Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)C.[CH2:5]([N:12]1[C@H:16]([C:17]([O:19][C:20](C)(C)C)=[O:18])[CH2:15][CH2:14][C@@H:13]1[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[CH2:5]([N:12]1[C@@H:13]([CH2:24][CH2:25][C:26]([O:28][CH3:1])=[O:27])[CH2:14][CH2:15][C@H:16]1[C:17]([O:19][CH3:20])=[O:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](CCC(=O)O)N1Cc1ccccc1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)CC[C@H]1CC[C@@H](C(=O)OC)N1Cc1ccccc1
Yield: 68.8 %

Procedure:
Acetyl chloride (1.50 ml, 21.10 mmol) was added dropwise to MeOH (7.5 mL) at 0° C. After 15 min of stirring a solution of 3-((2R,5S)-1-benzyl-5-(tert-butoxycarbonyl)pyrrolidin-2-yl)propanoic acid (200 mg, 0.600 mmol) in MeOH (7.5 mL) was slowly added to the reaction. The reaction mixture was then heated at reflux overnight. The reaction was concentrated. The residue was partitioned between EtOAc and 10% Na2CO3. The organic phase was separated, washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) to give the product (2S,5R)-methyl 1-benzyl-5-(3-methoxy-3-oxopropyl)pyrrolidine-2-carboxylate (126 mg, 0.413 mmol, 68.8% yield) as colorless syrup. 1HNMR (400 MHz, CDCl3) δ ppm 7.35-7.17 (5 H, m), 3.95 (1 H, d, J=13.7 Hz), 3.71-3.61 (4 H, m), 3.47 (3 H, s), 3.37-3.26 (1 H, m), 2.86-2.73 (1 H, m), 2.53-2.41 (1 H, m), 2.38-2.25 (1 H, m), 2.08-1.79 (4 H, m), 1.79-1.66 (1 H, m), 1.66-1.53 (1 H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(CCC1CCC(=O)N1)Cc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CCC(CCC(O)Cc2ccc(F)cc2)N1
Reaction time: 20 h
Yield: 75.5 %

Procedure:
Analogous to the procedure described for Example 1A, Step B, 5-[4-(4-fluoro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (2.64 g, 10.6 mmol) was reduced with NaBH4 (400 mg, 10.5 mmol) at room temperature for 1 h. Additional NaBH4 (150 mg, 3.95 mmol) was added and the reaction mixture was stirred for 20 h. Purification by medium pressure chromatography using a solvent gradient (CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2) provided 5-[4-(4-fluoro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (2.01 g). 1H NMR (CDCl3) δ7.14 (m, 2H), 6.98 (m, 2H), 6.78 (m, 1H), 3.76 (m, 1H), 3.65 (m, 1H), 2.76 (m, 1H), 2.64 (m, 1H), 2.32-2.18 (m, 4H), 1.72-1.47 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[CH:22][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15](C(=O)C)=[CH:14][C:13]=1[F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=[C:30]([C:35]([O:37]O)=[O:36])C=1>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[C:35]([O:37][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:22]=[CH:23][C:24]([CH2:26][CH3:27])=[CH:25][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:21])[CH:14]=1)(=[O:36])[CH3:30]
Reactant: CCc1ccc(Oc2ccc(C(C)=O)cc2F)c(OCc2ccccc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCc1ccc(Oc2ccc(OC(C)=O)cc2F)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
To a solution of 1-{4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenyl}ethanone (3 g, 8.24 mmol) in dry dichloromethane (30 ml), was added PTSA (0.047 g, 0.247 mmol). The reaction mixture was cooled in an ice bath and mCPBA (50% H2O)(2.84 g, 8.24 mmol) was added portionwise. The resulting mixture was stirred at RT for 3 days, then concentrated at 35-40 C. The residue was purified by column chromatography, (pet ether:EtOAC). The resulting solid was dissolved in pet ether, filtered then concentrated the yield the title compound (1.6 g; 51%)
