Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[NH:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1CCCCC1NC1CCCCC1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCCC1N(C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1)C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.333 g, 1.0 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). 2-Cyclohexylamino-cyclohexanecarboxylic acid ethyl ester (0.253 g, 1.0 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.201 g, 1.05 mmol). Then N-methylmorpholine (212 mg, 2.1 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-{cyclohexyl-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid ethyl ester (0.48 g, 0.845 mmol, 84.5%), as a yellow oil. LC-MS (ESI) calcd for C25H36N4O7S2 568.20, found 569.3 [M+H+].
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]#[N:30])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.CN(C=O)C.[N-:38]=[N+:39]=[N-:40].[Na+].[Cl-].[NH4+]>O>[N:30]1[NH:38][N:39]=[N:40][C:29]=1[CH2:28][CH:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:20]=[CH:21][C:16]([C:13]3[N:14]=[N:15][C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:4][CH:5]=4)=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)[CH2:27][CH2:26]1
Reactant: N#CCC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Nc2ccc(-c3ccc(C4CCC(Cc5nn[nH]n5)CC4)cc3)nn2)cn1
Temperature: 140 °C

Procedure:
To a mixture of (4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetonitrile (0.12 g, 0.29 mmol, 1.0 equiv) in 3 Ml DMF was added sodium azide (0.057 g, 0.88 mmol, 3.0 equiv), followed by solid ammonium chloride (0.062 g, 4.0 equiv). The reaction was heated to 140° C. over the weekend. The cooled reaction mixture was diluted with 10 Ml water and then acidified to Ph 4-5. The precipitate was filtered to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 103-1.16 (m, 2 H) 1.33-1.45 (m, 2 H) 1.73 (t, J=14.27 Hz, 5 H) 2.60-2.68 (m, 3 H) 7.27 (dd, J=17.94, 8.84 Hz, 3 H) 7.79 (d,J=8.84 Hz, 1 H) 7.86-7.95 (m, 2 H) 8.01 (d, J=9.09 Hz, 1 H) 8.63 (dd, J=8.59, 1.77 Hz, 1 H) 8.87 (d, J=2.27 Hz, 1 H) 9.99 (s, 1 H); (M+H)+ 481.7.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][NH2:13]>O>[CH3:12][N:13]1[C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]2[C:1]1=[O:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN
Solvent: O
Product: CN1C(=O)c2ccccc2C1=O
Temperature: 250 °C
Yield: 72 %

Procedure:
An addition funnel is charged with 46 parts of phthalic anhydride. After the anhydride is melted, it is added as a slow stream through an adaptor heated at 250° C containing a side arm. The adaptor is connected to a glass tube filled with glass beads. Through the side arm of the adaptor there is introduced methylamine gas. The mixture of the methylamine gas and the liquid phthalic anhydride is allowed to flow into the glass tube heated at 300° C which contains glass beads. At the bottom of the glass tube there is a receiver in the form of 100 ml flask fitted with a side arm. The methylamine gas is introduced at a rate of 1-2 parts per minute. The addition of the molten phthalic anhydride is completed in about 10-15 minutes while excess methylamine and water produced in the reaction being vented through the side arm. There is obtained a 72% yield of N-methylphthalimide as a white solid having a melting point of 129.5°-132° C. No unreacted phthalic anhydride and less than 1% by weight of bis-(N-methyl)amide of phthalic anhydride was detected in the final product based on liquid chromotography.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.Br[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]>>[CH2:28]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]2=[N:3][C:2]=3[NH2:1])=[C:15]([CH3:21])[CH:16]=1)[CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)CCBr
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCC(C)C)cc3C)cc12

