Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH2:40][N:41]4[CH:45]=[CH:44][N:43]=[CH:42]4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: BrCCn1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCn3ccnc3)cc2)c2ccccc21
Temperature: 80 °C
Yield: 75.6 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.065 g, 0.15 mmol) was dissolved in DMF at room temperature and K2CO3 (0.12 g, 0.87 mmol) was added. 1-(2-Bromo-ethyl)-1H-imidazole (0.08 g, 0.45 mmol) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (10% methanol/90% dichloromethane) to afford the product (0.06 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].O>C(Cl)Cl>[C:25]([NH:29][C@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]3[N:12]([C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[CH:9][N:10]=3)[N:13]=2)[CH2:19][CH2:20]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Reactant: CC(C)(C)N
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanone (80 mg, 0.23 mmol) and t-Butylamine (17.2 mg, 0.23 mmol) in CH2Cl2 (1.2 mL) was added dropwise Ti(Oi-Pr)4 (0.27 mL, 0.92 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The mixture was poured into water (150 mL) and extracted with EtOAc (100 mL*3). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep. HPLC to give EX. 8-78 (15 mg, 16.5%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([C:20]([OH:22])=[O:21])=[CH:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:28](=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([C:20]([O:22][CH3:28])=[O:21])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2ccc(O)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cn(-c2ccc(F)cc2)c2ccc(O)cc2c1=O
Yield: 74 %

Procedure:
Compound K (383 mg, 1.28 mmol, 1.00 eq) was dissolved in methanol (6.4 mL) and concentrated sulfuric acid (0.64 mL) was added dropwise. The reaction was heated to reflux for 3 hours at which point it was cooled and neutralized with a saturated solution of sodium bicarbonate. The mixture was extracted with a solution of 3:1 CHCl3:IPA (2×) and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using 0-20% 89:10:1 DCM:methanol:NH40H afforded 296 mg (74%) of the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.36 (s, 1H), 7.72-7.68 (m, 2H), 7.61 (d, J=2.8 Hz, 1H), 7.49 (t, J=8.7 Hz, 2H), 7.11 (dd, J=9.0, 2.8 Hz, 1H), 6.84 (d, J=9.1 Hz, 1H), 3.71 (s, 3H); ES-MS [M+1]+: 314.2.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:7]([CH2:8][OH:9])=[CH:6][NH:5][N:4]=1>CC#N.O=[Mn]=O>[F:11][C:2]([F:1])([F:10])[C:3]1[C:7]([CH:8]=[O:9])=[CH:6][NH:5][N:4]=1
Reactant: OCc1c[nH]nc1C(F)(F)F
Agent: O=[Mn]=O
Solvent: CC#N
Product: O=Cc1c[nH]nc1C(F)(F)F
Temperature: 120 °C
Yield: 33.8 %

Procedure:
(3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (600 mg, 3.61 mmol) was dissolved in MeCN (5 mL). MnO2 (785 mg, 9.03 mmol) was added. The reaction mixture was heated at 120° C. for 5 min in the microwave. The reaction mixture was filtered through decalite, washed with MeCN (30 mL), then concentrated in vacuo and purified by flash column chromatography (silica gel; eluent EtOAc:heptane, 1:1) to give the desired product (200 mg, 1.22 mmol, 34%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]1[N:25]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:26]=[C:27]([CH3:29])[CH:28]=1)=[O:4].[OH-].[Li+]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([C@H:8]2[CH2:7][N:6]([C:24]3[N:25]([C:30]4[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)[N:26]=[C:27]([CH3:29])[CH:28]=3)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]2)(=[O:12])=[O:11])=[C:14]([C:20]([F:23])([F:21])[F:22])[CH:15]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1c1cc(C)nn1-c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)O)n(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow oil. MS (ESI): m/z=566.1 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[OH:11])[CH2:8]2.[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]([F:26])=[C:17]([CH:25]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:14]1[C:13]([Cl:12])=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[C:16]([F:26])[CH:15]=1)[CH2:8]2
Reactant: OC1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OC2C3CC4CC(C3)CC2C4)cc1F
Temperature: 70 °C
Yield: 21.1 %

