Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:14]=2[S:13][C:12]=1[C:20](O)=[O:21].C(Cl)(=O)C(Cl)=O.[CH:29]([O:31][CH2:32][CH2:33][O:34][NH2:35])=[CH2:30].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH:29]([O:31][CH2:32][CH2:33][O:34][NH:35][C:20]([C:12]1[S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:11]=1[NH:10][C:3]1[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:30]
Reactant: C=COCCON
Reactant: CSc1ccc(Nc2c(C(=O)O)sc3ccncc23)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1sc2ccncc2c1Nc1ccc(SC)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
A suspension of 3-(2-fluoro-4-methylsulfanyl-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid (0.107 g, 0.32 mmol) in dry dichloromethane (5 ml) under an atmosphere of nitrogen was cooled to 0° C. and treated with DMF (1 drop) and oxalyl chloride (0.081 ml, 0.96 mmol). The reaction mixture was stirred for 1 hour then the solvent removed in vacuo. The resultant residue was re-suspended in dry dichloromethane (1 ml) and treated dropwise with a solution of O-(2-vinyloxy-ethyl) -hydroxylamine (0.066 g, 0.64 mmol) and DIPEA (0.167 ml, 0.96 mmol) in dry dichloromethane (4 ml) before being stirred for 18 hours. The reaction mixture was washed (water, brine), dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-SPE, gradient 0-30% ethyl acetate in dichloromethane) to provide the title compound as a yellow solid (0.024 g, 18%). LCMS (method B): RT=3.17 min, M+H+ 420.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].[N+](C1C=CC=CC=1N)([O-])=O.ClCl.C1(N)C=CC=CC=1N>C(OCC)(=O)C.C(O)(=O)C.C(Cl)(Cl)Cl.[Fe].O>[Cl:1][C:2]1[CH:8]=[C:6]([NH2:7])[C:5]([NH2:9])=[CH:4][C:3]=1[O:12][C:13]([F:18])([F:17])[CH:14]([F:15])[F:16]
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: ClCl
Agent: Nc1ccccc1N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(OC(F)(F)C(F)F)cc1N
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
5.6 Grams of 5-chloro-2-nitro-4-(1',1',2',2'-tetrafluoroethoxy)aniline [i.e. the o-nitroaniline compound (VI) containing chlorine as the substituent X] was dissolved in a mixed solvent of 25 ml of ethyl acetate and 25 ml of acetic acid. The resulting solution was dropwise added to a suspension of 4.7 g of iron powders in a mixed solution of 5 ml of acetic acid and 50 ml of water while maintaining the temperature at 50° C. Thereafter, stirring was continued for 20 minutes at 50° C. to 60° C. The reaction solution was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and water in this order, dried over anhydrous magnesium sulfate and concentrated. The residue obtained was subjected to column chromatography on silica gel with chloroform and ethyl acetate as eluents to obtain 5.2 g of 4-chloro-5-(1',1',2',2'-tetrafluoroethoxy)-1,2-benzenediamine [i.e. the o-phenylenediamine compound (IV) containing chlorine as the substituent X]. 1H-NMR (CDCl3): δ(ppm) 6.65-6.75(2H), 5.95(1H, tt, J=53, 3 Hz), 3.40(4H, s, broad)
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37]C(=O)C)(=O)C.O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:36][OH:37])[O:7]2)=[CH:20][C:21]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C(C)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-acetylbenzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (95 mg, 0.17 mmol) in a mixture of tetrahydrofuran/methanol/water (2.4 mL, 2:3:1) was added lithium hydroxide monohydrate (11.2 mg, 0.27 mmol). After stirring overnight at RT, volatiles were removed under reduced pressure. The residue was partitioned between water and ethyl acetate (3×), and the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated to give crude product 48 (68 mg), which was used in the next step without further purification. MS ESI: 407 [M+H]+, 451 [M+HCO2]−.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)[N:6]2[N:5]=1)=O.[O:23]=[S:24]1(=[O:38])[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>COCC(O)C>[O:38]=[S:24]1(=[O:23])[CH2:25][CH2:26][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:14]=5)[N:6]4[N:5]=3)=[CH:33][CH:32]=2)[CH2:28][CH2:29]1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(C)(=O)=O)c3)n2n1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(CN5CCS(=O)(=O)CC5)cc4)nn23)c1
