Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:3][CH:4]=[CH:5][CH:6]=1.C(N(CC)CC)C.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>C1COCC1.C(Cl)Cl>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[Br:1])=[O:19]
Reactant: COc1ccccc1C(=O)Cl
Reactant: Brc1ccc[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)n1cccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To the stirred solution of 2-bromo-pyrrole (22.3 mmol) in 60 mL of dry THF and 120 mL of CH2Cl2 at -78° C. in an atmosphere of nitrogen, was added triethylamine (6.22 mL, 44.6 mmol) followed immediately by dropwise addition of a solution of 2-methoxybenzoyl chloride (5.0 mL, 33.6 mmol) in 40 mL CH2Cl2. The reaction mixture was stirred overnight while it was allowed to warm to room temperature. The mixture was washed with water and brine, dried (Na2SO4) and concentrated in vacuo at room temperature. The crude product was purified by chromatography on triethylamine-treated neutral silica, using EtOAc-Hex (5:95) as the eluent, to give 3.81 g of the title compound as a colorless oil. 1H NMR (CDCl3) δ: 7.58-7.36 (2 H, m), 7.10-6.86 (3 H, m), 6.36 (1 H, dd, J=3.5, 1.8), 6.16 (1 H, t, J=3.5), 3.78 (3 H, s).
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[S:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C=O)C>[C:24]([O:23][C:21]([NH:20][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:11][C@H:10]([OH:28])[C@@H:2]([NH:1][C:21]([O:23][CH2:24][C:33]1[S:29][CH:30]=[N:31][CH:32]=1)=[O:22])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: c1cscn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reaction time: 4 h
Yield: 159.3 %

Procedure:
The product of Example 68D (6.0 g, 15.6 mmoles) was dissolved in 60 ml of DMF under nitrogen atmosphere. To this stirred solution at room temperature was added 5-p-nitrophenyloxycarbonyloxymethyl)thiazole (4.67 g, 15.6 mmole) and the resulting solution was stirred for 4 h. The solvent was removed under reduced pressure by rotary evaporation and the residue dissolved in 150 mL EtOAc. This solution was washed with 5×75 mL 1N NaOH solution, 100 mL brine, dried over Na2SO4. The solvent was removed to afford 8.02 g of a slightly yellowish oil. This material was crystallized from 30 mL EtOAc and 40 mL hexane to afford 6.53 g (80%) of the desired product as a white solid. mp 118°-120° C. H 1NMR (CDCl3) δ8.79 (s, 1H), 7.83 (s, 1H), 7.30-7.15 (m, 8H), 7.08 (m, 2H), 5.23 (s, 2H), 5.14 (d, 1H, J=9 Hz), 4.52 (m, 1H), 3.92-3.72 (m, 3H), 3.65 (m, 1H), 2.85 (d-apparent 2H, J=7.5 Hz), 2.72 (d-apparent, 2H, J=7 Hz), 1,61 (m, 2H), 1.38 (s, 9H). CIMS m/z (526) (M+H)+, 543 (M+18)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=3[C:13]#[N:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Br[CH2:23][CH:24]([O:27][CH3:28])[O:25][CH3:26]>CN(C)C(=O)C>[CH3:26][O:25][CH:24]([O:27][CH3:28])[CH2:23][N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=3[C:13]#[N:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: N#Cc1cc(F)ccc1Oc1ccc2[nH]ncc2c1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21)OC
Temperature: 80 °C
Yield: 57.7 %

Procedure:
2-(1H-Indazol-5-yloxy)-5-fluorobenzonitrile (5.000 g, 19.7 mmol) was suspended in N,N-dimethylacetamide (50 mL) and sodium hydride (0.684 g, 25.7 mmol) was added portionwise at room temperature. 2-Bromo-1,1-dimethoxyethane (3.49 mL, 29.6 mmol) was added dropwise in one portion and the reaction mixture was heated to 80° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude material, which was partitioned between EtOAc and saturated aqueous NH4Cl. The combined organic layers were washed with water (3×), brine and dried (MgSO4) and then concentrated under reduced pressure to afford the crude material. The crude product was purified by flash column chromatography (eluant 25% EtOAc/Hexanes) to furnish 3.88 g (57.6%) of the desired compound. The N-2 isomer was not isolated. MS (APCI+) m/z 342 (M+1) was detected. 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.54 (d, 1H, J=9 Hz), 7.36 (m, 2H), 7.16 (m, 2H), 6.82 (dd, 1H, J=4.3 Hz, J=9.3 Hz), 4.76 (t, 1H, J=5.3 Hz), 4.49 (d, 2H, J=5.3 Hz), 3.41 (s, 6H).
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[C:11]([Br:13])[C:10]([NH:14][C:15]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[CH2:19][C@H:18]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:16])=[CH:9][C:8]=1[O:31][CH3:32])(C)(C)C.FC(F)(F)C(O)=O.P([O-])([O-])([O-])=O>ClCCl>[Br:13][C:11]1[C:10]([NH:14][C:15]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[CH2:19][C@H:18]2[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[O:16])=[CH:9][C:8]([O:31][CH3:32])=[C:7]([CH:12]=1)[C:6]([OH:33])=[O:5]
Reactant: COc1cc(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)c(Br)cc1C(=O)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)c(Br)cc1C(=O)O
Yield: 71.2 %

