Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([Br:29])[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:36]1([C:42](Cl)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[CH2:1]([C@H:8]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([Br:29])[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:9][O:10][C:42]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Br)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc2[nH]c(-c3c(N[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a solution of (S)-4-(1-benzyl-2-hydroxy-ethylamino)-3-(6-bromo-4-methyl-1H-benzimidazol-2-yl)-1H-pyridin-2-one (0.9 g, 1.98 mmol) in THF (30 mL), was added Cs2CO3 (1.29 g, 3.96 mmol) followed by triphenylmethyl chloride (1.10 g, 3.96 mmol). The reaction mixture was heated to reflux for 14 h under nitrogen and then cooled to room temperature. After removal of the solvent, the residue was diluted with ethyl acetate and washed with water. The aqueous fraction was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over Na2SO4. After concentration in vacuo, the residue was purified by flash column chromatography (30% EtOAc/hexane) to yield the title compound (1 g, 73%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.77 (1H, broad s), 11.73 (1H, d, J=5.2 Hz), 11.46 (1H, broad s), 7.13–7.54 (23H, m), 5.87 (1H, d, J=4.5 Hz), 4.09–4.14 (1H, m), 3.07–3.42 (4H, m), 2.54 (3H, s). LCMS (M+H)+ m/z 695 (t=2.79 min.).
Reaction SMILES: CO[C:3]1[CH:20]=[C:19]2[O:21][CH2:22][O:23][C:18]2=[CH:17][C:4]=1[CH2:5][CH:6]([C:12]([O:14]CC)=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[OH-].[K+]>C(O)C.O>[CH2:10]([O:9][C:7]([CH:6]([CH2:5][C:4]1[CH:3]=[CH:20][C:19]2[O:21][CH2:22][O:23][C:18]=2[CH:17]=1)[C:12]([OH:14])=[O:13])=[O:8])[CH3:11]
Reactant: CCOC(=O)C(Cc1cc2c(cc1OC)OCO2)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc2c(c1)OCO2)C(=O)O
Yield: 98.5 %

Procedure:
To a solution of the diethyl 2-(2-methoxy-4,5-methylenedioxybenyl)-malonate (20.0 g, 0.066 mol) of in ethanol (50 ml) was added a solution of potassium hydroxide (3.5 g, 0.066 mol) in water (25 ml). The solution was stirred at reflux for 6 h. After concentrating the aqueous layer was washed with ether and acidified with concentrated HCl to pH 1 and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and concentrated to afford the title compound as a yellow solid (17.3 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].N1C(C)=CC=CC=1C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[N:8][C:22](=[O:23])[O:24][CH2:25][CH3:26])[O:5][CH2:6][CH3:7]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=N)c1ccccc1Cl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)N=C(OCC)c1ccccc1Cl

