Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:17]([O:18]C(=O)C)[C@H:16]([O:22][C@@H:23]2[O:40][C@H:39]([CH2:41][O:42]C(=O)C)[C@H:34]([O:35]C(=O)C)[C@H:29]([O:30]C(=O)C)[C@H:24]2[O:25]C(=O)C)[C@@H:15]([CH2:46][O:47]C(=O)C)[O:14][C@H:6]1[O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])(=O)C>C[O-].[Na+]>[C@@H:23]1([O:22][C@@H:16]2[C@@H:15]([CH2:46][OH:47])[O:14][C@@H:6]([O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[C@H:5]([OH:4])[C@H:17]2[OH:18])[O:40][C@H:39]([CH2:41][OH:42])[C@H:34]([OH:35])[C@H:29]([OH:30])[C@H:24]1[OH:25]
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCC[Si](C)(C)C)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: C[Si](C)(C)CCO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Yield: 82.5 %

Procedure:
2-Trimethylsilylethyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-B-D-glucopyranoside (1) (Jansson et al., 1988) (29.4 g, 40 mmol) was stirred in methanolic sodium methoxide (5.8 mM, 515 mL) for 15 h. Neutralization with acetic acid, evaporation and crystallization from ethanol gave (2) (14.6 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S-:9])[CH:6]=[CH:7][CH:8]=1.[K+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: COc1cccc([S-])c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 0 °C
Yield: 91.7 %

Procedure:
A solution of potassium 3-methoxybenzenethiolate (6.37 g, 35.7 mmol) and 4-chloronitrobenzene (5.11 g, 32.5 mmol) in dimethylformamide (30 mL) was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and a yellow solid was collected by filtration. Recrystallization from 90% ethanol yielded the title anisole (7.79 g, 92%) as a yellow solid; mp 81°-83° C. 1H-NMR (250 MHz, d6-DMSO): 3.80 (s, 3H, OCH3) 7.10-7.19 (m, 3H, aromatic) 7.32 (d, 2H, J=7.1 Hz, aromatic) 7.43-7.49 (m, 1H, aromatic) 8.15 (d, 2H, J=7.0, aromatic). MS (CI, CH4): 262 (M+1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.C(N(CC)CC)C.[O-:34][C:35]#[N:36].[K+].C(O)(=O)C>ClCCl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:35]([NH2:36])=[O:34])=[CH:7][CH:8]=1
Reactant: N#C[O-]
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.5 g, 2 mmol) (Example 9, step 3) in dichloromethane (10 mL) was treated with pyridine (1.4 mL, 17 mmol), triethylamine (0.5 mL, 4 mmol), potassium cyanate (0.3 g, 3 mmol), glacial acetic acid (1.00 mL, 17 mmol) and the resulting suspension was stirred at RT for 12 h. The reaction mixture was concentrated to a gummy residue which was taken up in dichloromethane (75 mL), washed with brine (35 mL), dried over anhydrous sodium sulfate, removed dichloromethane, and dried under high vacuum to yield (4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI pos. ion) m/z: 321 (M+1).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][NH:13][C:22](=[O:24])[CH3:23])=[CH:8][CH:9]=1
Reactant: CCN(CCN)c1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CCNC(C)=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 69.2 %

Procedure:
To a mixture of N-(4-bromophenyl)-N-ethylethane-1,2-diamine dihydrochloride (1.044 g, corresponding to 2.33 mmol), pyridine (4 ml) and anhydrous dichloromethane (8 ml) was added dropwise acetic anhydride (0.28 ml, 2.92 mmol) at 0° C. After stirring at room temperature for 70 mins, the reaction mixture was diluted with dichloromethane (50 ml), washed twice with diluted aqueous sodium hydrogen carbonate solution and with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4→1:0) to give N-{2-[(4-bromophenyl)(ethyl)amino]ethyl}acetamide (460 mg, overall yield of 2 steps 92%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CC(C)(C)CCOc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OCCC(C)(C)C)ncn1
Reaction time: 0.17 h
Yield: 84.3 %