Procedure:
(S)-5-Bromo-4-{[2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carbonyl]-amino}-2-methoxy-benzoic acid tert-butyl ester (170 mg) was stirred in 10 ml dichloromethane with 0.1 ml trifluoroacetic acid for 5 hours. Phosphate buffer (pH 7) was added, the layers separated, and the dichloromethane removed in vacuo. The residue was dissolved in acetone and recrystallized by slow addition of water. The crystals were filtered and dried to give 108 mg of (S)-5-bromo-4-{[2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carbonyl]-amino}-2-methoxy-benzoic acid.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:22][CH3:23])=[O:13])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Cc2ccccc2)cc1

Procedure:
By using 4-benzylbenzoic acid (211.58 g), ethanol (1.8 l) and concentrated sulfuric acid (20 ml), there was prepared the title compound (232.55 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:18][CH:19]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CN)cc2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CNS(C)(=O)=O)cc2)n1
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of [6-(4-aminomethyl-phenyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (5.7 g 19 mmol) and Et3N (2.88 g, 29 mmol) in dichloromethane (50 mL) was added dropwise MsCl (2.7 g, 19 mmol) at 0° C. The reaction mixture was stirred at this temperature for 30 min, and then washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was recrystallized with DCM/Petroleum Ether (1:3) to give {6-[4-(methanesulfonylamino-methyl)-phenyl]-pyridin-2-yl}carbamic acid tert-butyl ester (4.0 g, 44% over two steps). 1H NMR (300 MHz, CDCl3) δ 7.90-7.97 (m, 3H), 7.75 (t, J=8.4, 8.4 Hz, 1H), 7.54-7.59 (m, 1H), 7.38-7.44 (m, 3H), 4.73 (br, 1H), 4.37 (d, J=6.0 Hz, 2H), 2.90 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11](SC)[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:12]=[N:13][CH:14]=2)=[CH:3][C:2]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:22][N:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CSc1nncc(-c2ccc(F)c(Br)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Fc1ccc(-c2cnnc(-c3ccccn3)n2)cc1-c1ccccn1
Temperature: 60 °C
Yield: 15.9 %

Procedure:
To a mixture of 5-(3-bromo-4-fluorophenyl)-3-methylsulfanyl-[1,2,4]triazine (0.2 g, 0.67 mmol), cuprous 3-methylsalicylate (0.315 g, 1.5 mmol), 2-(tri-n-butylstannyl)pyridine (0.736 g, 2.2 mmol) and lithium chloride (0.085 g, 2.0 mmol) in dry 1,4-dioxane (8 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.077 g, 0.032 mmol) and the mixture heated at 60° C. Fog 24 h. The reaction was allowed to cool to ambient temperature, diluted with DCM (20 ml) and washed with 10% ammonia solution (10 ml). The organic layer was washed with water (40 ml) and the combined organics dried over Mg2SO4, filtered and the solvent removed at reduced pressure. The crude product was purified by preparative thin-layer chromatography on silica gel, eluent 3% methanol in dichloromethane. The solid obtained was triturated with diethyl ether to give 5-[4-fluoro-3-(pyridin-2-yl)phenyl]-3-(pyridin-2-yl)-[1,2,4]triazine as a powdery orange solid (35 mg): δH (400 MHz, CDCl3) 7.39-7.48 (3H, m), 7.51 (1H, m), 7.81-8.00 (3H, m), 8.47 (1H, m), 8.71 (1H, m), 8.80 (1H, m), 8.93 (1H, m), 9.81 (1H, s); m/z (ES+) 330 (M++H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[S:9])[S:4][CH2:5][C:6]([CH3:8])=[O:7].C=O.[C:13](=S)=S.CN(C)C(=S)[S-].C[NH2+]C>CO>[CH3:1][N:2]([CH3:10])[C:3](=[S:4])[SH:9].[C:6]([CH:5]=[CH2:13])(=[O:7])[CH3:8]
Reactant: CC(=O)CSC(=S)N(C)C
Reactant: S=C=S
Agent: C=O
Agent: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: CO
Product: C=CC(C)=O
Product: CN(C)C(=S)S