Reaction SMILES: [CH:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1N)=[CH2:2].C([N:12](CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([Cl:22])[C:19]([NH:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:3]([CH:1]=[CH2:2])[CH:4]=1)=[O:20]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C=Cc1ccccc1N
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cccc(NC(=O)C(Cl)Cl)c1

Procedure:
Commercially available (Aldrich Chemical Co.) 2-vinylaniline can be dissolved in dichloromethane containing triethylamine and can be treated at 0° C. with dichloroacetyl chloride to yield 2.2-dichloro-N-(3-vinylphenyl)acetamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12](S(C3C=CC=CC=3)(=O)=O)[CH:11]=[C:10]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:9]=2[F:32])=[CH:6][CH:5]=[CH:4][N:3]=1.O1CCCC1.CC(O)C.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])[C:9]=2[F:32])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a mixture of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (5.50 g), tetrahydrofuran (25 mL), 2-propanol (25 mL) and methanol (20 mL) was added a 1 mol/L aqueous sodium hydroxide solution (50 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=1:1) to give the title compound as a yellow solid (yield 3.59 g, 92%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14]2=[O:22])=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=c1[nH]c2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cn2c(=O)[nH]c3ccccc32)cc1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
Referring to Schemes 1 and 2, a solution of methyl 4-bromomethylbenzoate (0.5 mmol) in DMF (2.5 mL) was treated with 1,3-Dihydro-benzoimidazol-2-one (0.5 mmol) and solid K2CO3 (0.6 mmol). After stirring at 23° C. for 4 h, the reaction was poured into water (10 mL) and the resulting solid was isolated by filtration. The filter cake was rinsed with water and allowed to dry in vacuo to yield 4-(2-Oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-benzoic acid methyl ester.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][C:6]1[CH:11]=[C:10]([NH:12][CH3:13])[CH:9]=[C:8]([CH3:14])[C:7]=1/[CH:15]=[CH:16]/[S:17]([N:20]1[CH2:41][CH2:40][C:23]2([N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=3)[NH:25][C:24]2=[O:39])[CH2:22][CH2:21]1)(=[O:19])=[O:18].C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH3:5][C:6]1[CH:11]=[C:10]([N:12]([CH3:13])[C:1]([Cl:4])=[O:2])[CH:9]=[C:8]([CH3:14])[C:7]=1/[CH:15]=[CH:16]/[S:17]([N:20]1[CH2:21][CH2:22][C:23]2([N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:36])([F:38])[F:37])[CH:29]=3)[NH:25][C:24]2=[O:39])[CH2:40][CH2:41]1)(=[O:18])=[O:19]
Reactant: O=C(Cl)Cl
Reactant: CNc1cc(C)c(/C=C/S(=O)(=O)N2CCC3(CC2)N=C(c2cccc(OC(F)(F)F)c2)NC3=O)c(C)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N(C)C(=O)Cl)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(OC(F)(F)F)c1)NC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
Phosgene (20% solution in toluene, 35 μL, 67 μmol) was added to a mixed solution of 8-[(E)-2-(2,6-dimethyl-4-methylamino-phenyl)-ethenesulfonyl]-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (30 mg, 56 μmol) and triethylamine (15 μL, 84 μmol) in dichloromethane (1.5 ml) and dimethylformamide (0.5 ml) at 0° C. The mixture was stirred at room temperature for three hours, and then quenched with water and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to give N-(3,5-dimethyl-4-{(E)-2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-N-methyl-chloroformamide (28 mg, 85%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](C1NC=CN=1)([C:20]1[NH:21]C=CN=1)=[O:19].C(CN)O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:21][CH2:20][CH2:18][OH:19])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: NCCO
