Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][N:15]([CH3:23])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[S:10][C:9]1=[S:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:31][O:32][CH2:33][CH2:34]Br>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][N:15]([CH3:23])[C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:34][CH2:33][O:32][CH3:31])=[CH:20][CH:21]=2)[S:10][C:9]1=[S:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C=C1SC(=S)N(Cc2ccccc2)C1=O)c1ccc(O)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COCCOc1ccc(N(C)C=C2SC(=S)N(Cc3ccccc3)C2=O)cc1
Temperature: 50 °C
Yield: 72.4 %

Procedure:
To a solution of 3-benzyl-5-{[N-(4-hydroxyphenyl)-methylamino]-methylene}-2-thioxothiazolidin-4-one (71 mg, 0.20 mmol) in DMF (1.0 mL, anhyd) was added anhyd K2CO3 (29 mg, 0.21 mmol) and 2-bromoethyl methyl ether (20 μL, 0.21 mmol). The reaction mixture was heated at 50° C. After 20 h the reaction mixture was cooled, diluted with CHCl3 (50 mL), washed with H2O (3×25 mL) and brine, dried over anhyd Na2SO4, concentrated and then chromatographed (silica gel, 0:100 to 20:80 EtOAc-DCM) to give the title product (60 mg, 73%) as a yellow solid. 1H-NMR (CDCl3): δ 7.73 (1H, s), 7.44 (2H, d), 7.21-7.30 (3H, m), 7.11 (2H, d), 6.97 (2H, d), 5.23 (2H, s), 4.15 (2H, m), 3.79 (2H, m), 3.48 (3H, s), 3.47 (3H, s).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C>O1CCCC1>[OH:8][CH:9]1[CH2:10][CH2:11][C:12]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:14]1
Reactant: COC(=O)C1(C)CCC(O[Si](C)(C)C(C)(C)C)CC1
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCC(O)CC1
Reaction time: 5 h
Yield: 96.5 %

Procedure:
To a solution of methyl 4-[(tert-butyldimethylsilyl)oxy]-1-methylcyclohexane-1-carboxylate (10.0 g, 34.91 mmol, 1.00 equiv) in 100 mL of tetrahydrofuran was added TBAF-3H2O (16.5 g, 52.30 mmol, 1.50 equiv) at room temperature and stirred for 5 h. Then the reaction was quenched with water, extracted with 3×100 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/2) to give 5.8 g (96%) of methyl 4-hydroxy-1-methylcyclohexane-1-carboxylate as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][N:4]=[N:3]1.Br[C:21]1[CH:22]=[C:23]([C:27]([O:29][CH3:30])=[O:28])[S:24][C:25]=1[Cl:26].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:26][C:25]1[S:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=1[C:6]1[N:2]([CH3:1])[N:3]=[N:4][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2cnnn2C)c(Cl)s1
Temperature: 110 °C
Yield: 31.7 %