Yield: 11.8 %

Procedure:
2-Methanesulfinyl-7-(3-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (100 mg, 0.298 mmol), 4-(1,1-dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenylamine (158 mg, 0.656 mmol), and N,N-diisopropylethylamine (114 μL, 0.656 mmol) were placed in 1-methoxy-2-propanol (728 μL). The reaction was microwaved on 300 watts, 170° C. for 8 hours. Purification by prep-HPLC using a gradient of 10-70% AcN/water both containing 0.1% TFA as the eluting solvent. The product was then free based to obtain the title compound as an orange foam (18 mg, 12%). LCMS (m/e) 512 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.76 (s, 1H), 8.71 (s, 1H), 8.34 (d, 1H, J=7.9 Hz), 7.94 (d, 1H, J=7.8 Hz), 7.73-7.66 (m, 1H), 7.58 (d, 2H, J=8.3 Hz), 7.31 (d, 2H, J=8.3 Hz), 7.05 (d, 1H, J=4.8 Hz), 6.99 (s, 1H), 6.87 (d, 1H, J=4.8 Hz), 3.63 (s, 2H), 3.09 (s, 3H), 3.09-3.03 (m, 4H), 3.03-2.94 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[CH2:16](I)[CH2:17][CH3:18].[Na+].[Cl-]>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:16][CH2:17][CH3:18])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Reactant: CCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1cccc2c(Cl)cc(C)nc12
Reaction time: 1 h
Yield: 49.3 %

Procedure:
4-Chloro-8-hydroxy-2-methylquinoline (500 mg, 2.58 mmole) was suspended in dimethylformamide (4 mL) and mixed with sodium hydride (60% in paraffin liq., 113 mg). After stirring for 1 h, propyliodide (461 mg, 2.71 mmole) in dimethylformamide (1 mL) was added dropwise and the mixture was kept under stirring at RT for 16 hrs. Diluted NaCl solution was added and the mixture was extracted with ethyl acetate. The organic phases were dried, concentrated and the residue thus obtained was purified using silica gel chromatography, eluting with dichloromethane:methanol 95:5. Precipitation in isopropanol/iso-propyl ether/HCl gave the product (300 mg, 49%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][S:24][CH3:25])=[CH:17][CH:16]=4)[C:11]=3[CH:26]=2)=[N:5][N:6]=1.CN(C)C(=[O:31])C.ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][S:24]([CH3:25])=[O:31])=[CH:19][CH:20]=4)[C:11]=3[CH:26]=2)=[N:5][N:6]=1
Reactant: CSCCOc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Reactant: CC(=O)N(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Cc1nnc(-c2ccc3occ(-c4ccc(OCCS(C)=O)cc4)c3c2)o1
Reaction time: 2 h
Yield: 27 %

Procedure:
To a mixture of 2-methyl-5-[3-[4-[2-(methylthio)ethoxy]phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (186 mg, 0.51 mmol), N,N-dimethylacetamide (2.5 mL) and acetonitrile (2.5 mL) was added m-chloroperbenzoic acid (122 mg, 0.51 mmol) at room temperature, and the resulting mixture was stirred for 2 hr. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/1-0/1) and recrystallized from hexane/ethyl acetate to give the title compound (53.0 mg, yield 27%) as colorless crystals.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][S:11]([C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)(=[O:13])=[O:12]
Reactant: OB(O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 93.4 %

Procedure:
A mixture of 15 mmol 2-iodo-5-methanesulfonyl-benzoic acid, 31 mmol phenylboronic acid, 45 mmol sodium carbonate and 34 mg palladium(II)-acetate in 100 ml water is stirred at room temperature for 60 hours. The reaction mixture is acidified by careful addition of concentrated hydrochloric acid and extracted 3 times with ethyl acetate. The organic phase is dried, concentrated and the residue crystallized from diethyl ether to yield the title compound (3.87 g, 91%) as a slightlyyellow solid, MS (m/e): 275.0 (M−H+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][SH:21])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:30]=[C:31]([NH:34][CH2:35][CH:36]3[CH2:38][CH2:37]3)[S:32][CH:33]=2)=[CH:25][CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(N(C(C)C)CC)(C)C>O1CCOCC1.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]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[N:30]=[C:31]([NH:34][CH2:35][CH:36]5[CH2:37][CH2:38]5)[S:32][CH:33]=4)=[CH:27][CH:28]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1ccc(-c2csc(NCC3CC3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CS)c2CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3ccc(-c4csc(NCC5CC5)n4)cc3)c2CC1
Temperature: 100 °C
Yield: 97.6 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-mercaptomethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.051 g, 0.155 mmol) in dry dioxane (0.7 mL) add N-[4-(4-bromo-phenyl)-thiazol-2-yl]-cyclopropylmethylamine (0.043 g, 0.14 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.2 mg, 0.0035 mmol), Xantphos (4.1 mg, 0.014 mmol) and diisopropylethylamine (0.049 mL, 0.28 mmol) at room temperature. Purge the reaction mixture with nitrogen and heat the mixture at 100° C. overnight. Cool the reaction mixture to room temperature, dilute with DCM (50 mL) and filter through Celite®. Concentrate the filtrate in vacuo. Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (0:100 to 25:75 EtOAc/hexane over 33 min; 35 mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-{4-[2-(cyclopropylmethyl-amino)-thiazol-4-yl]-phenylthiomethyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.076 g, 97%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:21][C:22]([F:30])(S(F)(=O)=O)C(O)=O>C(#N)C.[Cu]I>[F:21][CH:22]([F:30])[O:1][CH2:2][C@@H:3]([N:10]1[C:11](=[O:20])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]1=[O:19])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: O=C1c2ccccc2C(=O)N1[C@H](CO)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1[C@H](COC(F)F)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
(S)-2-(2-hydroxy-1-phenylethyl)isoindoline-1,3-dione (1.06 g, 3.97 mmol) was dissolved in anhydrous acetonitrile (20 ml), charged with copper (I) iodide (1.133 g, 5.95 mmol), 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.615 ml, 5.95 mmol), degassed under nitrogen and heated to 80° C. The solution was allowed to stir at 80° C. for 1 hr. The reaction was cooled in an ice bath, quenched with 5 mL water, filtered through a 10 g celite cartridge, and the solvents were removed in vacuo. The residue was purified by MPLC 10-50% EtOAc/hexanes to provide (S)-2-(2-(difluoromethoxy)-1-phenylethyl)isoindoline-1,3-dione. MS: [M+H]+ m/z 318.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:47])[C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Br:29])=[C:24]([S:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[O:39][Si](C(C)(C)C)(C)C)[CH:23]=1>O1CCCC1>[CH3:19][O:20][C:21](=[O:47])[C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Br:29])=[C:24]([S:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[OH:39])[CH:23]=1
Reactant: COC(=O)c1cc(C)c(Br)c(SCc2cccc(Cl)c2O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(Br)c(SCc2cccc(Cl)c2O)c1
Reaction time: 0.5 h

Procedure:
A solution of tetra-n-butylammonium fluoride (6.12 g, 19 mmol) in tetrahydrofuran (20 mL) was added dropwise to a solution of 4-bromo-3-[2-(tert-butyl-dimethyl-silanyloxy)-3-chloro-benzylsulfanyl]-5-methyl-benzoic acid methyl ester (5 g, 96.9 mmol) in tetrahydrofuran (50 mL) under nitrogen at 5° C. and stirring was continued for 0.5 h. It was concentrated, treated with chilled water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, ethyl acetate/pet ether) to obtain the title compound as a white solid. Yield: 3.0 g, (95%); 1H NMR (CDCl3): δ 2.42 (s, 3H, CH3), 3.88 (s, 3H, OCH3), 4.34 (s, 2H, CH2), 6.81 (t, 1H, Ar), 7.29 (t, 2H, Ar), 7.7 (s, 2H, Ar); MS: m/e (EI+) 401 (M+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:44]=[C:43]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][C:52]5[CH2:57][CH2:56][C:55]([CH3:59])([CH3:58])[CH2:54][C:53]=5[C:60]5[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][CH:61]=5)[CH2:47][CH2:46]4)[CH:42]=[CH:41][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]4)=[C:21]([N+:38]([O-:40])=[O:39])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.FC(F)(F)C(O)=O>ClCCl>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:44]=[C:43]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][C:52]5[CH2:57][CH2:56][C:55]([CH3:59])([CH3:58])[CH2:54][C:53]=5[C:60]5[CH:61]=[CH:62][C:63]([Cl:66])=[CH:64][CH:65]=5)[CH2:47][CH2:46]4)[CH:42]=[CH:41][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:30][NH:29][CH2:28]4)=[C:21]([N+:38]([O-:40])=[O:39])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CN(C(=O)OC(C)(C)C)C5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CNC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 161A (0.257 g) in dichloromethane (5 mL) was added trifluoroacetic acid (0.211 mL), After 30 minutes an additional 0.2 ml of trifluoroacetic acid was added. After 3 hours, the reaction was concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C@@H:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])=O)[CH2:8][CH2:7]1.B>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][C@@H:14]([NH2:18])[CH:15]([CH3:16])[CH3:17])[CH2:10][CH2:11]1
Reactant: CC(C)[C@H](N)C(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)[C@H](N)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
The product from Example 7, Step (b) (1.12 g) was dissolved in THF (10 ml) and borane [22.7 ml (1M in THF)] was added. The reaction was stirred for 2 hr and the solvents evaporated. The reaction was quenched slowly with MeOH followed by aqueous HCl (5 ml Concentrated HCl: 5 ml H2O). The MeOH was evaporated and NaOH (2M) added until pH 9 was reached. The product was extracted with ethyl acetate and the combined organic extracts were washed with saturated aqueous NaHCO3, dried, filtered and solvents evaporated to give the sub-title compound as an oil (0.98 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18]>CC(C)=O.C(OCC)C>[C:17]([O:20][CH2:21][CH2:22][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1])(=[O:19])[CH3:18]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(=O)OCCOc1ccc(C=O)cc1F
Temperature: 55 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
A mixture of 3-fluoro-4-hydroxybenzaldehyde (2.0 g, 14.3 mmol), K2CO3 (5.92 g, 42.8 mmol) and 2-bromoethyl acetate (4.77 g, 28.5 mmol) in acetone (30 mL) is stirred at 55° C. for 24 h before it is diluted with diethyl ether (150 mL) and washed with water (3×50 mL). The organic extract is dried over MgSO4 and concentrated. The remaining residue is chromatographed on silica gel to give the title aldehyde (1.65 g) as a colourless oil. 1H NMR (CDCl3): δ 9.85 (s, 1H), 7.64-7.58 (m, 2H), 7.07 (t, J=8.2 Hz, 1H), 4.49-4.45 (m, 2H), 4.35-4.30 (m, 2H), 2.10 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[N:5][NH:6][C:7]=1[N:8]=[CH:9]OCC)#[N:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>C(O)C>[Cl:22][C:23]1[CH:24]=[C:25]([N:26]2[C:1](=[NH:2])[C:3]3[C:4]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)=[N:5][NH:6][C:7]=3[N:8]=[CH:9]2)[CH:27]=[CH:28][CH:29]=1
Reactant: CCOC=Nc1[nH]nc(Nc2cccc(OC)c2)c1C#N
Reactant: Nc1cccc(Cl)c1