Procedure:
2-(4-(Isopentyloxy)-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) following the procedure described for Example 136, but using 1-bromo-3-methylbutane. 1H NMR (Acetone-d6): δ 8.75 (s, 1H), 8.72 (s, 1H), 8.29 (d, 1H), 7.43 (s, 1H), 7.17 (D, 1H), 7.10 (d, 1H), 6.76 (d, 1H), 6.68 (d, 1H), 6.56 (br, 2H), 4.00 (t, 2H), 3.17 (t, 2H), 3.07 (t, 2H), 2.48 (s, 3H), 1.76-1.91 (m, 1H), 1.60-1.71 (m, 2H), 0.96 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[Cl:21])[C:3]=12.C(N(CC)CC)C.[CH2:30]([C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:30]([C:33]1([S:36]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][N:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=3[Cl:21])[C:12]2=[O:22])(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]
Reactant: O=c1[nH]c2cc3snnc3c(F)c2n1-c1ccc(Br)cc1Cl
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(Br)cc3Cl)c3c(F)c4nnsc4cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of 4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (40 mg, 0.10 mmol) in DCM (5 mL) was added triethylamine (21 mg, 0.20 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (27 mg, 0.15 mmol) and DMAP (10 mg). After stirring at room temperature for 1 h, the mixture was washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with DCM (20 mL×2). The combined organic phase was washed by water (20 mL) and brine (20 mL) sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (50 mg, 87.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 7.78-7.76 (d, 2H), 7.33 (m, 1H), 5.76-5.58 (m, 1H), 5.08 (m, 2H), 2.93-2.86 (m, 1H), 2.13-2.0 (m, 1H), 1.97-1.87 (m, 2H), 1.28-1.16 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:28][CH3:29])=[CH:6][C:7]([O:23][CH2:24][CH:25]([F:27])[F:26])=[C:8]([CH:22]=1)[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:13]1)=[O:10])([O-])=O.[H][H]>[Pd]>[NH2:1][C:4]1[C:5]([NH:28][CH3:29])=[CH:6][C:7]([O:23][CH2:24][CH:25]([F:26])[F:27])=[C:8]([CH:22]=1)[C:9]([NH:11][C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:17]1)=[O:10]
Reactant: CNc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Product: CNc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N

Procedure:
The sub-title compound was prepared from 5-nitro-2-(2,2-difluoroethoxy)-4-(methylamino)-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-benzamide, hydrogen and Pd/C in analogy to example 86c.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][CH2:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: O=Cc1ccncc1
Product: Cc1ccc(NCc2ccncc2)c(C(=O)O)c1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from 2-amino-5-methylbenzoic acid (Aldrich) and pyridine-4-carbaldehyde. 13C-NMR (DMSO-d6) δ 169.9, 149.5, 149.1, 148.3, 135.1, 131.5, 123.2, 121.9, 111.7, 110.5, 44.7, 19.6.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]([SH:15])([CH3:14])[CH3:13].[OH-].[Na+]>CS(C)=O.O>[CH:12]([S:15][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])([CH3:14])[CH3:13]
Reactant: CC(C)S
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Sc1ccc(N)cc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 96.8 %

Procedure:
To a stirred solution containing 34.5 g (0.20 mole) of 4-chloro-3-nitroaniline and 24 g (0.30 mole) of isopropyl mercaptan in 200 ml of DMSO was added dropwise at ambient temperature a solution of 8.0 g (0.20 mole) of sodium hydroxide in 10 ml of water. The addition was exothermic to 60° and the mixture became deep red in color. After three days, the reaction mixture was poured into water and extracted with methylene chloride. The combined extracts were washed with water, dried with anhydrous MgSO4, filtered and concentrated to give 41.1 g (97%) of product as a red-brown syrup.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[CH2:11][CH:12]([CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[O:13][C:9]=2[CH:8]=[C:7]([C:26](=[O:34])[NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=2)[CH:6]=1)([CH3:3])[CH3:2].[CH3:35][CH2:36][O-].[Na+]>CCO>[CH3:33][N:30]1[CH:31]=[CH:32][C:28]([NH:27][C:26]([C:7]2[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:10]3[CH2:11][CH:12]([CH2:14][O:15][CH2:35][CH3:36])[O:13][C:9]=3[CH:8]=2)=[O:34])=[N:29]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(OC(C)C)cc(C(=O)Nc4ccn(C)n4)cc3O2)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCC1Cc2c(OC(C)C)cc(C(=O)Nc3ccn(C)n3)cc2O1
Temperature: 50 °C
Yield: 36 %

