Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].Cl.[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23])([O-:18])=[O:17].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCc1cccc([N+](=O)[O-])c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a round bottom flask was added 4-chloro-3-(trifluoromethyl)-phenyl isocyanate (443 mg, 2.0 mmol, 1.0 eq.) and acetonitrile (3.0 mL). The solution was cooled to 0° C. before a mixture of 3-nitrobenzylamine HCl (377 mg, 2.0 mmol, 1.0 eq.), DMP (1.0 mL), and triethyl amine (0.27 mL, 2.0 mmol, 1.0 eq.) was added dropwise. The reaction was then allowed to warm to RT slowly, and then stirred for an additional 2 h. The reaction was then concentrated to remove acetonitrile. EtOAc and water were added, and the mixture was extracted, washed with brine, dried with Na2SO4, and concentrated to give an oil. Upon sitting at RT, the oil crystallized to give urea 26 (728 mg, 97% yield). LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 374.1 (M+H)+1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 9.23 (br. s, 1H), 8.14 (m, 1H), 8.09 (m, 1H), 8.04 (d, 1H), 7.74 (d, 1H), 7.62 (m, 2H), 7.52 (d, 1H), 7.04 (br t, 1H), 4.40 (s, 2H) ppm.
Reaction SMILES: [C:1](#[N:4])[CH:2]=C.[CH3:5][NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>CO>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][NH:6][CH2:5][CH2:2][C:1]#[N:4]
Reactant: C=CC#N
Reactant: CNCCc1ccccn1
Solvent: CO
Product: N#CCCNCCc1ccccn1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Acrylonitrile (10.1 ml, 1.1 eq) is added slowly to a solution cooled down to approximately 4° C. of 2-[2-(methylamino)ethyl]pyridine (19.5 ml, 1 eq) in methanol (200 ml). The reaction medium is then stirred for 3 hours at approximately 20° C. then concentrated under reduced pressure at 40° C. in order to produce 3-[(2-pyridin-2-ylethyl)amino]propanenitrile in the form of a yellow oil (25.6 g, 96% yield).
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5]CC)OCC.[F:11][CH:12]([F:21])[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=O>>[CH2:9]([O:8][C:1](=[O:5])/[C:14](=[CH:15]\[O:17][CH2:18][CH3:19])/[C:13](=[O:20])[CH:12]([F:21])[F:11])[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)C(F)F
Product: CCO/C=C(\C(=O)OCC)C(=O)C(F)F
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
Process step c): 778.1 g (5.25 mol) of triethyl orthoformate were charged in a stirred vessel, the pressure within the vessel was slowly reduced to 310 mbar and the triethyl orthoformate was heated to 104° C. 121.1 g (0.175 mol-100% conversion in process steps a) and b) assumed) of ethyl 4,4-difluoroacetoacetate (in the form of a suspension coming from process step b)) were added at 103° C. to 104° C. within 2 hours. Thereafter, the reaction mixture was stirred at 105° C. for further 30 minutes. During the entire reaction time low boiling compounds were removed by distillation under reduced pressure. Afterwards, the suspension was cooled down to room temperature. The resulting suspension (761 g) comprised 4.36% (w/w) of the desired product (GC analysis, quantification with internal standard). This corresponds to an overall yield over the two synthetic steps of 85.4%, based on ethyl difluoroacetate used.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[CH:7][C:6]=1[CH3:16])[CH3:2].Cl.[Cl:19][C:20]1[C:21]([F:28])=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:23]3[C:22](=[C:21]([F:28])[C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[CH:8]=[CH:7][C:6]=1[CH3:16])[CH3:2]
Reactant: CCOC(=O)c1cc(SCC(C)=O)ccc1C
Reactant: NNc1cccc(Cl)c1F
Agent: Cl
Product: CCOC(=O)c1cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)ccc1C