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.10 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.15 g of 2-butyn-1-ol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of a solution containing 0.41 g of 4-chloro-6-(3,3-dimethylbutyloxy)pyrimidine in tetrahydrofuran at 0° C., followed by stirring at the same temperature for 5 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.40 g of 4-(2-butynyloxy)-6-(3,3-dimethylbutyloxy)pyrimidine (the present compound (11)).
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH:32]([C:37](O)=[O:38])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].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>C(Cl)Cl>[CH3:36][CH:33]1[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH2:31][CH:32]1[C:37](=[O:38])[NH:22][CH2:21][C:19]1[N:20]=[C:15]2[CH:14]=[CH:13][N:12]([S:2]([C:5]3[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=3)(=[O:3])=[O:4])[C:16]2=[N:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC1C(=O)O
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: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)C4CN(C(=O)OC(C)(C)C)CCC4C)cnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (29.6 g, 87.0 mmol, Step F), 1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (21.2 g, 87.0 mmol, Step G) and HATU (33.2 g, 87.0 mmol) in DCM (400 mL) was added DIEA (46.0 mL, 263 mmol). After stirring for about 18 h at ambient temperature, the reaction mixture was washed with aqueous saturated NaHCO3 (400 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (330 g column) eluting with a gradient of 50-100% EtOAc in heptane to give tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (44 g, 95%) as a tan foam: LC/MS (Table 2, Method a) Rt=2.38 min; MS m/z: 528 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CCO>O.C(COC)OC.C(OCC)(=O)C.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>[CH3:9][N:8]([CH3:10])[C:5]1[N:4]=[CH:3][C:2]([C:16]2[CH:17]=[C:12]([CH:13]=[CH:14][CH:15]=2)[NH2:11])=[CH:7][N:6]=1
Reactant: CN(C)c1ncc(Br)cn1
Reactant: Nc1cccc(B(O)O)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: COCCOC
Solvent: CCOC(C)=O
Solvent: OCCCO
Product: CN(C)c1ncc(-c2cccc(N)c2)cn1
Temperature: 80 °C
Yield: 74 %

Procedure:
A mixture of 5-bromo-2-(dimethylamino)pyrimidine (6.76g, 33.17mmol), 3-aminophenylboronic acid hemisultat (7.4g, 39.78mmol) potassium carbonate (13.73g, 99.49mmol), 1,3-propanediol (12ml, 166mmol) and tetrakis(triphenylphosphine)palladium(0) (0.2g) in a mixture of water (30ml) and dimethoxyethane (60ml) is heated to 80° C. under nitrogen overnight. After cooling the mixture is diluted with water and ethyl acetate and is filtered through a fluted filterpaper. The layers are separated and the aqeous phase is extracted once with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated to dryness. The residue is triturated with a mixture of ethyl acetate and petroleum ether (1:1) to leave crystalline 2h (5.26g, 74%). Mp 115.5-117° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CNC(=O)CCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of N-methyl-8-phenyloctanamide (25.2 g, 108.0 mmol, 1 eq) in THF (500 mL) cooled to 0° C. was added lithium aluminum hydride (12.3 g, 466.8 mmol, 4.3 eq) portionwise over 20 minutes. The cold bath was removed and the reaction was stirred at rt 3 hours. The reaction was then heated at reflux for 2½ hours. It was then cooled to rt and quenched by the slow addition of H2O (30 mL). EtOAc (300 mL) was added, followed by 2 M NaOH (40 mL). The solids were then filtered off and washed with EtOAc. The filtrate was dried over MgSO4 and concentrated in vacuo to afford N-methyl-N-(8-phenyloctyl)amine (19.7 g, 83%) as a light yellow oil. 1H NMR (CDCl3) δ 7.30–7.14 (m, 5H); 2.63–2.52 (m, 4H); 2.43 (s, 3H); 2.05 (s, 1H); 1.62 (m, 4H); 1.30 (m, 8H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:16][CH:15]=1.[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1.O>CN(C)C=O>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:19]([CH2:35][CH:32]2[CH2:34][CH2:33]2)[C:18](=[O:20])[C:17]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccc(-c2ccccc2Cl)[nH]c1=O)OCc1ccccc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccccc2Cl)n(CC2CC2)c1=O)OCc1ccccc1
Reaction time: 4 h
Yield: 38.2 %