Procedure:
A mixture of 1-methyl-5-(tributylstannanyl)-1H-1,2,3-triazole (2.0 g, 5.37 mmol), methyl 4-bromo-5-chloro-2-thiophenecarboxylate (1.25 g, 4.9 mmol), Pd(PPh3)2Cl2 (171 mg, 0.244 mmol), TRIETHYLAMINE (0.68 ml, 4.89 mmol) and toluene (3 ml) was heated at 110° C. for 4 hr under N2. The reaction mixture was purified via column chromatography (silica, 50%-70% EtOAc in hexane) to give the title compound as a white solid (400 mg, 32%): LCMS (ES) m/z 258.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:5]=1)(=[O:3])[CH3:2].[Br:21]Br>CC(O)=O.O.C([O-])(O)=O.[Na+]>[C:1]([C:4]1[C:9](=[O:10])[C:8]([Br:21])=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
To a solution of 3-acetyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (1.00 g, 3.54 mmol) in AcOH (3.5 mL) was added Br2 (0.181 mL, 3.54 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and NaHCO3 aqueous solution, extracted with EtOAc, dried over MgSO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title compound (332 mg, 26% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.57 (3H, s), 7.79-7.91 (2H, m), 8.09-8:17 (1H, m), 8.22 (1H, s), 9.58 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[F:35])(=[O:27])=[O:26].[OH-].[NH4+:37]>>[NH2:37][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:22])([CH3:21])[CH3:23])=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:24][S:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])(=[O:26])=[O:27])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: [NH4+]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)c(-c2ccnc(Cl)n2)s1
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (100 mg, 0.180 mmol) and ammonium hydroxide (3 mL, 77 mmol), the title compound was obtained as an off white solid (88 mg, 87% yield). MS (ESI): 536 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[OH-].[Na+].[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>CO.O>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:19]=[CH:20][C:21](/[CH:22]=[CH:12]/[C:11](=[O:13])/[CH:10]=[CH:9]/[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(/C=C/C(C)=O)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(/C=C/C(=O)/C=C/c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
(E)-4-(4-Methoxyphenyl)but-3-en-2-one (1 g, 5.7 mmol) was dissolved in MeOH (18 mL) and stirred for 5 min at room temperature. A solution of NaOH (500 mg, 12.5 mmol) in H2O (34 mL) was added and the reaction mixture was stirred for further 1 h. After the dropwise addition of 4-(trifluoromethyl)-benzaldehyde (822 μl, 6.0 mmol), the mixture was stirred overnight at ambient temperature. The resulting yellow precipitate was filtered and dried in vacuo to obtain NW336.2 as a pale yellow solid (1.75 g, 92%). mp: 144-146° C. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.66 (d, 3J=15.9 Hz, 1H, Hvin), 7.64 (d, 3J=15.5 Hz, 1H, Hvin), 7.63 (d, 3J=9.0 Hz, 2H, HAr), 7.58 (d, 3J=8.6 Hz, 2H, HAr), 7.50 (d, 3J=8.8 Hz, 2H, HAr), 7.06 (d, 3J=16.0 Hz, 1H, Hvin), 6.87 (d, 3J=16.0 Hz, 1H, Hvin), 6.86 (d, 3J=8.8 Hz, 2H, HAr), 3.78 (s, 3H, OCH3). 13C NMR (75 MHz, CDCl3) δ (ppm): 188.4 (C), 161.9 (C), 143.9 (CH), 140.8 (CH), 138.4 (q, 4J(C, F)=1.3 Hz, CH), 131.7 (q, 2J(C, F)=32.7 Hz, C), 130.3 (CH), 128.4 (CH), 127.6 (CH), 127.3 (C), 125.9 (q, 3J(C, F)=3.8 Hz, CH), 123.9 (q, 1J(C, F)=272.2 Hz, C), 123.2 (CH), 114.5 (CH), 55.5 (OCH3). MS (FAB) m/z: 333.1 (M+). Anal. calcd for C19H15F3O2: C, 68.67; H, 4.55. Found: C, 68.81; H, 4.63%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[O:14]([CH2:13][CH2:12][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCOc1ccccc1
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nccn1CCOc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of ethyl imidazole-2-carboxylate (0.505 g, 3.60 mmol) in N,N-dimethylformamide (6 ml) were added β-bromophenetole (0.804 g, 4.00 mmol) and potassium carbonate (0.598 g, 4.32 mmol), and the mixture was stirred at 80° C. for 1 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give ethyl 1-(2-phenoxyethyl)imidazole-2-carboxylate (0.869 g, 3.34 mmol, yield 93%). This was dissolved in methanol (9 ml), 1N-aqueous sodium hydroxide solution (9 ml) was added at room temperature, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 5%-aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 1-(2-phenoxyethyl)imidazole-2-carboxylic acid (0.573 g, 2.47 mmol, yield 74%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[C:8]([C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12]Br)#[N:9].O>CN(C=O)C>[N:1]1([CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[C:8]#[N:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1ccccc1CBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1Cn1ccnc1
Reaction time: 0.5 h