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 2-Methyl-5-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and (3-chloro-2-fluoro-phenyl) hydrazine hydrochloride.
Reaction SMILES: [NH2:1][C:2]([NH2:7])=[CH:3][N+:4]([O-:6])=[O:5].[C:8]([CH2:11][C:12](=O)[CH3:13])(=O)[CH3:9]>COCCO>[NH2:1][C:2]1[C:3]([N+:4]([O-:6])=[O:5])=[C:12]([CH3:13])[CH:11]=[C:8]([CH3:9])[N:7]=1
Reactant: CC(=O)CC(C)=O
Reactant: NC(N)=C[N+](=O)[O-]
Solvent: COCCO
Product: Cc1cc(C)c([N+](=O)[O-])c(N)n1

Procedure:
3 g (29.1 mmol) of 1,1-diamino-2-nitroethene and 11.6 (17.4 mmol) of acetylacetone were maintained at reflux in 40 ml of 2methoxyethanol for 6 hours. The solvent was then removed in vacuo, the residue was slurried in 20 ml of iced water and filtered. Drying of the filter cake gave 4.52 (93 percent) of the title product. The product had a melting point of 165° C. Other data concerning the product was:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[O:20]([CH2:27][CH2:28][NH2:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:29][CH2:28][CH2:27][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Reactant: NCCOc1ccccc1
Product: Clc1nc(SCc2ccccc2)nc2nc(NCCOc3ccccc3)sc12

Procedure:
Prepared by the method of Example 231, using the product of Example 219 and 2-phenoxyethylamine.
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][C:6](=O)[CH2:7][CH2:8][CH3:9])C.[C:12]1([NH:18][C:19]([NH:21][C:22]([NH2:24])=[NH:23])=[NH:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[O:11]=[C:4]1[NH:24][C:22]([NH:21][C:19]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[NH:20])=[N:23][C:6]([CH2:7][CH2:8][CH3:9])=[CH:5]1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N=C(N)NC(=N)Nc1ccccc1
Solvent: CCO
Product: CCCc1cc(=O)[nH]c(NC(=N)Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
In a 50 milliliter round-bottom flask, 3-oxohexanoic acid ethyl ester (3.2 grams, 0.020 mol, obtained from Aldrich Chemical Co., Milwaukee, Wis.) was added at room temperature to a solution of 1-phenylbiguanide (3.5 grams, 0.020 mol, prepared as described in Part D of Example I) in anhydrous ethanol (15 milliliters). The mixture was heated at reflux and stirred for 4 hours. After a few minutes, all the components dissolved. Cooling the resulting yellow solution mixture to room temperature gave a colorless precipitate. The precipitate was isolated by filtration and thoroughly washed with water, then with cold ethanol (0° C.), and finally with acetone. The solid was then recrystallized from anhydrous ethanol, recovered by filtration, and dried under reduced pressure to give the targeted N-(6-oxo-4-propyl-1,6-dihydropyrimidin-2-yl)-N′-phenylguanidine as a colorless solid (3.90 grams, 72 percent yield): mp=196° C.; Exact mass calculated for C14H17N5O=271.1433. Measured High Resolution Mass Spectrum (MAB/HR/N2)=271.1431. Anal. Calcd for C14H17N5O: C, 61.98; H, 6.32; N, 25.81. Found: C, 62.32; H, 6.44; N, 25.68.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:12][CH:13]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CCC(=O)O)cc1
Yield: 100.5 %

Procedure:
10% Palladium-on-carbon (200 mg) was added to a solution of 5.34 g of 4-methoxycinnamic acid in methanol, and the mixture was stirred under hydrogen until hydrogen gas absorption ceased. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 5.43 g of 3-(4-methoxyphenyl)propionic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>ClCCl>[CH3:16][S:17]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:2]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1CCCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl piperidin-3-ylmethylcarbamate (500 mg) was dissolved in anhydrous dichloromethane (10 mL), and methanesulfonyl chloride (0.181 mL) was added followed by the addition of triethylamine (1.3 mL). The reaction mixture was stirred at room temperature overnight. The organic solvent was removed under vacuum. The residue was purified with flash column chromatography on silica gel eluting with 0-70% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: O=C1OCCC1=CO
Agent: [Na]
Product: O=C1OCCC1=CNCc1ccccc1