Procedure:
Cesium carbonate (1.07 g, 3.30 mmol) was added to a solution of benzyl 6-(2-chlorophenyl)-2-oxo-1,2-dihydropyridin-3-ylcarbamate (J. Med. Chem. 1994, 37, 3303-3312) (585 mg, 1.65 mmol) and cyclopropylmethyl bromide (0.19 mL, 1.98 mmol) in N,N-dimethylformamide (5 mL). After 4 h, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (hexanes→30% ethyl acetate/hexanes) gave the title compound (258 mg). MS 409.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[C:4]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C(#N)C>[C:32]([O:31][C:29](=[O:30])[CH2:28][O:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[C:4]([O:13][S:14]([C:17]([F:20])([F:18])[F:19])(=[O:16])=[O:15])[CH:3]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CCCc2c(O)cc(OS(=O)(=O)C(F)(F)F)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1cc(OS(=O)(=O)C(F)(F)F)cc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.1 %

Procedure:
To a suspension of trifluoro-methanesulfonic acid 4-hydroxy-8-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester (XXVIII, 177 mg, 0.57 mmol) and cesium carbonate (372 mg, 1.14 mmol) in acetonitrile (5 mL) was added tert-butyl bromoacetate (167 mg, 0.86 mmol) at room temperature under nitrogen. The resulting suspension was stirred for 15 h at room temperature, and then concentrated under vacuum. The residue was diluted with water (10 mL) and ethyl acetate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by ISCO (40 g) column chromatography, (gradient elution with 5-25% ethyl acetate in hexanes) to provide (5-oxo-3-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (143 mg, 59%) as a white solid: ES(+)-HRMS m/e calcd. for C17H19F3O7S (M+H)+425.0877, obsd. 425.0876.
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=1)[C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl>CO>[CH3:1][S:2][CH2:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(=NOCSC)c1csc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 30 °C
Reaction time: 2.5 h
Yield: 51.9 %

Procedure:
A mixture of ethyl 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (2.4 g.), 1N aqueous sodium hydroxide (23.8 ml.) and methanol (19.8 ml.) was stirred at 30° C. for 2.5 hours. The resultant solution was adjusted to pH 7 with 10% hydrochloric acid and methanol was distilled off in vacuo. The aqueous solution was adjusted to pH 1 with 10% hydrochloric acid under ice-cooling, and extracted with ethyl acetate three times. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give 2-methylthiomethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.13 g.), mp. 157° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8](O)=[O:9].S(Cl)([Cl:18])=O>>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([Cl:18])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1cccc(C(F)(F)F)c1
Product: O=C(Cl)COc1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of 6 g of the product of Step B in 36 ml of thionyl chloride was refluxed with stirring for one hour and was evaporated to dryness under reduced pressure to obtain 6.44 g of the desired product which was used as is for the next step.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].F[C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:15]=[C:16]([CH3:18])[CH:17]=2)[CH:9]=[N:10][CH:11]=1.[H-].[Na+]>C1COCC1>[CH3:18][C:16]1[CH:17]=[C:12]([C:8]2[CH:7]=[C:6]([NH:4][CH2:3][CH2:1][OH:2])[CH:11]=[N:10][CH:9]=2)[CH:13]=[C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][N:21]=2)[CH:15]=1
Reactant: NCCO
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(F)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(NCCO)c2)c1
Temperature: 80 °C

Procedure:
Ethanolamine (26.3 mg, 0.431 mmol) was added to a mixture of N-[3-(5-fluoropyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (50.0 mg, 0.144 mmol) and sodium hydride (17.2 mg, 0.431 mmol) in THF (0.718 mL, 0.2 M). The reaction mixture was heated overnight at 80° C. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with chloroform. The organic layer was concentrated in vacuo and purified by reverse phase liquid chromatography (10:90 to 60:40, acetonitrile:water) afforded 2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]amino}ethanol as the formic acid salt. MS APCI calc'd for C19H19F3N5O [M+H]+ 390. found 390. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.83 (d, J=4.9 Hz, 1H), 8.48 (s, 1H), 8.34 (d, J=2.6 Hz, 1H), 7.99 (d, J=11.4 Hz, 3H), 7.59 (d, J=26.7 Hz, 2H), 7.34-7.12 (m, 2H), 4.33 (t, J=4.9 Hz, 2H), 3.77 (br s, 3H), 3.27 (t, J=5.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:21](O)(=[O:23])[CH3:22]>>[C:21]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: OCc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)OCc1cccc(Cl)c1
Yield: 93 %