Solvent: CN(C)C=O
Product: O=C(NCCO)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94.6 %

Procedure:
A solution of 4-benzyloxy benzoic acid (20 g, 87.6 mmol), 1,1,-carbonyl-diimidazole (14.9 g, 91.8 mmol) and DMF (80 ml) was stirred at 50° C. for 1 h. The solution is cooled to 0° C., and ethanolamine (25% in water, 81.2 g) is added. After 45 min., the precipitate was filtered to give 4-benzyloxy-N-(2-hydroxy-ethyl)-benzamide (22.49 g, 94.5%) as a white solid. MS: me/e=271 (M)+.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([CH:8]=O)=[CH:6][CH:7]=1)#[N:2].[C:10]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1>[C:1]([C:3]1[S:4][C:5]([CH:8]=[CH:18][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:17])=[CH:6][CH:7]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)s1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(C=CC(=O)c2ccccc2)s1
Yield: 56.6 %

Procedure:
A mixture of 2-cyano-5-formylthiophene (4 g) and benzoylmethylenetriphenylphosphorane (11.09 g) in tetrahydrofuran (40 ml) was refluxed for 30 minutes. The reaction mixture was evaporated in vacuo to give 3-(5-cyano-2-thienyl)-1-phenyl-2-propen-1-one (3.95 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[CH3:9][C:10]([CH2:12][C:13]([C:15]([F:18])([F:17])[F:16])=O)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:10]=2[CH3:9])[N:3]=1.[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:10]([CH3:9])=[CH:12][C:13]=2[C:15]([F:18])([F:17])[F:16])[N:3]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1cccc(N)n1
Product: Cc1cc(C(F)(F)F)c2ccc(N)nc2n1
Product: Cc1cc(C(F)(F)F)nc2nc(N)ccc12

Procedure:
A process as claimed in claim 1 wherein 2,6-diaminopyridine is reacted with 1,1,1-trifluoroacetylacetone and the 2-amino-5-methyl-7-trifluoromethyl-1,8-naphthyridine and 2-amino-5-trifluoromethyl-7-methyl-1,8-naphthyridine thus obtained converted to the 2-oxo analogs by reaction with an alkali metal nitrite in the presence of trifluoroacetic acid or pentafluoropropionic acid to provide 5-methyl-7-trifluoromethyl-1,8-naphthyridin-2(1H)-one and 5-trifluoromethyl-7-methyl-1,8-naphthyridin-2(1H)-one.
Reaction SMILES: OO.C(O[C:10]([C:12](F)(F)F)=[O:11])(C(F)(F)F)=O.N1(CCCNC2N=[N+:28]([O-:39])[C:29]3[CH:38]=[C:37]4[C:33]([CH2:34][CH2:35][CH2:36]4)=[CH:32][C:30]=3[N:31]=2)CCOCC1.C(O)(C(F)(F)F)=[O:41]>C(Cl)Cl.N>[N+:28]([C:29]1[CH:38]=[C:37]2[C:33]([CH2:34][CH2:35][CH2:36]2)=[CH:32][C:30]=1[NH:31][C:10](=[O:11])[CH3:12])([O-:39])=[O:41]
Reactant: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)CCC3
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
H2O2 (70%, 0.60 mL, ca. 11.9 mmol) was added dropwise to a stirred solution of TFAA (1.7 mL, 11.9 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 60 (412 mg, 1.2 mmol) and TFA (0.46 mL, 6.0 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 60 (208 mg, 50%) and (ii) 1,4-dioxide 61 (122 mg, 30%) as a red solid: mp (MeOH) 158-160° C.; 1H NMR δ 8.37 (br s, 1H, NH), 8.11 (s, 1H, H-5), 8.09 (s, 1H, H-9), 3.80-3.84 (m, 4H, 2×CH2O), 3.64-3.69 (m, 2H, CH2N), 3.02-3.10 (m, 4H, H-6, H-8), 2.56 (dd, J=6.2, 6.1 Hz, 2H, CH2N), 2.48-2.52 (m, 4H, 2×CH2N), 2.15-2.22 (m, 2H, H-7), 1.85-1.91 (m, 2H, CH2); 13C NMR δ 155.5, 149.5, 145.6, 138.0, 129.6, 115.8, 111.6, 66.9 (2), 57.7, 53.8 (2), 41.6, 33.3, 32.3, 25.5, 24.5. Anal. calcd for C17H23N5O3.¼CH3OH: C, 58.6; H, 6.9; N, 19.8. Found: C, 58.4; H, 6.7; N, 19.9%.