Procedure:
A mixture of 40 g (22 mmol) of ethyl o-chlorobenzimidate and 22.2 g (21 mmol) of 2,6-lutidine in 500 ml of petroleum ether (b.p. 100°-130° C.) is treated with 27.2 g (25 mmol) of ethyl chloroformate and the whole is then heated at reflux temperature for about 16 hours. The precipitated salt is subsequently filtered off, the filtrate is evaporated under reduced pressure and the residue is recrystallized from diethyl ether. In this manner there is obtained ethyl (o-chloro-α-ethoxybenzylidene)carbamate, m.p. 65°-66° C.; 1H--NMR (CDCl3, 60 MHz): 4.02 (q,OCH2CH3), 4.58 (q, OCH2CH3); mass spectrum: 220(100).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[C:7](=[O:17])[C:6]3([CH3:22])[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1.[CH:23]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)=[O:28])[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>CC1CCCO1>[CH:23]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[C:7](=[O:17])[C:6]5([CH3:22])[CH2:18][O:19][CH2:20][CH2:21][N:5]5[C:4]=4[N:3]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:25][CH2:24]1
Reactant: CC(F)(F)CN1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: CC(F)(F)CN1C(=O)C2(C)COCCN2c2nc(-c3ccc(NC(=O)NC4CC4)cc3)ncc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2-Chloro-5-(2,2-difluoropropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (707 mg, 2.125 mmol) and 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (770 mg, 2.55 mmol) where combined in methyltetrahydrofuran (10 mL) and aqueous sodium carbonate (2 M) (2.2 mL). The reaction mixture was heated in a 50° C. oil bath and then 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride (38 mg) was added. The reaction mixture was then placed in an 80° C. oil bath. After about 1 hour the oil bath was reduced to 74° C. After about 4 hours some solvent had evaporated, 6 mL de-gassed methyltetrahydrofuran was added and decreased the oil bath temperature to 70° C. After about 6 hours, solvent had again evaporated, 6 mL de-gassed methyltetrahydrofuran was added. After another hour, 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride (9 mg) was added and heating continued at 70° C. for 3 hours, then cooled to room temperature and allowed to stir overnight. The reaction mixture was then diluted with 4 mL 1:1 methyltetrahydrofuran/water, stir for 15 minutes, the solids were collected by filtration, the filter cake washed with 2×3 mL portions of 1:5 water/methyltetrahydrofuran, air-dried for 1 hour, then under vacuum for 1 hour to give the title compound.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:18][CH:19]=1.Cl>ClCCl>[F:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([C:4]2[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: CSc1ccccc1
Reactant: O=C(Cl)Cc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)Cc2cccc(F)c2)cc1

Procedure:
To a stirred solution of 68 ml thioanisole in 600 ml dichloromethane at 0° C., were added slowly in a series aluminum chloride (77.3 g) and (3-fluorophenyl)acetyl chloride (100 g). The reaction mixture was stirred for an hour, after which 1 L of aqueous HCl was added slowly to the reaction mixture. The quenched mixture was stirred for another hour, which was followed by extraction with methylene chloride. The organic layer was washed with brine and then was dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resulting residue was purified by recrystallization from hexane/dichloromethane to yield 142.9 g of 2-(3-fluorophenyl)-1-{4-(methylthio)-phenyl}-ethanone. mp: 94.5-95.5° C. NMR: δ2.52 (s, 3H), 4.23 (s, 2H), 6.95-7.05 (m, 3H),7.25-7.30 (m, 3H), 7.92 (d, J=8.7 Hz, 2H).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH2:32][C:33]([N:8]1[C:9]2[C:5](=[C:4]([F:3])[C:12]([C:13]3[C:21]4[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=4[N:15]([CH3:23])[CH:14]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)=[O:34]
Reactant: Cn1cc(-c2ccc3c(c2F)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cc(-c2ccc3c(c2F)CCN3C(=O)Cc2cc(F)ccc2F)c2c(N)ncnc21
Yield: 36 %