Procedure:
Using 3-hydroxymethylenedihydrofuran-2-one sodium salt (50 mmol) and benzylamine (55 mmol) and using the abovementioned method A1, 3-benzylaminomethylenedihydrofuran-2-one is produced (7.50 g, efficiency: 70%) in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]([C:12]1[CH:17]=[C:16]([NH:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[N:15]=[C:14]([CH3:24])[N:13]=1)[CH2:6][CH2:5]2.[Cl:25]N1C(=O)CCC1=O>C(#N)C>[Cl:25][C:17]1[C:12]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=3[Cl:11])[CH2:5][CH2:6]2)=[N:13][C:14]([CH3:24])=[N:15][C:16]=1[NH:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21]
Reactant: CCC(CC)Nc1cc(N2CCc3cc(Cl)cc(Cl)c32)nc(C)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCC(CC)Nc1nc(C)nc(N2CCc3cc(Cl)cc(Cl)c32)c1Cl
Yield: 98.7 %

Procedure:
4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine (140 mg, 0.38 mmol) and N-chlorosuccinimide (60 mg, 0.45 mmol) were stirred in dry acetonitrile (5 mL) at 20° C. for 20 h. The reaction mixture was stripped in vacuo and the residue was chromatographed on silica gel using 20% EtOAc/hexanes to give the product, 5-chloro-4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine (150 mg, 99% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]#[N:14])=[C:8]2O.P(Cl)(Cl)(Cl)(Cl)[Cl:20].P(Cl)(Cl)(Cl)=O>CCCCCC>[Cl:20][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=2)[N:11]=[CH:10][C:9]=1[C:13]#[N:14]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cc([N+](=O)[O-])cc2c(O)c(C#N)cnc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: COc1cc([N+](=O)[O-])cc2c(Cl)c(C#N)cnc12
Yield: 48.6 %

Procedure:
A mixture of 4 g (16 mmol) of 8-Methoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 6.66 g (32 mmol) of phosphorous pentachloride, and 15 ml of phosphorous oxychloride was refluxed for 2.5 hours. The mixture was diluted with hexane and the solid was collected. The solid was dissolved in 500 ml of ethyl acetate and washed with cold diluted sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel. The solvent was removed giving 2.05 g of tan solid: mass spectrum (electrospray, m/e) M+H 263.7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13]CC)=[O:12].C(N(CC)CC)C.[CH2:27]([O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)Cl>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([C:39]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([OH:13])=[O:12])=[O:40])=[CH:42][CH:43]=1)/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCC/C=C/COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1ccccc1Sc1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC/C=C/COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C(=O)O)cc1
Yield: 79 %

Procedure:
In 30 ml of methylene chloride were dissolved 2.1 g of ethyl 2-(2-aminophenylthio)benzoate and 1.8 g of triethylamine, followed by dropwise addition of 2.2 g of (E)-4-(2-heptenyloxy)benzoyl chloride with ice-cooling and stirring. The mixture was stirred at room temperature for 10 hours, and then the methylene chloride was distilled off. The residue was diluted with water and extracted with ether. The ether layer was washed with diluted hydrochloric acid and saturated sodium hydrogen carbonate solution and dried and the ether was distilled off. The oily residue was dissolved in 50 ml of ethanol followed by addition of 7 ml of 10% aqueous sodium hydroxide solution, and the mixture was heated on a water bath for 40 minutes. After cooling, the reaction mixture was acidified with hydrochloric acid and diluted with water and the crystals separated out therefrom were collected by filtration and washed with water and aqueous ethanol in that order to give 2.8 g of the title compound as white crystals.
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[CH:16][C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.C(O)C.[Pd]>[C:22]1([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:20][CH2:21][NH:8][CH2:9][CH2:10][C:11]=4[NH:12][C:13]=3[CH:14]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCc3[nH]c4cc(-c5ccccc5)ccc4c3CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc(-c2ccc3c4c([nH]c3c2)CCNCC4)cc1
Yield: 50.8 %