Reaction SMILES: C(O[CH2:7][C:8]1[CH:13]=[CH:12]C=[CH:10][CH:9]=1)(=O)C(C)=C.[C:14]([O:18]C)(=O)[CH:15]=[CH2:16].S[CH2:21]CC(OC)=O.CC(N=NC(C#N)(C)C)(C#N)C.CCCCCCCCC(C)C>>[CH3:10][CH2:9][CH:8]([CH2:13][CH2:12][C:14]([OH:18])([CH2:15][CH3:16])[CH3:21])[CH3:7]
Reactant: C=C(C)C(=O)OCc1ccccc1
Reactant: C=CC(=O)OC
Reactant: COC(=O)CCS
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCCCCCCC(C)C
Product: CCC(C)CCC(C)(O)CC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixed solution of the whole amount of the above-described resin grain dispersion (as seed) and 10 g of Dispersion Stabilizing Resin (Q-1) was heated to a temperature of 60° C. under nitrogen gas stream with stirring. To the mixture was added dropwise a mixture of 85 g of benzyl methacrylate, 15 g of methyl acrylate, 1.0 g of methyl 3-mercaptopropionate, 0.8 g of AIVN and 200 g of Isopar H over a period of 2 hours, followed by further reacting for 2 hours. Then 0.8 g of AIVN was added to the reaction mixture, the temperature thereof was raised to 70° C., and the reaction was conducted for 2 hours. Further, 0.6 g of AIVN was added thereto, followed by reacting for 3 hours. After cooling, the reaction mixture was passed through a nylon cloth of 200 mesh to obtain a white dispersion which was a latex of good monodispersity having a polymerization ratio of 98% and an average grain diameter of 0.25 μm.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:26]=[CH:25][C:17]([O:18]C(C)C(OC)=O)=[CH:16][CH:15]=1)[C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1.Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>ClCCl>[CH3:1][N:2]([C:14]1[CH:26]=[CH:25][C:17]([O:18][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][CH:15]=1)[C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COC(=O)C(C)Oc1ccc(N(C)c2nnc3cc(Cl)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(N(C)c2nnc3cc(Cl)ccc3n2)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 55.8 %

Procedure:
A mixture of 4-[N-methyl-N-(7-chloro-1,2,4-benzotriazin-3-yl)amino]phenol (1.5 g; Example 6 part (a)), ethyl 2-bromo-2-methylpropionate (1.23 g), anhydrous potassium carbonate (0.87 g) and dimethylformamide (15 ml) was heated, with stirring, at a temperature of 100° C. for a period of 3 days. The cooled solution was poured into dichloromethane and the mixture was washed with water. The aqueous phase was dried (over anhydrous magnesium sulfate) and the solvent was removed by distillation under reduced pressure to give an oil. The crude product was purified by chromatography over silica gel (eluent dichloromethane) to give the title compound (0.9 g) as a red oil.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[C:13]1([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.Cl>C1COCC1>[C:13]1([S:19]([CH2:22][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)c1ccccc1
Reactant: BrCCC1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=S(=O)(CCCC1CCCCC1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
A solution of 2.5M nBuLi in hexanes (1.9 mL, 4.7 mmol) was added to a solution of diisopropylamine (660 μL, 4.7 mmol) in THF (9.0 mL) at ambient temperature. After 10 min, the mixture was cooled to −78° C. and methyl phenyl sulfone (700 mg, 4.5 mmol) was added to the reaction vessel. The cold bath was removed and after stirring for 30 min, 1-bromo-2-cyclohexylethane (1.3 g, 6.7 mmol) was added to the reaction mixture. The mixture was allowed to warm to ambient temperature and stir for 18 hours. A solution of 2N HCl was added to the reaction mixture followed by extraction with EtOAc (2×). The organic phases were combined, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes, 1:8) to afford a clear oil (620 mg, 52%). 1H NMR (CDCl3, MHz) δ 0.75-0.91 (m, 2H), 1.07-1.26 (m, 6H), 1.58-1.76 (m, 7H), 3.06 (t, J=8 Hz, 2H), 7.55-7.70 (m, 3H), 7.92 (m, 2H); MS (CI/NH3) m/z: (M+NH4)+ 284.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1.O>CN(C=O)C>[CH2:17]([NH:16][C:11]1=[N:12][C:13](=[O:15])[S:14]/[C:10]/1=[CH:9]\[CH:6]1[CH2:7][CH2:8][N:3]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=2)[CH2:4][CH2:5]1)[C:18]#[CH:19]