Procedure:
A solution of 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (100 mg, 0.281 mmol), 2,5-difluorophenylacetic acid (48.3 mg, 0.281 mmol), HATU (107 mg, 0.281 mmol), and DIEA (0.196 mL, 1.123 mmol) was stirred at room temperature overnight. The reaction mixture was poured into water (10 mL) and a precipitate formed. The precipitate was collected by filtration, and dried at the pump for 1 hour. The residue was adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtAc) to afford 5-{1-[(2,5-difluorophenyl)acetyl]-4-fluoro-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (44.2 mg, 36.0% yield) as a white solid. LC-MS (ES) m/z=438 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.23-3.29 (m, 2H), 3.75 (s, 3H), 3.97 (s, 2H), 4.36 (t, J=8.34 Hz, 2H), 5.78-6.19 (m, 2H), 7.13-7.32 (m, 5H), 7.89 (d, J=8.08 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH3:17])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:25][CH2:26][C:27]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH3:17])[N:9]=2)=[CH:4][CH:3]=1)=[O:28]
Reactant: CCc1c(C)nc(-c2ccc(N)cn2)nc1O
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1c(C)nc(-c2ccc(NC(=O)CCl)cn2)nc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 52 (0.100 g, 0.434 mmol) in THF (5 mL), was added triethylamine (0.065 g, 0.65 mmol) and chloroacetylchloride (0.073 g, 0.65 mmol), and the reaction mixture was stirred at room temperature for a period of 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.CCCCCC>C1COCC1>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])=[CH:11][CH:10]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1ccc(Br)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 9.48 g (80 mmol) of 3,3-dimethylacryloyl chloride in 200 ml of dry THF was added with vigorous shaking a solution of 13.76 g (80 mmol) of 4-bromoaniline in 300 ml of dry THF. The mixture was stood at room temperature for 2 h and then treated with 80 g of ice followed by 200 ml of hexane. The organic layer was separated and the aqueous layer was extracted with 2×50 ml of hexanes. The organic layers were combined and washed successively with 30 ml of water and 2×30 ml of saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by recrystallization from an ethyl acetate and hexanes mixture to give the title compound as colorless crystals. PMR (CDCl3): & 1.91 (3H, s), 2.23 (3H, s), 5.73 (1H, broad s), 7.38-7.55 (5H, m).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])(=[O:3])[CH3:2].[O:14]=O.[OH-].[Na+:17]>O.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+:17]
Reactant: CC(=O)NCCOCCOCCO
Reactant: O=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NCCOCCOCC(=O)[O-]
Temperature: 70 °C
Yield: 94 %

Procedure:
95.5 g of 8-acetylamino-3,6-dioxa-1-octanol were dissolved in 405 g of water, and 2.90 g of Pd/C (10% by weight) were added. The solution was heated to 70° C. and, while stirring vigorously, about 17 ml/min O2 were passed continously through the solution under atmospheric pressure for 14 h. Throughout the reaction, the pH was kept at 10 by continuously metering in a total of 105 g of 20% by weight aqueous NaOH. The remaining solution was then extracted with ethyl acetate in a perforator for 3 days. The aqueous phase was then distilled to dryness to leave 106 g (corresponding to 94% of theory) of sodium 8-acetylamino-3,6-dioxaoctanoate as viscous oil.
Reaction SMILES: C(C1OC2C=C(C[Br:13])C=CC=2N=1)#N.[C:14]([C:16]1[O:17][C:18]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1)#[N:15]>>[Br:13][CH2:25][C:24]1[C:18]2[O:17][C:16]([C:14]#[N:15])=[N:20][C:19]=2[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc2nc(C#N)oc12
Reactant: N#Cc1nc2ccc(CBr)cc2o1
Product: N#Cc1nc2cccc(CBr)c2o1

Procedure:
When the 2-cyano-6-bromomethylbenzoxazole in Example 10, Step 2 is replaced with 2-cyano-7-methylbenzoxazole, 7-bromomethyl-2-cyanobenzoxazole is obtained.
Reaction SMILES: S([Cl:5])(C)(=O)=O.[F:6][C:7]1[C:8]([O:15][CH3:16])=[C:9]([CH2:13]O)[CH:10]=[CH:11][CH:12]=1>>[Cl:5][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[C:8]=1[O:15][CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(F)cccc1CO
Product: COc1c(F)cccc1CCl

Procedure:
In an analogous manner to that described in (γ) (3-fluoro-2-methoxy-phenyl)-methanol was treated with mesylchloride to obtain 1-chloromethyl-3-fluoro-2-methoxy-benzene as a colorless liquid; MS: 174 (M)+.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[CH:15]=[N:16][C:17]([C:18]([O-])=[O:19])=[C:13]3[CH2:12][N:11]([CH3:21])[C:10](=[O:22])[C:9]=2[CH:23]=1>C(O)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[CH:15]=[N:16][C:17]([C:18]([NH:2][NH2:3])=[O:19])=[C:13]3[CH2:12][N:11]([CH3:21])[C:10](=[O:22])[C:9]=2[CH:23]=1
Reactant: NN
Reactant: CN1Cc2c(C(=O)[O-])ncn2-c2ccc(F)cc2C1=O
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)NN)ncn2-c2ccc(F)cc2C1=O
Yield: 96 %