Procedure:
A solution of acetonyl dimethyldithiocarbamate (3.6 grams, 0.020 mole), formaldehyde (1.6 grams of 37% aqueous solution, 0.020 mole), carbon disulfide (0.010 mole, 0.8 gram), and dimethylammonium dimethyldithiocarbamate (3.3 grams, 0.02 mole) in methanol (15 ml.) was stirred and heated at 39° C.-43° C. for 160 minutes. The reaction mixture was then cooled in ice and the precipitated product was filtered off, washed with cold methanol, and dried in air. The yield of product melting at 104° C.-106.5° C. (prior sintering) was 5.2 grams (84%). Repeated recrystallization from methylene chloride-methanol solution without heat gave the analytical sample of 1-acetylethylene dimethyldithiocarbamate melting at 105° C.-107.5° C. (prior sintering). The structure was determined from the infrared spectrum and elemental analysis.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH:6]([C:8]1[S:12][C:11]2[C:13](=[O:21])[C:14]3[CH:18]=[CH:17][S:16][C:15]=3[C:19](=[O:20])[C:10]=2[CH:9]=1)[CH3:7]>ClCCCl>[C:1]([O:5][CH:6]([C:8]1[S:12][C:11]2[C:13](=[O:21])[C:14]3[CH:18]=[CH:17][S:16][C:15]=3[C:19](=[O:20])[C:10]=2[CH:9]=1)[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(O)c1cc2c(s1)C(=O)c1ccsc1C2=O
Solvent: ClCCCl
Product: CC(=O)OC(C)c1cc2c(s1)C(=O)c1ccsc1C2=O
Temperature: 0 °C
Yield: 74 %