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (300 mg) in DMF (3 mL) were added potassium carbonate (517 mg) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (0.15 mL). The reaction mixture was stirred at room temperature for 4 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (64 mg).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[Cl:12][CH:13]([Cl:17])[C:14](O)=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:12][CH:13]([Cl:17])[C:14]([CH:8]1[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]1=[O:7])=[O:15]
Reactant: O=C(O)C(Cl)Cl
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1C(=O)C(C(=O)C(Cl)Cl)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (5.00 g, 32.05 mmol), dichloroacetic acid (6.19 g, 48.03 mmol), 4-dimethylaminopyridine (1.95 g, 16.01 mmol) in dry CH2Cl2 (30 ml) was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (7.26 g, 35.22 mmol) added. The reaction mixture was stirred at room temperature overnight and filtered. The solid was washed with CH2Cl2 (150 ml) and the combined solution was washed with 2 N HCl solution (40 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallised from MeOH giving 5-dichloroacetyl-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 7 (5.41 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.CCOC(C)=O>[CH2:22]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)[CH:13]=[C:5]1[C:3]([O:2][CH3:1])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccc(OC)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of methyl6-methoxy-1H-indole-2-carboxylate (Compound 1, 1.0 g, 4.9 mmol) in DMF (10 ml) was added K2CO3 (2.0 g, 14.6 mmol) and benzyl bromide (0.87 ml, 7.3 mmol). The mixture was stirred at room temperature for 40 h and was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by crystallization from Et2O to yield the title compound as an off-white solid.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](OC)(=[O:16])[CH2:11][C:12](OC)=[O:13]>CS(C)=O>[C:2]1([C:1]2[N:9]=[C:12]([OH:13])[CH:11]=[C:10]([OH:16])[N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)c1ccccc1
Reactant: COC(=O)CC(=O)OC
Solvent: CS(C)=O
Product: Oc1cc(O)nc(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
A mixture of benzamidine (7.42 g) and dimethyl malonate (8.09 g) in dry dimethyl sulfoxide (7 mL) was allowed to stand at room temperature for 24 h. The precipitated product was collected and washed with water and ether to afford 2-Phenyl-4,6-dihydroxy-pyrimidine as a white solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[N:26]([CH2:27][CH2:28][O:29]C6CCCCO6)[C:25]([CH3:36])=[N:24][CH:23]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:37]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH:38]([N:41]1[C:45]([C:46]2[N:47]=[C:48]3[C:54]4[CH:55]=[CH:56][C:57]([C:59]5[N:60]=[C:61]([CH3:73])[N:62]([CH2:64][CH2:65][O:66]C6CCCCO6)[CH:63]=5)=[CH:58][C:53]=4[O:52][CH2:51][CH2:50][N:49]3[CH:74]=2)=[N:44][CH:43]=[N:42]1)([CH3:40])[CH3:39].Cl>CO>[CH:38]([N:41]1[C:45]([C:46]2[N:47]=[C:48]3[C:54]4[CH:55]=[CH:56][C:57]([C:59]5[N:60]=[C:61]([CH3:73])[N:62]([CH2:64][CH2:65][OH:66])[CH:63]=5)=[CH:58][C:53]=4[O:52][CH2:51][CH2:50][N:49]3[CH:74]=2)=[N:44][CH:43]=[N:42]1)([CH3:40])[CH3:39].[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[N:26]([CH2:27][CH2:28][OH:29])[C:25]([CH3:36])=[N:24][CH:23]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:37]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1ncc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)n1CCOC1CCCCO1
Reactant: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1CCOC1CCCCO1
Agent: Cl
Solvent: CO
Product: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1CCO
Product: Cc1ncc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)n1CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %
Yield: 21 %

Procedure:
The mixture of 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (left above) and 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (right above) (90 mg, 0.18 mmol) was dissolved in methanol (3 mL) and a HCl solution in MeOH (4 mol/L, 3.0 mL) was added dropwise at 0° C. The mixture was allowed to warm up to room temperature slowly and stirred at room temperature for 2 h. It was concentrated and the residue was washed with EtOAc to give 255 (65 mg, 72%) and 301 (20 mg, 21%) as HCl salts. 301: 1H NMR (CDCl3, 400 MHz): δ 8.54 (d, J=8.4 Hz, 1H), 7.85 (s, 1H), 7.66 (s, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.11 (s, 1H), 6.89 (s, 1H), 6.04-5.95 (m, 1H), 4.51-4.45 (m, 4H), 4.12-4.06 (m, 2H), 3.78-3.74 (m, 2H), 2.44 (s, 3H), 1.60 (d, J=6.4 Hz, 6H). LC-MS m/z 420 [M+H+]