Procedure:
To a solution of imidazole (1.0 g, 14.6 mmol) in DMF (10 mL) is added sodium hydride (60% wt. in mineral oil, 0.887 g, 22.17 mmol) at room temperature. The mixture is stirred for 30 min, whereupon 2-cyanobenzyl bromide (2.87 g, 14.6 mmol) is added. After an additional 30 min, water is added and the mixture is extracted with ethyl acetate. The aqueous phase is poured into aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic phase is dried over sodium sulfate, filtered and concentrated in vacuo to give a residue which is purified by silica gel chromatography (dichloromethane-methanol, 19:1) to give 2-imidazol-1-ylmethyl-benzonitrile; MS (ESI) m/z 184.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][C:6]([CH2:12][CH3:13])=[C:5]([CH3:14])[N:4]=1.C(N1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])(OCC)=O>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][N:11]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])=[CH:7][C:6]([CH2:12][CH3:13])=[C:5]([CH3:14])[N:4]=1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCc1cc(CCN)c(OC)nc1C
Solvent: CCO
Product: CCc1cc(CCN2C(=O)c3ccccc3C2=O)c(OC)nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.4 %

Procedure:
To a solution of crude 2-methoxy-3-(2-aminoethyl)-5-ethyl-6-methylpyridine (332 mg) in ethanol (7 mL) was added N-(carbethoxy) phthalimide (406 mg, 1.85 mmol). After stirring at ambient temperature for three hours the solvent was evaporated and the residue was chromatographed on silica gel by gradient elution with 20-100% ethyl acetate/hexane. The appropriate fractions were combined, the solvent evaporated and the residue triturated with hexane as the product slowly crystallized out to yield 202 mg of pure product, m.p. 77°-79° C.
Reaction SMILES: [Cl:1][C:2]([C:4]1([C:10]([O:12]C)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[CH2:3].[OH-].[K+].C(O)(C)C>O>[Cl:1][C:2]([C:4]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[CH2:3]
Reactant: C=C(Cl)C1(C(=O)OC)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: C=C(Cl)C1(C(=O)O)CCCCC1

Procedure:
13 g of methyl 1-(1'-chlorovinyl)-cyclohexylcarboxylate were refluxed with 4 g of potassium hydroxide, 20 cm3 of isopropanol and 10 cm3 of water for 6 hours. A solid was obtained by evaporating off the alcohol and this solid was dissolved in water. The basic aqueous solution was washed with ether and then acidified with dilute hydrochloric acid. The expected 1-(1'-chlorovinyl)-1-cyclohexyl-carboxylic acid was extracted with ether. After evaporating off the solvent, the product was purified by recrystallisation from pentane and colourless crystals were obtained.
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:7]=2[CH2:6][CH2:5]1.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[OH:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:16][O:15][C:14]1[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:33][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:23]=3)[CH2:10][CH2:9][C:8]=2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]=1[O:17][CH3:18]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCI)CC2
Reactant: Oc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccc3ccccc3n1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.5 %

Procedure:
A mixture of 7-(2-iodoethyl)-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene (1.50 g), 2-quinolinol (621 mg), and potassium carbonate (987 mg) in DMF (15 ml) was stirred at room temperature for 12 hr. After being stirred at 60° C. for 6 hr, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was diluted with dilsopropylether. The crystals were collected by filtration and recrystallized from hexane-ethyl acetate to obtain 2-[2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethoxy]quinoline (680 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]=3)[CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22]
Reactant: COc1ccc(C(=O)c2c[nH]c3ncccc3c2=O)cc1C
Reactant: FC(F)(F)c1cccc(CBr)n1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C(F)(F)F)n3)c3ncccc3c2=O)cc1C
Yield: 18.2 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 50 mg (0.17 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-[1,8]naphthyridin-4-one, and 2-Bromomethyl-6-trifluoromethyl-pyridine 53 mg (0.22 mmol), to give 14 mg of desired compound. LCMS (M+H)+: 454.1.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[C:8]1([CH2:14][CH2:15][CH2:16]I)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:8]1([CH2:14][CH2:15][CH2:16][CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ICCCc1ccccc1
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)C(CCCc1ccccc1)C(C)=O
Yield: 40.1 %