Procedure:
13 ml of hydrazine hydrate were added to a suspension of 7.0 g (23 mmol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxylate in 70 ml of ethanol and the mixture was heated at reflux for 3 hours. After cooling to 0° the crystals obtained were filtered off and there were obtained 6.43 g (96%) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide as colourless needles of m.p. 288°-290°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)Cl.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(Br)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1cccc(Br)c1

Procedure:
prepared by reaction of 3-(3-bromo-phenyl)-3-chloro-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=1.00 min; [M+H]+=312.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[S:39]1[CH:43]=[C:42]([CH2:44][CH:45]([NH:62][CH3:63])[C:46]([N:48]([CH3:61])[C@@H:49]([C:57](=[O:60])[NH:58][CH3:59])[CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47])[C:41]2[CH:64]=[CH:65][CH:66]=[CH:67][C:40]1=2.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:62]([C@@H:45]([C:46](=[O:47])[N:48]([CH3:61])[CH:49]([C:57](=[O:60])[NH:58][CH3:59])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:44][C:42]1[C:41]2[CH:64]=[CH:65][CH:66]=[CH:67][C:40]=2[S:39][CH:43]=1)[CH3:63])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)C(Cc1csc2ccccc12)NC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)C(Cc1ccccc1)N(C)C(=O)[C@@H](Cc1csc2ccccc12)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (0;19 g; 0.78 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.11 g; 0.78 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.16 g; 0.86 mmol) were added. The reaction mixture was stirred for 15 min at room temperature. 3-(Benzo[b]thiophen-3-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide (0.32 g ; 0.78 mmol) was dissolved in methylene chloride (10 mL) and added. Diisopropylethylamine (0.13 mL; 0.78 mmol) was added. The reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (10 mL) was added. The reaction was washed with water (20 mL), an aqueous solution of sodium hydrogen sulfate (10%; 20 mL), an aqueous solution of sodium hydrogen carbonate (saturated; 20 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2×20 cm) using ethylacatate/methylene chloride (1:1) as eluent to afford 0.26 g of ((3E)-4-(((1R)-2-(benzo[b]thiophen-3-yl)-1-(methyl-(1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butylester.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1.[CH:13]1[CH:18]=[CH:17][C:16]([O:19][C:20](OC2C=CC=CC=2)=[N:21][C:22]#[N:23])=[CH:15][CH:14]=1>COCCOC>[C:22]([N:21]=[C:20]([O:19][C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1)[NH:9][C:6]1[CH:5]=[N:4][C:3]([N:2]([CH3:12])[CH3:1])=[CH:8][CH:7]=1)#[N:23]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN(C)c1ccc([N+](=O)[O-])cn1
Solvent: COCCOC
Product: CN(C)c1ccc(NC(=NC#N)Oc2ccccc2)cn1
Reaction time: 3 h
Yield: 74.4 %

Procedure:
A stirred mixture of the crude amine prepared from 5.00 g (0.0299 mol) of the product from Step 1, diphenylcyanocarbonimidate (7.20 g, 0.0302 mol) and ethylene glycol dimethyl ether (60 ml) was kept under nitrogen for 3 hours and diluted with Et20. The solid was collected by filtration, washed with Et2O and dried to give 6.26 g of the titled product.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[OH:3].Cl.[CH3:11]O>>[OH:3][C@@H:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[C:1]([O:9][CH3:11])=[O:8]
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H](O)CC(C)C
Temperature: 25 °C

Procedure:
To a solution of L-leucic acid (1.33 g, 10 mmol) in methanol (20 mL) was added 12 N HCl (0.2 mL, 2.4 mmol) and the solution was refluxed for 3 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc in hexane to afford methyl (2S)-2-hydroxy-4-methylpentanoate as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].[Cl:14][C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][C:16]=1[CH2:27][OH:28]>CC(C)=O.C(N(CC)CC)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:24]2[CH2:23][CH2:22][N:21]([C:19]3[CH:18]=[CH:17][C:16]([CH2:27][OH:28])=[C:15]([Cl:14])[CH:20]=3)[CH2:26][CH2:25]2)=[CH:8][CH:9]=1
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Reactant: OCc1ccc(N2CCNCC2)cc1Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCCN1CCN(c2ccc(CO)c(Cl)c2)CC1)c1ccc(Cl)cc1