Procedure:
A mixture of 3-benzyl-8-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.07 g, 3.0 mmol), glacial acetic acid (2 drops) and Pd/C (10%, 0.6 g) in ethanol (150 mL) was reacted in a manner similar to Example 8 to give 0.40 g (51%) of the title compound as a tan crystalline solid: mp 220-222° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.41, 7.61-7.59, 7.46, 7.42-7.38, 7.28-7.22, 3.04-3.01, 2.96-2.94, 2.87-2.84; 13C NMR (100 MHz, DMSO-d6) δ 142.4, 138:2, 135.3, 133.0, 128.5, 128.4, 126.8, 126.0, 117.9, 117.5, 111.8, 108.8, 50.5, 48.8, 32.5, 28.0; IR (drift) 3305, 2929, 2918, 2893, 2827, 1468, 1324, 1242, 869, 814, 787, 762, 753, 743, 700 cm−1; MS (EI) m/z 262 (M+); HRMS (FAB) calcd for C18H18N2+H: 263.1548, found: 263.1543; Anal. Calcd for C18H18N2.0.1 C2H4O2: C, 81.46; H, 6.91; N, 10.44. Found: C, 81.11; H, 7.01; N, 10.35.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH2:16][OH:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.ClC1C=CC(Cl)=CC=1C1(C[O:32][S:33]([CH3:36])(=O)=[O:34])CCCC1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH2:16][O:17][S:33]([CH3:36])(=[O:34])=[O:32])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OCC1(c2ccc3ccccc3c2)CCCC1
Reactant: CS(=O)(=O)OCC1(c2cc(Cl)ccc2Cl)CCCC1
Product: CS(=O)(=O)OCC1(c2ccc3ccccc3c2)CCCC1
Yield: 54 %

Procedure:
Methanesulfonic acid 1-naphthalen-2-yl-cyclopentylmethyl ester (214) (16.0 g, 54.0%) was synthesized as a white solid from (1-naphthalen-2-yl-cyclopentyl)-methanol (213) (22.0 g, 97.34 mmol) following the procedure described for methanesulfonic acid 1-(2,5-dichlorophenyl)-cyclopentylmethyl ester (201).
Reaction SMILES: Br[CH:2]([C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([F:23])=[CH:15][CH:14]=1)=[O:12])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C([O-])=[O:25].[Na+].CO>C(OCC)(=O)C>[F:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([C:11](=[O:12])[CH:2]([OH:25])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:14][CH:15]=1
Reactant: O=C[O-]
Reactant: CCOC(=O)CCCC(Br)C(=O)c1ccc(F)c2ccccc12
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCC(O)C(=O)c1ccc(F)c2ccccc12

Procedure:
A mixture of ethyl 5-bromo-6-(4-fluoro-1-naphthyl)-6-oxohexanoate (34.3 g), sodium formate (34.0 g) and methanol (150 ml) was stirred with heating under reflux for 16 hours. The reaction mixture was diluted with ethyl acetate (500 ml) and washed with water (200 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 6-(4-fluoro-1-naphthyl)-5-hydroxy-6-oxohexanoate was obtained as a yellow oil (19.0 g, 65%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][S:9][C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[C:6]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:12]([F:23])([F:22])[F:11])[CH:18]=2)[N:5]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1nc(N)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a stirred solution of 4-amino-6-chloro-2-methylthiopyrimidine (3.5 g) in toluene (45 mL) under a nitrogen atmosphere was added, sequentially, (3-trifluoromethylphenyl)boronic acid (4.15 g), potassium carbonate (25 mL, 2M) and tetrakis(triphenylphosphine)palladium(0) (1.16 g). The mixture was heated to reflux for ten hours and stirred at room temperature over the weekend. Ethyl acetate (150 mL) was added and the mixture washed with water (2×100 mL). Organics were separated, washed with saturated sodium chloride (100 mL), dried over sodium sulphate and solvent was evaporated under reduced pressure to yield crude product. Purification by flash chromatography yielded product 2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine (3.45 g)
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH3:33])[CH:22]([C:24]1OC2C=CC=CC=2N=1)[OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[K+].[Br-]>CCOC(C)=O>[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH3:33])[CH:22]([C:24]1[O:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH3:9])[C:2]=2[N:1]=1)[OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc(O)c1N
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O)c1nc2ccccc2o1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cccc2oc(C(O)[C@H](C)NC(=O)OCc3ccccc3)nc12
Yield: 35 %