Procedure:
To a solution of 2-adamantanol (3.09 g, 20.26 mmol) in anhydrous dimethylsulfoxide (40 mL) was added tert-butyl 5-chloro-2,4-difluorobenzoate (6.56 g, 26.38 mmol) and cesium carbonate (13.20 g, 40.51 mmol), and the reaction mixture was heated at 70° C. for 16 hours. The solution was then cooled to ambient temperature and charged with an additional portion of 2-adamantanol (0.51 g, 3.34 mmol) and the reaction mixture was heated at 70° C. for an additional 24 hours. This process was repeated twice by addition of 2-adamantanol (0.49 g, 3.21 mmol) and (0.51 g, 3.31 mmol) respectively over an additional 48 hours. The mixture was cooled to ambient temperature and diluted with water (300 mL) and extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL); dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from hexanes and then triturated with methanol to give the title compound (1.63 g, 16%): 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=7.8 Hz, 1H), 6.62 (d, J=12.5 Hz, 1H), 4.49 (br s, 1H), 2.20-2.10 (m, 4H), 1.99-1.68 (m, 10H), 1.57 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:31][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][CH:27]([OH:30])CO)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:31][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][CH:27]=[O:30])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CC(O)CO)cnc3[nH]2)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CC=O)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a stirred solution of 3-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propane-1,2-diol (prepared as in Example 11, 70 mg, 0.16 mmol) in 50% aqueous tetrahydrofuran (10 mL) was added sodium metaperiodate (40 mg, 0.19 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 h, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acetaldehyde (65 mg, quant.) as a light yellow solid: LC/MS m/e calcd for C23H26N2O3S [M+H]+ 411.54, observed 411.1.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:25])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]([CH3:24])[CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>ClCCl>[C:1]1([C:7]2[NH:8][C:9](=[O:25])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:34](=[O:35])[CH2:33][Cl:32])[CH:19]([CH3:24])[CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1Cc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc2N1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1Cc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc2N1C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
4-Phenyl-1-(2-methylindoline-5-sulfonyl)-2-imidazolone (300 mg, 0.85 mmol) prepared in Preparation 3 was dissolved in 10 ml of dichloromethane. Pyridine (75 μl, 0.93 mmol) and chloroacetylchloride (74 μl, 0.93 mmol) were added thereto one after another, and then the reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. After stirring, the reaction mixture was diluted with 50 ml of dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1, v/v) to afford 342 mg of the title compound as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH3:14])([CH3:13])[CH:11]=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:15][OH:16].N1C=CC=CC=1>C(O)C.Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH3:14])([CH3:13])[CH:11]=[N:15][OH:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NO
Reactant: CC(C)(C=O)c1ccc2c(c1)OCO2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)(C=NO)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To a solution of Compound I (511 mg, 2.66 mmol) in ethanol (1 mL), HCl.NH2OH (277 mg, 4.00 mmol) and pyridine (2.2 mL, 26.58 mmol) were added and it was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated to dryness and added 10 mL of ethyl acetate. The organic layer was washed with distilled water, dried over anhydrous sodium sulfate, filtered and evaporated. The crude reaction mixture was purified over silica gel column using 5:1 petroleum ether-ethyl acetate as solvent to afford Compound J (528 mg, 96%) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:22][CH2:21][C:20]4(OCC[O:23]4)[CH2:19][CH2:18]3)[C:8]2=[N:11]S(C(C)(C)C)=O)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)[C:8]2=[NH:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC1(CC2)OCCO1
Agent: Cl
Solvent: C1COCCO1
Product: N=C1c2cc(Br)ccc2CC12CCC(=O)CC2
Reaction time: 8 h
Yield: 115.8 %

Procedure:
To N-(6″-bromodispiro[1,3-dioxolane-2,1′-cyclohexane-4′,2″-inden]-1″(3″H)-ylidene)-2-methylpropane-2-sulfinamide (Example 115, Step 1, 288 mg, 0.65 mmol) in 1,4-dioxane (2 mL) under N2 (g) was added HCl (4 M in 1,4-dioxane, 1.635 mL, 6.54 mmol). The mixture was stirred at r.t overnight and was then concentrated. The crude product was dissolved in DCM and was washed with NaHCO3 (sat. aq). The aqueous phase was extracted with DCM. The combined organics were dried using a phase separator and concentrated to give the title compound (220 mg, quantitative yield) that was used directly in the next step: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.24 (m, 2 H) 1.25-1.35 (m, 2 H) 1.66-1.75 (m, 2 H) 1.83-1.93 (m, 2 H) 2.86 (s, 2 H) 5.83 (s, 1 H) 7.40 (d, 1 H) 7.64 (dd, 1 H) 7.69 (d, 1 H); MS (ES+) m/z 292 [M+H]1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])([O-])=O.[H][H]>CO.[Pt]=O>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14]
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cc2)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: NC(=O)c1ccc(N)c(C(=O)Nc2ccc(Cl)cc2)c1
Yield: 98.4 %

Procedure:
4-Nitro-3-N-(4-chlorophenyl)-isophthalamide (46 mg) obtained in Example 1-2-20 was dissolved in 7 mL of methanol, and 10 mg of platinum oxide was added to the solution, followed by stirring the mixture for 30 minutes at room temperature in an atmosphere of hydrogen. The reaction mixture was filtered to remove insolubles, and the filtrate was concentrated under reduced pressure. The resulting solid was dried under reduced pressure to obtain 41 mg (99%) of 4-amino-3-N-(4-chlorophenyl)-isophthalamide.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]1[CH2:63][CH2:62][CH:61]([NH2:64])[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][CH:61]5[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.78 (m, 10H) 1.98 (m, 4H) 2.18 (s, 3H) 2.79 (d, J=11.4 Hz, 2H) 3.33 (s, 3H) 3.74 (m, 1H) 3.94 (s, 3H) 4.04 (t, J=14.0 Hz, 2H) 4.75 (q, J=7.9 Hz, 1H) 7.50 (s, 1H) 7.47 (d, J=1.5 Hz, 1H) 7.94 (s, 1H) 8.09 (d, J=7.8 Hz, 1H) 8.27 (d, J=8.1 Hz, 1H) 8.26 (s, 1H). [M+H] calc'd for C27H35F2N7O3, 544. found 544.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:11][C:10](=O)[N:9]=2)=[CH:4][C:3]=1[CH3:19].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:19])[CH:4]=2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2cc(C(F)(F)F)[nH]c(=O)n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1Cl