Solvent: CCO
Product: COc1cccc(Nc2n[nH]c3ncn(-c4cccc(Cl)c4)c(=N)c23)c1
Temperature: 25 °C

Procedure:
A mixture of 3.85 g (13.49 mmol) of 4-cyano-5-(ethoxy-methyleneamino)-3-(3-methoxy-phenylamino)-pyrazole, 2.84 ml (27.02 mmol) of 3-chloro-aniline and 75 ml of ethanol is heated under reflux for 2 hours. The reaction mixture is then cooled to RT and filtered. Washing the crystals with ethanol and diethyl ether yields the title compound; m.p. 190-192° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH3:12][S:13][CH3:14].ClN1C(=O)CCC1=O>C(Cl)Cl>[CH3:12][S:13]([CH3:14])=[N:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: CSC
Reactant: COc1cc(OC)nc(N)n1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COc1cc(OC)nc(N=S(C)C)n1
Temperature: -20 °C
Reaction time: 2 h
Yield: 27.9 %

Procedure:
To a solution of 15.5 g (0.10 mole) of 2-amino-4,6-dimethoxypyrimidine and 8 ml (0.109 mole) of methylsulfide in 100 ml of methylene chloride at -20° C. was added dropwise a solution of 13.3 g (0.10 mole) of N-chlorosuccinimide in 300 ml of methylene chloride. After addition, the resulting solution stirred at -20° C. for 2 hours and then warmed up to room temperature. The solution was stirred at room temperature for another hour. The solution was washed with 400 ml of 2.5% sodium hydroxide aqueous solution and then 400 ml of water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was washed with ethyl ether, and dried under vacuum at ambient temperature to afford 6 g of the title compound as a solid, m.p. 102°-103° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][Cl:16]>>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: ClCCCCBr
Product: CC(=O)c1cccc(OCCCCCl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 1-(3-hydroxyphenyl)ethanone and 1-bromo-4-chlorobutane.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[NH3:21]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:21]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: N
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of paraformaldehyde (147.2 g.) and methanol (550 ml.) was stirred and heated to reflux with a steady stream of ammonia bubbling in. The crystal slurry of hexamethylenetetramine which formed was cooled to room temperature and 2-chloroacetamido-5-chlorobenzophenone (308.2 g., 1.0 mol) was added in one portion. With ammonia bubbling in, the reaction mixture was heated at reflux for 10 hours. The flow of ammonia was interrupted and the reaction mixture was cooled to room temperature, filtered, washed with methanol (2 × 125 ml.) and hot water (4 × 500 ml) and dried. There was obtained 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (220.4 g., 81.4%) melting at 212.5° to 215° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[Cl:12][CH2:13][CH2:14][O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]=[C:28]=[O:29])(=[O:26])=[O:25])=[O:17]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:28]([NH:27][S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:16]([O:15][CH2:14][CH2:13][Cl:12])=[O:17])(=[O:25])=[O:26])=[O:29])[N:7]=1
Reactant: COc1nc(N)nc(OC)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1C(=O)OCCCl
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OCCCl)nc(OC)n1
Temperature: 25 °C

Procedure:
To 0.7 g of 2-amino-4,6-dimethoxy-1,3,5-triazine in 10 ml anhydrous methylene chloride solvent was added 1.45 g 2-(β-chloroethoxycarbonyl)benzensulfonyl isocyanate. After stirring at ambient temperature for sixteen hours the solvent was removed under reduced pressure, the residue triturated with ether and the solid product filtered off, yield 1.21 g m.p. 171°-174° C. The solid showed infrared absorption peaks at 1705 and 1715 cm-1, consistent for N-[(4,6-dimethoxy-1,3,5-triazin-2-yl)aminocarbonyl]-2-(2-chloroethoxycarbonyl)benzenesulfonamide.