Procedure:
This material was prepared as a 1:1 mixture of isomers in 35% yield from the above cyanohydrin (707 mg, 3.02 mmol) and 2-amino-m-cresol (409 mg, 3.32 mmol) using the procedure described above for compound 16. An analytical sample was obtained by recrystallization from EtOAc in hexanes (1.3:1 mixture of isomers). mp: 98° C.; IR (KBr) υ 1701, 1690 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.38-7.20 (m, 7H), 7.15-7.10 (m, 1H), 5.39 and 5.29 (2×d, J=7.9 and 5.4 Hz, 1H), 5.15-4.90 (m, 3H), 4.40 and 4.23 (2×br s, 2H), 2.58 (S, 3H), 1.34 and 1.14 (2×d, J=6.7 and 7.0 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3) δ 164.82, 164.22, 156.28, 156.12, 150.72, 150.65, 139.40, 136.27, 130.61, 130.43, 128.51, 128.40, 128.14, 128.01, 127.91, 125.20, 125.14, 125.04, 124.98, 108.20, 108.13, 71.02, 70.62, 66.96, 66.77, 50.45, 50.27, 17.35, 16.39, 12.24; FAB MS m/z: 341 (MH+); HRMS calcd for C19H21N2O4 (MH+) 341.1501, found: 341.1490; Anal (C19H2ON2O4) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH:12]=O)=[CH:6]2.[CH:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](/[CH:12]=[CH:16]/[CH:14]=[O:15])=[CH:6]2
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2[nH]c(C=O)cc2c1
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c(/C=C/C=O)cc2c1
Temperature: 85 °C
Reaction time: 5 h
Yield: 26.3 %

Procedure:
5-Methoxyindole-2-carboxaldehyde (1.5 g, 8.5 mmol) was dissolved in dry toluene (30 ml) and treated with (formylmethylene)triphenylphosphorane (3 g, 9.8 mmol). The reaction mixture was stirred at 85° C. for 5 h, allowed to cool and chromatographed over silica gel using hexane/EtOAc (7:3). Evaporation of the solvent yielded 0.45 g (26 %) of (E)-3-(5-methoxy-2-indolyl)-2-propenaldehyde, m.p.=145-147° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][CH:37]([F:40])[CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][CH:37]([F:40])[CH2:36][CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: FC1CCN(C2CNC2)CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(F)CC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.165 g, 0.42 mmol), 1-azetidin-3-yl-4-fluoropiperidine (0.1 g, 0.63 mmol) and 4 Å molecular sieves (0.8 g) in DCE (8 mL) was stirred for 18 h at room temperature. Sodium triacetoxyborohydride (0.179 g, 0.84 mmol) was added and the reaction mixture was stirred for 6 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give 491 as a yellow solid (0.1 g, 45%). LCMS (Method I): RT=2.52 min, [M+H]+ 534.2. 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.99 (m, 1 H); 7.64-7.61 (m, 1 H); 7.26-7.21 (m, 2 H); 4.81-4.52 (m, 1 H); 4.51-3.96 (m, 4 H); 3.86 (s, 2 H); 3.79-3.76 (m, 7 H); 3.43 (t, J=6.3 Hz, 2 H); 3.26 (q, J=7.4 Hz, 2 H); 2.97 (t, J=6.3 Hz, 2 H); 2.95-2.91 (m, 1 H); 2.37-2.33 (m, 2 H); 2.18-2.13 (m, 2 H); 1.90-1.75 (m, 2 H); 1.76-1.64 (m, 2 H); 1.33 (t, J=7.4 Hz, 3 H)