Procedure:
To a solution of toluene-4-sulfonic acid 4-isopropoxy-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-2-ylmethyl ester (216a) (84 mg, 0.17 mmol) in anhydrous EtOH (2 mL) was added NaOEt (1.5 mL, 21% wt). The mixture was heated at 50° C. for 4 hr, then quenched with H2O and extracted with 3× EtOAc. The organic layers were washed with 2× H2O, dried over Na2SO4, and concentrated. The residue was purified by reverse phase HPLC to give a white glass (22 mg, 36% yield). 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1 H) 7.20-7.34 (m, 1 H) 7.02 (s, 1 H) 6.86 (dd, J=13.26, 1.64 Hz, 2 H) 4.92-5.09 (m, 1 H) 4.57-4.69 (m, 1 H) 3.78 (s, 3 H) 3.63-3.72 (m, 1 H) 3.54-3.62 (m, 3 H) 3.22 (dd, J=16.42, 9.60 Hz, 1 H) 2.92 (dd, J=16.29, 7.45 Hz, 1 H) 1.34 (dd, J=5.81, 1.77 Hz, 6 H) 1.23 (t, J=7.07 Hz, 3 H); LCMS for C19H25N3O4 m/z 360.20 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([NH2:7])=[O:6].C(Cl)(=O)[C:13](Cl)=[O:14]>C(Cl)CCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([N:7]=[C:13]=[O:14])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccc(I)c(F)c1
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(I)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 3-fluoro-4-iodobenzamide (2.0 g), oxalyl chloride (0.120 mL) and EDC (25 mL) to afford 1.0 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].C([O:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=O)C>CCOCC.O1CCCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:19]2[CH2:20][CH:15]([CH2:13][OH:12])[CH2:16][CH2:17][N:18]2[C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:3][CH:4]=1
Reactant: CCOC(=O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccc(F)cc2)C1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
1-Bromo4-fluorobenzene (154 ml; 1.402 mol) in anhydrous ether (640 ml) was added to a suspension of magnesium turnings (34.1 g; 1.404 mol) in anhydrous ether (250 ml) and the mixture was stirred under nitrogen, at a rate which gave a gentle reflux. The solution was cooled, stirred at room temperature for 45 min and then cooled in an ice bath. To this solution was added dropwise over 40 min. a solution of 1-(triphenylmethyl)-4-piperidinecarboxylic acid ethylester (90 g; 0.225 mol) in anhydrous tetrahydrofuran (1.2 l). After 1 h the cooling bath was removed and the reaction was allowed to stand at room temperature overnight. The reaction mixture was then heated under reflux for 30 min, poured into ice-water and the product was extracted into ethyl acetate. The extract was filtered to remove insolubles, washed with water, dried over sodium sulfate and evaporated to yield an oil which on trituration with hot n-hexane gave the product as crystals (68.0 g); m.p. 243° C.
Reaction SMILES: ClC1C=CC=CC=1Cl.[Cl:9][C:10]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:11]=1[NH2:12].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[Cl:9][C:10]1[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[CH:13][C:11]=1[NH:12][S:32]([C:23]1[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:22]=1[Cl:21])(=[O:34])=[O:33]
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Cl
Solvent: c1ccncc1
Solvent: Clc1ccccc1Cl
Product: O=S(=O)(Nc1ccc(C(F)(F)F)cc1Cl)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 400 ml flask, 200 ml of o-dichlorobenzene, 1 ml of pyridine and 2.0 g (0.01 mole) of 2-chloro-4-trifluoromethylaniline were charged. While stirring the contents, 2.8 g (0.01 mole) of 2-chloro-5-trifluoromethylbenzenesulfonylchloride was added dropwise at room temperature over 5 minutes. Thereafter, the reaction mixture was heated and stirred for 8 hours under reflux (175°-180° C.). After cooling the reaction mixture to room temperature, it was thoroughly washed first with dilute hydrochloric acid and then with water. Subsequent to its dehydration with anhydrous sodium sulfate, o-dichlorobenzene was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent: benzene) to isolate the intended Compound 2. m.p. 122°-123° C., yield 2.2 g (50%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][N+:3]=1[O-:20]
Reactant: Cc1cc(C(F)(F)F)ccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-4-(trifluoromethyl)pyridine (3.9 g, 24 mmol) in methylene chloride (50 mL) was added m-chloroperbenzoic acid (7.0 g, 31 mmol). After being stirred at room temperature overnight, the solution was washed with 50 mL of 1 N NaOH. The water phase was back-extracted with methylene chloride. The combined organic phases were dried over Na2SO4 and concentrated under vacuum to give the title compound. MS (M+H) 178.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:19]([F:25])([F:24])C(OC)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH:19]([F:25])[F:24]
Reactant: O=C(CCc1ccc(O)c(Cl)c1)C1CCCC1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(OC(F)F)c(Cl)c1)C1CCCC1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A mixture of 3-(3-chloro-4-hydroxyphenyl)-1-cyclopentylpropan-1-one (15 g, 59.35 mmol, Example B(58), Step 2)), methyl 2-chloro-2,2-difluoroacetate (17.15 g, 118.7 mmol, 2 equiv) and K2CO3 (12.4 g, 124.6 mmol, 2.1 equiv) in dry DMF (150 mL) was stirred at 75–80° C. for 2 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with aqueous 1 M NaOH and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to fractional distillation affording 15.3 g (72%) of material that was about 80% pure by 1H NMR (bp 70° C./2 Torr).
Reaction SMILES: C(N(CC)CC)C.[C:8]([CH:10]1[C@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14][C@@H:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=2[F:32])[CH2:12][NH:11]1)#[N:9].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+]>ClCCl>[C:33]([N:11]1[CH2:12][C@H:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=2[F:32])[CH2:14][CH2:15][C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]1[C:8]#[N:9])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.8 %