Procedure:
A solution of 4,4'-dichlorobutyrophenone (4.5 g, 20.7 mmole) in 25 ml of acetone was added to a warm suspension of 2-chloro-4-(1-piperazinyl)benzenemethanol (4.7 g, 20.7 mole) in 50 ml acetone and 2.5 ml of triethylamine. The reaction mixture was refluxed for four days, cooled at -10° for three hours, and then filtered. The product was washed with a little acetone, triturated on the filter with water (four times, 50 ml), and air dried. Recrystallization from acetonitrile (65 ml) gave 3.0 g (35%), mp 137°-139°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][C:18](=[O:20])[CH:19]=2)=[CH:10][CH:9]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:17][C:18](=[O:20])[CH:19]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
[4-(6-Morpholine-4-yl-4-oxo-4H-pyran-2yl)-phenyl]carbamic acid tert-butyl ester (402 mg, 1.08 mmol) was dissolved in 25% trifluoroacetic acid in dichloromethane mixture (5 ml) and stirred for 1 hour at room temperature. The reaction was concentrated in vacuo, precipitated with saturated NaHCO3, filtered, washed with diethyl ether and dried to yield (4-amino-phenyl)-6-morpholin-4-yl-pyran-4-one as a yellow solid (230 mg, 79%). m/z (LC-MS, ESP): 273 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[CH:17]=1)=[CH:5]/[O:6][CH3:7].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:17]=1)=[CH:5]/[O:6][CH3:7]
Reactant: C1COCCN1
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.9 %

Procedure:
326 mg (1.0 mmol) of the compound obtained in Step 1 was dissolved in 5 ml of methylene chloride, and 297 mg (1.4 mmol) of NaBH(OAc)3 and 87 μl (1.0 mmol) of morpholine were added thereto. After stirring at room temperature for 4 hours, the reaction mixture was treated with a saturated sodium bicarbonate aqueous solution, and the water layer was separated, and extracted twice with 20 ml portions of methylene chloride. The organic layers were combined, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The residue was subjected to column chromatography using 3% methanol/chloroform as an eluent to obtain 385 mg (yield 97%) of (E)-methyl-2-[2-((3-(morpholinomethyl)phenoxy)methyl)phenyl]-3-methoxyacrylate as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH:22]=[CH2:23])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH:22]=[CH2:23])[CH:17]=[CH:18][CH:19]=3)[C:7]=2[N:8]=1)=[O:33]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)ccc3cnc(SC)nc32)c1
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-n2c(=O)ccc3cnc(S(C)=O)nc32)c1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 84.4 %

Procedure:
At 0° C., to a suspension of N-(3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (11a) (450 mg, 1.33 mmol) in 25 mL of DCM was added MCPBA (319 mg of 77% max. from Aldrich, 1.42 mmol). After the reaction mixture was stirred at 0° C. for 35 min, it was diluted with 100 mL of DCM, washed with 20 mL of ice cold sat Na2CO3 solution. The DCM layer was dried over Na2SO4 and concentrated to give N-(3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (11b) (398 mg, 84% yield) as an off white crystalline solid. The crude material was used in next step without further purification. m/z (ESI, +ve ion) 355.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) 6 ppm 10.36 (1H, s), 9.30 (1H, s), 8.20 (1H, d, J=9.6 Hz), 7.76 (1H, m), 7.69 (1H, m), 7.51 (1H, t, J=8.0 Hz), 7.06 (1H, d, J=7.6 Hz), 6.94 (1H, m), 6.45 (1H, dd, J=16.9, 10.1 Hz), 6.26 (1H, d, J=16.8 Hz), 5.79 (1H, m), 2.72 (3H, s)