Procedure:
Acetyl chloride (1.1 g, 13.6 mmol) was added to a solution of 10 (2.0 g, 7.4 mmol) in 1,2-dichloroethane (100 mL) and the mixture was refluxed for 4 h. After this time, the solution was poured into ice water. The organic layer was separated, washed with saturated NaHCO3 and water, dried, and evaporated. The residue was subjected to column chromatography (silica gel, C6H6) to give 11 as a yellow solid (mp 174-176° C.) in a 74% yield: IR (KBr) 1645, 1655, 1724 (C═O) cm−1; 1H NMR (CDCl3) δ 1.68 (d, J=6.6 Hz, 3H, CHCH3), 2.13 (s, 3H, COCH3), 6.10-6.17 (q, J=6.6 Hz, 1H, CH), 7.53 (s, 1H, H-3), 7.63 (d, J=5.1 Hz, 1H, H-7), 7.68 (d, J=5.1 Hz, 1H, H-6); 13C NMR (CDCl3): δ 21.0 (C-2-COCH3), 22.0 (C-2-CHCH3), 67.4 (C-2-CH), 123.4 (C-3), 126.6 (C-7), 133.6 (C-6), 154.0 (C-2), 174.4×2 169.8 (C-2-C═O), (C-4, C-8); MS m/z 306 (M+); Anal. (C14H10O4S2) C, H.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])#[C-:31]>CO.CCCCCC>[CH3:36][O:35][C:33](=[O:34])[CH2:32][NH:30][C:31]1[N:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:8][C:13]=1[C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([F:9])[CH:11]=1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: Nc1ccc(F)cn1
Reactant: O=Cc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCCCCC
Solvent: O
Product: COC(=O)CNc1c(-c2cccc(F)c2)nc2ccc(F)cn12
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
5-Fluoropyridin-2-amine (200 mg, 1.78 mmol, Eq: 1.00), 3-fluorobenzaldehyde (240 mg, 205 μL, 1.87 mmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (102 mg, 535 μmol, Eq: 0.3) were dissolved in MeOH (2.5 mL) and the yellow solution was stirred for 10 min. To this yellow solution was added dropwise methyl 2-isocyanoacetate (182 mg, 167 μL, 1.78 mmol, Eq: 1.00) and the corresponding brown solution was stirred for 90 min. Hexane (2 mL) was added and the solvent was removed to give a beige gummy residue. To this residue, MeOH (2 mL) was added and the precipitate was filtered off, washed with MeOH (4 mL) and dried under vacuum to give the product as an off-white solid (172 mg, 30.4%). MS: 318.2 [M+H]+; 1H-NMR (CDCl3): δ 8.23 (m, 1H), 7.78-7.75 (m, 2H), 7.54 (m, 1H), 7.43 (m, 1H), 7.15-7.00 (m, 2H), 3.84 (d, 2H), 3.77 (s, 3H), 3.73 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10]C)[C:3]=1[N:12]([CH2:21][CH3:22])[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[N:14]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([OH:10])[C:3]=1[N:12]([CH2:21][CH3:22])[C:13]1[N:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[N:18]=1
Reactant: CCN(c1nc(C)cc(C)n1)c1c(Br)cc(OC)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCN(c1nc(C)cc(C)n1)c1c(O)cc(OC)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
N-(2-Bromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine (214 mg, 0.58 mmol) in 15 mL dichloromethane under nitrogen was cooled in a dry ice/acetone bath, and boron tribromide (1.0 M in dichloromethane, 0.58 mL) was slowly added. The reaction was allowed gradually to warm to room temperature whereupon it was stirred overnight. After quenching with water, the aqueous portion was basified with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried with magnesium sulfate and concentrated in vacuo to give a tan solid. The solid was recrystallized from ethyl acetate/hexanes to yield 58 mg product; mp 157-160° C. Anal. Calcd: %C, 51.15; %H, 5.15; %N, 11.93; %Br, 22.69. Found: %C, 51.02; %H, 5.10; %N, 11.83; %Br, 22.52.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[F:22])[NH2:18])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[C:17]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:19]=[CH:20][C:21]=1[F:22])([O-:14])=[O:13]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(F)c([N+](=O)[O-])c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-nitro-4-fluoroaniline to yield 2-[(3-nitro-4-fluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.CO>O1CCCC1>[CH:29]1([C:32]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([C@@H:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:7]3)=[O:33])[CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
A stirred mixture of 7-amino-2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one (1.7 g, 4.2 mmol) and cyclopropane carbonyl chloride (0.46 mL, 5.1 mmol) in tetrahydrofuran (10 mL) was heated to reflux for 15 min. To the mixture was added methanol (4 mL) at room temperature and the mixture stirred for 10 min. The solvent was removed in vacuo to give an oil. The oil was recrystallized from ethanol (20 mL) to give cyclopropyl-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide as a white solid (1.4 g, 71% yield); mp, 172-174° C.; 1H NMR (CDCl3) δ 0.86-0.93 (m, 2H, 2CHH), 1.07-1.14 (m, 2H, 2CHH), 1.46 (t, J=6.9 Hz, 3H, CH3), 1.63-1.73 (m, 1H, CH), 2.95 (s, 3H, CH3), 3.68 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.20 (d, J=16.7 Hz, 1H, CHH), 4.21 (dd, J=9.9, 14.3 Hz, 1H, CHH), 4.44 (d, J=16.7 Hz, 1H, CHH), 5.73 (dd, J=4.3, 9.9 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.44 (t, J=7.8 Hz, 1H, Ar), 8.43 (d, J=8.3 Hz, 1H, Ar), 10.46 (s, 1H, NH); 13C NMR (CDCl3) δ 8.24, 14.61, 16.10, 41.43, 47.81, 51.55, 55.75, 55.88, 64.56, 111.46, 112.09, 116.69, 116.99, 117.76, 119.17, 129.27, 133.54, 138.06, 141.22, 148.84, 149.67, 169.96, 172.59; Anal Calcd for C24H28N2O6S: C, 61.00; H, 5.97; N, 5.93. Found: C, 60.87; H, 6.13; N, 6.12.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:10][CH2:9][C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][N:4]=1)(=[O:21])=[O:20]
Reactant: OCc1ncc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ncc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Intermediate 9 (3,5-difluoro-2-pyridinyl)methanol (114 mg, 0.786 mmol) was dissolved in DCM (anh) (6 mL) at 0° C. N,N-diethylethanamine (ALDRICH, 0.131 mL, 0.943 mmol) and methanesulfonyl chloride (ALDRICH, 0.067 mL, 0.864 mmol) were added. Reaction mixture was stirred at 0° C. for 1 h 30 min. Crude of reaction was partitioned between water and DCM, aqueous layer was extracted with DCM (2×10 mL). Organic layers were dried over MgSO4 (anh) and filtered. Solvent was eliminated to yield title compound (3,5-difluoro-2-pyridinyl)methyl methanesulfonate (137 mg, 0.614 mmol, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.58 (d, 1H), 8.06-8.11 (m, 1H), 5.36 (d, 2H), 3.27 (s, 3H). [ES+MS] m/z 224 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1ccccc1
Yield: 73.4 %