Procedure:
Triethylamine (1.29 mL, 9.25 mmol) was added to a solution of tert-butyl [(3R,6S)-2-cyano-6-(2,3-difluorophenyl)azepan-3-yl]carbamate (0.65 g, 1.85 mmol) in dichloromethane (20 mL) at 0° C. Acetic anhydride (0.53 mL, 5.55 mmol) was added and the mixture was allowed to warm to ambient temperature. After 16 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (99% dichloromethane/ethyl acetate→70% dichloromethane/ethyl acetate) gave the title compound (144 mg). MS 394.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16]([CH3:18])=O)[N:3]=1.SC[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH2:18][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cc(Br)co2)c1C#N
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1cc(Br)co1

Procedure:
From 2-amino-4-(4-bromo-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 404 (M{81Br}+H+, 85), 402 (M{79Br}+H+, 100).
Reaction SMILES: CON(C)[C:4](=[O:24])[CH:5]([N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:8]1[CH3:23])[CH3:6].[CH3:26][Mg]Br>C1COCC1>[CH3:23][C:8]1[N:7]([CH:5]([C:4](=[O:24])[CH3:26])[CH3:6])[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CON(C)C(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In a 50 mL round-bottom flask, under an atmosphere of N2, was added (±)-tert-butyl 1-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (0.630 g, 1.813 mmol) and THF (30 mL). The solution was cooled to 0° C. then methylmagnesium bromide (2.59 ml, 3.63 mmol) was added and the reaction was slowly warmed to ambient temperature while being monitored by LCMS. The reaction was done in 3 h at ambient temperature. Quenched with 50 mL 1N HCl, 50 mL brine, extracted with EtOAc, dried over Na2SO4, filtered, concentrated to provide (±)-tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate, which was used directly in the following reaction. LRMS (M+H+) m/z: calcd 303.37. found 303.1.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[CH:22]=[C:21]([CH2:23]O)[CH:20]=[N:19]4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1.O=S(Cl)Cl.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][CH2:23][C:21]2[CH:20]=[N:19][N:18]([C:14]3[CH:13]=[C:12]([C:10]4[CH2:9][C:8](=[O:25])[NH:7][C:6]5[CH:26]=[C:27]([C:28]([F:30])([F:31])[F:29])[C:3]([N:2]([CH3:1])[CH3:32])=[CH:4][C:5]=5[N:11]=4)[CH:17]=[CH:16][CH:15]=3)[CH:22]=2)[CH2:39][CH2:38]1
Reactant: NC1CC1
Reactant: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cc(CO)cn3)c1)=N2
Solvent: O=S(Cl)Cl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cc(CNC4CC4)cn3)c1)=N2

Procedure:
The title compound was prepared from 7-dimethylamino-4-[3-(4-hydroxymethyl-pyrazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 68) (133 mg, 0.3 mmol) by treatment with SOCl2 (3 eq.) and cyclopropyl amine (10 eq.) as described in Example 45. Obtained as a yellow solid (45 mg).
Reaction SMILES: Br[C:2]1[N:3]([C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:21])[C:19]=2[N:20]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@@:5]1([CH3:13])[OH:6].[NH3:22]>>[NH2:22][C:2]1[N:3]([C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:21])[C:19]=2[N:20]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@@:5]1([CH3:13])[OH:6]
Reactant: N
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1c(Br)nc2c(N)ncnc21
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1c(N)nc2c(N)ncnc21

Procedure:
A solution of the compound from Step A (38 mg, 0.11 mmol) in liquid ammonia (10 mL) was heated in a stainless steel autoclave at 105° C. for 1 d, then cooled and evaporated. The residue was purified by HPLC [C-18 Phenomenex Luna (10 μt; 250×21.2 mm) RP-column; solvents: (A) water, (B) acetonitrile; Linear gradient: 2–35% B in 76 min.] to yield the title compound (12 mg) as a white fluffy material after freeze-drying.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=2)[C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=3[C:12]=2[CH2:13][O:14][CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=3[C:12]=2[CH2:13][O:14][CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1c(C(Nc2ccc(C(=O)OC)cc2)C2CCCCC2)oc2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a mixture of methyl 4-({cyclohexyl[5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl]methyl}amino)benzoate (454 mg) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10.0 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (10.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (423 mg, 96%) as a white solid.