Procedure:
A mixture of pentane-2,4-dione (3.87 g, 38.6 mmol), 3-phenyl-1-iodopropane (3.18 g, 12.9 mmol) and anhydrous potassium carbonate (1.7 g, 12.3 mmol) in acetone (7.5 mL) was heated to reflux for 24 hours. The room temperature reaction mixture was filtered, and the filter cake washed with acetone (25 mL×3). The combined filtrates were concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried (magnesium sulfate), and concentrated to an oil. Flash chromatography over silica (ethyl acetate/hexanes) afforded 1.13 g (42%) of a colorless oil. The proton spectrum in deuterochloroform showed the product exists as a mixture of keto and enol tautomers.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:13][N:12]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])[N:10]=2)[CH:6]=[CH:7][CH:8]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[S:13][N:12]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc(OCCCCl)ns2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(-c2nc(OCCCCl)ns2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
2 g of 3-[5-(3-methoxyphenyl)-1,2,4-thiadiazole-3-oxy]-propyl chloride [for preparation, see Example 65E)] were dissolved in 100 ml dichloromethane. A solution of 20 ml borotribromide in dichloromethane was added to the solution and the reaction mixture was stirred for 8 hours at room temperature under a nitrogen atmosphere. Then the reaction mixture was poured into water for workup and made alkaline by adding sodium carbonate. Then extraction was performed with dichloromethane and the organic phase was dried and concentrated. 1.9 g of crude 3-[5-(3-hydroxyphenyl)-1,2,4-thiadiazole-3-yloxy]-propyl chloride was obtained as a yellow oil.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][CH3:16])=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:32]C3C=CC=CC=3)=O)=[CH:25][CH:24]=2)[N:9]=1)=[O:7])[CH3:4]>O1CCOCC1>[CH2:3]([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][CH3:16])=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:2][CH3:1])=[O:32])=[CH:25][CH:24]=2)[N:9]=1)=[O:7])[CH3:4]
Reactant: CN
Reactant: CCOC(=O)c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc(NC(=O)NC)cc2)nc(N2CCOCC2)c1OCC
Yield: 50 %

Procedure:
2M Methyl amine (1.1 ml, 10 eq.) was added to a stirred solution of 5-ethoxy-6-morpholin-4-yl-2-(4-phenoxycarbonylamino-phenyl)-pyrimidine-4-carboxylic acid ethyl ester (110 mg, 1 eq.) in dioxane (3 ml), and the mixture was reacted at 80° C. overnight. The reaction mixture was concentrated and purified by flash chromatography to give a product (47.5 mg, 50%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:24])[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][O:14][CH2:15][F:16].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:9][O:10][C:11](=[O:24])[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][Br:1])=[CH:13][O:14][CH2:15][F:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(=COCF)c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=COCF)c1ccccc1CBr
Temperature: 25 °C

