(4-fluorophenyl)-2-hydroxynicotinonitrile (4.00 g), THF (30 mL), and methanol (30 mL), and the resultant mixture was stirred at room temperature for 10 minutes. The solvent was distilled off, and the obtained residue was suspended in a mixed solvent of water, ethyl acetate, and hexane. Then, the obtained solid was washed with hexane to obtain the title compound (5.18 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[NH:15][C:14]([O:16][CH3:17])=[N:13][C:12]([CH3:18])=[C:11]2[C:19](=[O:21])[CH3:20])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].N1C=CC=CC=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[N:15]([C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:30])[C:14]([O:16][CH3:17])=[N:13][C:12]([CH3:18])=[C:11]2[C:19](=[O:21])[CH3:20])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: COC1=NC(C)=C(C(C)=O)C(c2cc(F)c(F)c(F)c2)N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1=NC(C)=C(C(C)=O)C(c2cc(F)c(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 6-(3,4,5-trifluorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-methylpyrimidine (2.8 g, 9.38 mmol) and pyridine (10 mL) in CH2Cl2 (200 mL) at 0-5° C., 4-nitrophenyl chloroformate (1.886 g, 9.38 mmol) was added and the mixture was allowed to warm to room temperature. After 12 hours solvent was evaporated and the residue was purified by flash column chromatography (SiO2, dichloromethane/EtOAc, 10%-15%) to obtain the product as a white powder (4.0 g, 92%).
Reaction SMILES: [OH:1][C@H:2]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[N:30][C:31]([O:34]C)=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[C@H:3]([CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=[N:10]1)[C:4]([OH:6])=[O:5].B(Br)(Br)Br.C(OCC)(=O)C.O>C1(C)C=CC=CC=1>[OH:1][C@H:2]([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[N:30][C:31]([OH:34])=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)[C@H:3]([CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=[N:10]1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(-c2ccc(CC[C@@H](O)[C@H](CCn3nnc4ccccc4c3=O)C(=O)O)cc2)cn1
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)[C@@H](CCn1nnc2ccccc2c1=O)[C@H](O)CCc1ccc(-c2ccc(O)nc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the compound obtained from Example 1A above (0.2 g) in dry toluene (5 mL), cooled to 78° C., boron tribromide (0.5 mL) was added and the contents were stirred at room temperature for 4 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain a residue which was purified by preparatory thin layer chromatography (2 mm thickness) using 15% methanol in dichloromethane as eluent to get the title compound (60 mg).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[N:3]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1>>[CH3:11][C:8]1[CH:9]=[CH:10][C:4]2[N:3]=[C:2]([N:23]3[CH2:24][CH2:25][N:20]([C:15]4[C:14]([C:13]([F:27])([F:12])[F:26])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:21][CH2:22]3)[NH:6][C:5]=2[CH:7]=1
Reactant: Cc1ccc2nc(Cl)[nH]c2c1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: Cc1ccc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The reaction of 2-chloro-6-methyl-1H-benzoimidazole (0.261 g, 1.57 mmol, Example 14b) with 1-(3-trifluoromethylpyridin-2-yl)piperazine (0.54 g, 1.6 mmol, Maybridge) under the conditions of Example 3c afforded the title compound as a white solid. M.p. 216-217° C. MS (ESI, pos. ion) m/z: 362 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[I:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([I:6])=[CH:8][CH:9]=1)=[O:4]
Reactant: Nc1ccc(I)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.0 mL (25.1 mmol) chloro-acetylchloride in 5 mL DCM are added to a solution of 5.00 g (22.83 mmol) 4-iodo-phenylamine and 7.0 mL (50.2 mmol) triethylamine in 100 mL DCM at 0° C. The ice bath is removed and the reaction is stirred for a further 1.5 h at RT. The reaction solution is diluted with 80 mL water and the organic phase is washed with saturated NaCl solution. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The residue is triturated with EtOAc, suction filtered and dried in the air.
Reaction SMILES: C(O)(=[O:3])C.FC(F)(F)C(O)=O.[F:12][C:13]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:14]=1[C:15]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])=[O:28])=[CH:23][C:22]=1[F:35])=[O:19])=[O:16].OO>O>[F:12][C:13]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:14]=1[C:15]([NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([C:29]([F:33])([F:34])[CH:30]([F:31])[F:32])(=[O:3])=[O:28])=[CH:23][C:22]=1[F:35])=[O:19])=[O:16]
Reactant: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(S(=O)C(F)(F)C(F)F)cc1F
Reactant: CC(=O)O
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(S(=O)(=O)C(F)(F)C(F)F)cc1F
Temperature: 90 °C

Procedure:
In a mixed solution consisting of 5 ml of acetic acid and 10 ml of trifluoroacetic acid was dissolved under heating 0.6 g of N-(2-fluoro-6-chlorobenzoyl)-N'-[2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfinyl)phenyl]urea, and 1.5 ml of 30% hydrogen peroxide aqueous solution was added to the solution, followed by heating at 90° C. for 2 hours. The reaction mixture was diluted with water, and the crystals which separated out were recovered by filtration, and washed with water and ethanol successively to give 0.6 g of N-(2-fluoro-6-chlorobenzoyl)-N'-[2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfonyl)phenyl]urea (Compound No. 6), m.p. of 176°-177° C.