Procedure:
Benzanilide is prepared by the method of Example 5 using 5.0 mls (0.05 mole) of aniline, 7.5 grams of 3A molecular sieves and 7.48 mls (0.064 mole) of benzoyl chloride in 100 mls of dichloromethane. The separated 3A sieves (16.37 g) are extracted with 200 mls of hot 3A alcohol, and the alcohol extract is evaporated to dryness to obtain 7.24 grams (68% of theoretical) of crude benzanilide; m.p. 161°-163° C. after recrystallization from 3A alcohol. Dichloromethane filtrates from above reaction are evaporated to dryness and extracted with ethyl ether to obtain an additional 1.39 grams of crude benzanilide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[O:14][CH3:15])[CH:6]=1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:8]([O:14][CH3:15])=[CH:9][C:10]([N:13]=[C:16]=[S:17])=[CH:11][N:12]=2)[CH:6]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc(N)cnc1-n1cnc(Cl)c1
Solvent: ClCCl
Product: COc1cc(N=C=S)cnc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
Step O (3): Dichloromethane (100 mL) was added to a flask charged with 6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-amine (3.0 g, 13.35 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (3.10 g, 13.35 mmol). The resulting mixture was stirred for 18 h at rt. The reaction mixture was concentrated in vacuo. The crude products were purified using silica gel chromatography (0-5% EtOAc/chloroform, linear gradient) to afford 2-(4-chloro-1H-imidazol-1-yl)-5-isothiocyanato-3-methoxypyridine (2.89 g, 81% yield) as a yellow solid. LC-MS (M+H)+ 267.1. 1H NMR (500 MHz, chloroform-d) δ ppm 8.30 (s, 1 H) 8.02 (s, 1 H) 7.72 (s, 1 H) 7.20 (s, 1 H) 4.00 (s, 3 H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:44]=[CH:43][C:13]2[N:14]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:42])[CH3:41])[C:15]([CH2:17][N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:28])[N:20]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:19]3=[O:34])=[N:16][C:12]=2[CH:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.Cl.O1CCOCC1>ClCCl>[NH2:8][CH2:9][C:10]1[CH:44]=[CH:43][C:13]2[N:14]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:42])[CH3:41])[C:15]([CH2:17][N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:28])[N:20]([CH2:29][C:30]([F:33])([F:31])[F:32])[C:19]3=[O:34])=[N:16][C:12]=2[CH:11]=1
Reactant: CC(=O)OCCCCn1c(Cn2c(=O)n(CC(F)(F)F)c(=O)c3ccccc32)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCCCCn1c(Cn2c(=O)n(CC(F)(F)F)c(=O)c3ccccc32)nc2cc(CN)ccc21

Procedure:
A solution of acetic acid 4-{5-(tert-butoxycarbonylamino-methyl)-2-[2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-quinazolin-1-ylmethyl]-benzoimidazol-1-yl}-butyl ester (98 mg, 0.16 mmol) and TFA (244 μL, 3.17 mmol) in dichloromethane (3 mL) was stirred for 4 hrs at room temperature. The volatiles were removed in vacuo and the residue dissolved in dichloromethane. A solution of 4N HCl in dioxane (0.4 mL, 10 equiv.) was added, followed by concentration. The residue was triturated from diethyl ether and filtered to give acetic acid 4-{5-aminomethyl-2-[2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-quinazolin-1-ylmethyl]-benzoimidazol-1-yl }-butyl ester; HCl salt (53 mg, 60%) as a white solid:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N:18]=[C:17]([C:23]([OH:25])=O)[CH:16]=[CH:15]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:34][NH:35][CH3:36].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N:18]=[C:17]([C:23](=[O:25])[N:35]([CH3:36])[CH3:34])[CH:16]=[CH:15]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C(=O)O)ccc2c1-c1ccc(Cl)cc1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
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: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C(=O)N(C)C)ccc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
To a stirred solution of (S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-7-methylquinoline-2-carboxylic acid (14 mg, 0.032 mmol), dimethylamine HCl salt (13 mg, 0.16 mmol) and DIPEA (0.056 mL, 0.32 mmol) in DMF (1 mL) was added HATU (61 mg, 0.16 mmol) at 0° C. The mixture was stirred for 2 hours at ambient temperature. The mixture was diluted with ethyl acetate (30 mL) and washed with water and brine, then dried over Na2SO4. Concentration and purification by column chromatography provided the product (7 mg, 45%). LCMS-ESI+ (m/z): 483.2, 485.3 (M+H)+.