Procedure:
The title compound was prepared from 4-(4-chloro-3-methyl-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (9.07 g, 31.4 mmol) and phosphoryl chloride (100 mL) according to the general procedure I. Obtained as a white solid (8.68 g, 99%). MS (EI) 306.1 [(M)+]; mp 90° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[N:23]=1.[C:24](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:24])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[N:23]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(CCc2ccccc2)CC1(F)F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(F)(F)CN(CCc2ccccc2)c2nc(Cl)ncc21
Reaction time: 4 h
Yield: 61.2 %

Procedure:
To a solution of 0.64 g (0.0019 mole) of 2-chloro-7,7-difluoro-9-phenethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-275) in 15 mL of dimethylformamide was added 0.92 g (0.0029 mole) of cesium carbonate, followed by 0.35 mL (0.0057 mole) of iodomethane. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. Ice water and dichloromethane were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.41 g of 2-chloro-7,7-difluoro-5-methyl-9-phenethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-275) as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(OCC)=O)=O)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[S:3]1[CH:4]=[CH:5][S:1][C:2]1=[C:6]([C:13](=[O:15])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: CCOC(=O)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: CC(C)OC(=O)C(C(=O)Nc1ccccc1)=C1SC=CS1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Isopropyl 2-(1,3-dithiol-2-ylidene)-2-(ethoxycarbonyloxy-carbonyl)acetate (12.72 g) and aniline (3.73 g) were dissolved in methylene chloride (100 ml). The mixture was stirred at room temperature for 24 hrs. The reaction mixture was washed with aqueous sodium hydroxide solution, dil-HCl and then water. The methylene chloride layer was dried and the solvent was distilled. The resultant residue was recrystallized from ethyl acetate to obtain the pure product. (11.3 g, 88.0%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH2:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[C:29](OCC)(=[O:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C1(C)C=CC=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH:28][C:29](=[O:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CCOC(=O)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
2-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethanamine (112 mg, 0.29 mmol) was dissolved in toluene (2.9 mL) before diethyl oxalate (0.39 mL, 2.88 mmol) was added and stirred at 110° C. for 16 h. The reaction mixture was diluted with 75 mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give ethyl 2-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethylamino)-2-oxoacetate after flash chromatography. MS (ESI) m/z: Calculated: 489.2; Observed: 490.4 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:26][S:27][C:28]1[S:29][C:30]2[CH:36]=[C:35]([CH:37]=O)[CH:34]=[CH:33][C:31]=2[N:32]=1>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:37][C:35]2[CH:34]=[CH:33][C:31]3[N:32]=[C:28]([S:27][CH3:26])[S:29][C:30]=3[CH:36]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: CSc1nc2ccc(C=O)cc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc2ccc(CNc3ccc(C)cc3[N+](=O)[O-])cc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.4 %

Procedure:
To a stirred mixture of 4-methyl-2-nitroaniline (1 g, 6.5 mmol) in TFA (15 mL) at 0 to 5° C. was added portionwise sodium triacetoxyborohydride (2.78 g, 13.2 mmol) and the mixture was stirred for 10 min. To the reaction mixture was added portionwise 2-(methylthio)benzo[d]thiazole-6-carbaldehyde (1.44 g, 6.9 mmol) from Step 1 of Example 100. After stirring at rt for 4 h, the mixture was poured into ice-water and extracted with EtOAc (100 mL×3). The combined organic layers were washed with saturated aq NaHCO3 (100 mL×2) and brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% EtOAc in petroleum ether to afford 4-methyl-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (0.93 g, 41%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.37 (br s, 1H), 8.01 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.38 (dd, J=8.4, 2.4 Hz, 1H), 7.19 (dd, J=8.7, 2.1 Hz, 1H), 8.71 (d, J=8.7 Hz, 1H), 4.83 (d, J=6.0 Hz, 2H), 2.83 (s, 3H), 2.25 (s, 3H); LCMS (ESI) m/z 346 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:10]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCCOS(C)(=O)=O
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Product: CCCCCCCCCCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCCCCCCCCCC

Procedure:
Compound VI-11 (324 mg, 97.6%) was obtained in the same manner as that in Reference Example 5, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 100 mg, 0.517 mmol) and hexadecyl methanesulfonate (Nu-Chek Prep, Inc; 415 mg, 1.29 mmol).