Procedure:
71 g. of 3-chlorobenzyl alcohol, 60 cm3. of acetic acid and 1 g of p-toluene sulfonic acid are refluxed for 5 hours then the excess of acetic acid distilled off in vacuo. The residue is dissolved in 100 cm3. of 1,2-dichloro ethane and the solution washed with 10% sodium hydrogen carbonate solutin then with water and evaporated. The residue is distilled in vacuo. 85.5 g. of 3-chlorobenzyl acetate are obtained. Boiling point 105°-110° C./933.4 Pa, nD25 : 1.5185, yield 93%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH2:31][CH3:32])[CH2:26]1>>[CH2:31]([N:27]1[CH2:28][CH2:29][CH2:30][CH:25]([NH:24][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:26]1)[CH3:32]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CCN1CCCC(N)C1
Product: CCN1CCCC(NC(=O)c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)C1
Yield: 95 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 3-amino-N-ethylpiperidine (1 M in DMF) instead of methylamine, to the title compound (64 mg, 95%) which was obtained as an off white foam. MS: m/e=421.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([OH:16])=O)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:48]([NH2:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:48]([NH:55][C:14]([C:4]1[S:3][C:2]([NH2:1])=[N:6][C:5]=1[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:16])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: Nc1nc(Cc2ccccc2)c(C(=O)O)s1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nc(Cc2ccccc2)c(C(=O)NCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 2-amino-4-benzylthiazole-5-carboxylic acid (0.033 g, 0.14 mmol) and diisopropylethylamine (0.08 mL, 0.46 mmol) in N,N-dimethylformamide (5 mL) was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.039 g, 0.20 mmol), followed by the addition of 1-hydroxybenzotriazole (0.026 g, 0.19 mmol). After 30 minutes, benzylamine (0.02 mL, 0.18 mmol) was added. The reaction mixture was stirred at ambient temperature for 12 h, diluted with ethyl acetate, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (5/95 to 100/0) to afford the title compound (0.029 g, 65% yield).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[NH:12][C:11]2[C:10](=[O:13])[N:9]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:8](=[O:18])[N:7]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]=2[N:5]=1.[CH:23]([S:26](Cl)(=[O:28])=[O:27])([CH3:25])[CH3:24].O>C(COC)OC.C(OCC)(=O)C>[NH2:3][C:4]1[N:12]([S:26]([CH:23]([CH3:25])[CH3:24])(=[O:28])=[O:27])[C:11]2[C:10](=[O:13])[N:9]([CH2:14][CH:15]3[CH2:16][CH2:17]3)[C:8](=[O:18])[N:7]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]=2[N:5]=1
Reactant: Nc1nc2c([nH]1)c(=O)n(CC1CC1)c(=O)n2CC1CC1
Reactant: CC(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)n1c(N)nc2c1c(=O)n(CC1CC1)c(=O)n2CC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
Sodium hydride (0.35 g of a 60% suspension in oil, 8.7 mmol) was added to a suspension of 8-amino-1,3-di(cyclopropylmethyl)xanthine (2 g, 7.3 mmol ) in dimethoxyethane (40 ml) and the resulting mixture stirred at ambient temperature for 2 hr. Isopropylsulphonyl chloride (1.24 g, 8.7 mmol) was added and the mixture was heated at reflux for 18 hours. The reaction mixture was allowed to cool and then water (1 ml) was added dropwise. The mixture was added to ethyl acetate (200 ml), washed with water (50 ml) and dried (MgSO4). The solvent was removed at reduced pressure to afford the crude residue which was chromatographed on silica (acetone/hexane 1:3) to afford 8-amino-1,3-di(cylcopropylmethyl )-7-(isopropylsulphonyl)xanthine (1.25 g, 45%) as a yellow foam. Recrystallisation from ethyl acetate/hexane afforded a white flocculent solid, m.p. 119°-120° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:28]O)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:15][CH:14]=2)[O:10][N:9]=1)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:55]1[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:28][N:55]2[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:17][CH:18]=2)[O:10][N:9]=1)[CH3:2]
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3OC)cc2)n1
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3OC)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (4-ethyl-5-{5-[4-(2-methoxyphenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methanol (0.14 g, 0.35 mmol) that was obtained in Example 21 (21b), carbon tetrabromide (0.17 g, 0.53 mmol), triphenylphosphine (0.14 g, 0.53 mmol), methyl 3-azetidinecarboxylate hydrochloride (80 mg, 0.53 mmol), and N,N-diisopropylethylamine (0.18 mL, 1.1 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:5 to 1:2) as the eluent to afford the title compound (89 mg) in a yield of 50% as a colourless oily product.