Procedure:
Preparation of ##STR7## 11.75 g of N-bromosuccinimide are added in several small portions, under reflux, to a solution of 14.75 g of 3-fluoromethoxy-2-(o-tolyl)-acrylic acid methyl ester and 0.53 g of dibenzoyl peroxide in 90 ml of carbon tetrachloride and then the mixture is refluxed for a further 0.5 hour. The suspension is cooled to room temperature, filtered and concentrated to dryness by evaporation. Chromatography on silica gel with hexane/ethyl acetate (6:1) yields pure 2-(2-bromomethylphenyl)-3-fluoromethoxy-acrylic acid methyl ester; m.p. 73°-76° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][C:15]([O:20][CH3:21])([O:18][CH3:19])[CH2:16]Br.O>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:16][C:15]([O:20][CH3:21])([O:18][CH3:19])[CH2:14]2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: COC(CBr)(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(OC)CC(C#N)(c2ccc(Br)cc2)C1
Temperature: 60 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
To a suspension of NaH (0.733 g, 18.32 mmol, 60% in mineral oil) in DMF (14 mL) was added 2-(4-bromophenyl)acetonitrile (1.796 g, 9.16 mmol) followed by 1,3-dibromo-2,2-dimethoxypropane (2.0 g, 7.64 mmol) and the reaction mixture was heated to 60° C. and stirred for 12 h. The reaction mixture was cooled to RT, poured into water (150 mL) and extracted with EtOAc (3×40 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (24 g REDISEP® column, eluting with 5% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 314A as a white solid (2 g, 88%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.68-7.57 (m, 2H), 7.46-7.40 (m, 2H), 3.18 (s, 3H), 3.08 (s, 1H), 3.07 (s, 3H), 3.05-3.02 (m, 1H), 2.74-2.71 (m, 1H), 2.70-2.67 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:19][C:20]1([CH3:44])[CH2:29][CH2:28][C:27]2[N:26]=[CH:25][N:24]=[C:23]([N:30]3[CH2:36][C:35]4[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:34]=4[O:33][CH2:32][CH2:31]3)[C:22]=2[CH2:21]1>>[NH2:1][C:2]1[C:7]([S:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][C:5]([C:38]2[CH:39]=[CH:40][C:34]3[O:33][CH2:32][CH2:31][N:30]([C:23]4[C:22]5[CH2:21][C:20]([CH3:19])([CH3:44])[CH2:29][CH2:28][C:27]=5[N:26]=[CH:25][N:24]=4)[CH2:36][C:35]=3[CH:37]=2)=[CH:4][N:3]=1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: CN1CC[C@@H](NS(=O)(=O)c2cc(Br)cnc2N)C1
Product: CN1CC[C@@H](NS(=O)(=O)c2cc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cnc2N)C1

Procedure:
Prepared according to the method of example 5 by using 2-amino-5-bromo-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-3-sulfonamide (reagent preparation 25) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.45 (s, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.50 (s, 1H), 7.42 (d, 1H), 7.04 (d, 1H), 4.71 (s, 2H), 4.33 (m, 2H), 3.96 (m, 2H), 3.84 (m, 1H), 2.94 (m, 1H), 2.83 to 2.69 (m, 4H), 2.61 (m, 1H), 2.47 (s, 2H), 2.45 (s, 3H), 1.74 to 1.65 (m, 3H), 0.91 (s, 6H); MS (EI) for C29H37N7O3S: 564 (MH+).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]2[CH2:16][O:15][CH2:14][CH2:13][C:11]=2[N:12]=1)[CH:2]([CH3:4])[CH3:3].[F:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([CH:25]2[CH2:26][CH2:27][N:28]([CH2:31][C:32]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]3[NH:8][C:9](=[O:17])[C:10]4[CH2:16][O:15][CH2:14][CH2:13][C:11]=4[N:12]=3)=[O:33])[CH2:29][CH2:30]2)=[O:24])=[CH:35][CH:36]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CC(C)CNCc1nc2c(c(=O)[nH]1)COCC2
Product: CC(C)CN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following the general procedure of Example 4, the title compound was prepared (36.4 mg) from 2-((isobutylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C26H33FN4O4 484.6. found 485.6 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.98 (dd, J=8.84, 5.31 Hz, 2H) 7.20 (t, J=8.59 Hz, 2H) 4.48-4.67 (m, 4H) 4.21 (br. s., 2H) 3.89-4.01 (m, 2H) 3.82 (br. s., 3H) 3.23 (br. s., 4H) 2.62-2.83 (m, 2H) 2.19 (br. s., 3H) 2.13 (s, 1H) 2.07 (d, J=6.57 Hz, 1H) 0.98 (d, J=6.57 Hz, 4H) 0.88 (d, J=5.56 Hz, 2H).