Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][CH:4]1[NH:7][C:6](=[O:8])[CH:5]1[CH2:9][CH2:10][O:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:2].C([O:27][CH:28](O)[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:30])C.C1C=CC=CC=1>O>[CH2:1]([S:3][CH:4]1[N:7]([CH:28]([OH:27])[C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[C:6](=[O:8])[CH:5]1[CH2:9][CH2:10][O:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:13])[CH3:2]
Reactant: CCOC(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCSC1NC(=O)C1CCOC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Solvent: O
Product: CCSC1C(CCOC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
4-Ethylthio-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxo-azetidine (9.0 g), p-nitrobenzyl glyoxylate ethyl hemiacetal (8.15 g) and benzene (350 ml) were heated at reflux for 20 hours under a nitrogen atmosphere using a Dean-Stark water separator. The solution was then concentrated in vacuo and the residue was dissolved in 700 ml of dichloromethane. The dichloromethane solution was washed two times with water, dried over anhydrous sodium sulfate and concentrated in vacuo to a yellowish semi-solid (15.0 g) of the title compound. The NMR spectrum in deuterochloroform showed peaks at 1.02-1.52 (c, 8H); 2.6 (m, 2H); 3.3 (m, 1H); 4.1 (b, 1H); 4.78-5.56 (c, 5H); 7.48 (d, 4H); and 8.18 (d, 4H) ppm. The IR spectrum in dichloromethane showed absorptions at 5.62 and 5.7 microns.
Reaction SMILES: C(N1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=O.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C.C(OCC)C>[CH2:13]([O:20][C:13]([CH:14]1[CH2:19][C:11](=[CH2:12])[CH2:15]1)=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C=C1CC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.2 %

Procedure:
A suspension of 1,1′-carbonyldiimidazole (1.59 g, 9.81 mmol) in ethyl acetate (5 ml) was added in portions to a solution of the product of Preparation 12 (1 g, 8.9 mmol) in ethyl acetate (5 ml). Gentle effervescence was observed. The mixture was stirred at room temperature for about 1.5 hours, benzyl alcohol (1.11 ml, 10.7 mmol) added and stirring continued overnight. The solution was diluted with diethyl ether (20 ml), washed with water (2×10 ml), dried over magnesium sulphate and evaporated in vacuo to a colourless liquid which was purified by filtering through 10 g SiO2, eluting with dichloromethane, to give the title compound as a colourless oil (1.246 g, 69%).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH3:18])[N:3]=1.[K+].[CH:20]([C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH-:32])(=[O:31])=[O:30])=[N:27][CH:28]=1)([CH3:22])[CH3:21]>CS(C)=O.O>[CH:20]([C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:32][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH3:18])[N:3]=2)(=[O:31])=[O:30])=[N:27][CH:28]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.1 %

Procedure:
To a solution of 2.15 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-methyl-pyrimidine in 40 ml of DMSO was added 3.59 g of 5-isopropyl-2-pyridine sulfonamide potassium salt. The mixture was stirred for 72 h at room temperature. The solution was diluted with 350 ml of water and extracted twice with 200 ml of diehtyl ether. The organic layers were extracted twice with water. The combined aqueous layers were acidified to pH 4 with 5 ml of acetic acid and extracted twice with DCM. The organic layers were washed with water, and dried over Na2SO4. The solution was treated with activated charcoal, filtered over Celite and evaporated. The residue was suspended in 30 ml of diethyl ether, filtered off and dried to give 3.15 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide as a pale beige powder. LC-MS: tR=5.18 min, [M+1]+=449.25, [M−1]−=447.31.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][CH2:12][CH2:11][NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][NH:10][C:9]2=[O:14])=[CH:6][CH:7]=1
Reactant: ClCc1ccccc1
Reactant: O=C1NCCNC1c1ccc(F)cc1
Product: O=C1NCCN(Cc2ccccc2)C1c1ccc(F)cc1

Procedure:
25 g (0.129 mol) of 3-(4-fluorophenyl)-piperazin-2-one, prepared in accordance with Example 13, are alkylated with 18.1 g (0.143 mol) of benzyl chloride, as described in Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([NH:23][CH2:24][CH2:25]N(C)C)=[CH:20][C:19]2=[O:29])=[CH:4][CH:3]=1.ClC1C=CC(C2N=C3C=CC=CN3C=2CN2C[C:50]([O:52]C)=[CH:49]C2=O)=CC=1.N1CCC(O)C1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([N:23]3[CH2:24][CH2:25][CH:50]([OH:52])[CH2:49]3)=[CH:20][C:19]2=[O:29])=[CH:6][CH:7]=1
Reactant: CN(C)CCNC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Reactant: COC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Agent: OC1CCNC1
Product: O=C1C=C(N2CCC(O)C2)CN1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to the experimental for compound 237 from 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-one and pyrrolidin-3-ol. (33 mg, 32%) m/e+=409 (M+H+). 1H-NMR (400 MHz, CDCl3, δ): 8.46 (d, 1H, D, J=7.0 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.61 (d, 1H, D, J=9.1 Hz), 7.46 (d, 2H, D, J=8.4 Hz), 7.25 (t, 1H, D, J=7.3 Hz), 6.84 (t, 1H, D, J=7.3 Hz), 5.09 (s, 2H), 4.57 (s, 1H), 4.53 (m, 1H), 3.55 (s, 2H), 3.2 (m, 4H), 2.1 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:8]=O)[CH3:3].[S:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[S:18].NCCC(O)=O>C(O)(=O)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[C:22]2[S:16][C:17](=[S:18])[NH:19][C:20]2=[O:21])[CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH3:3]
Reactant: O=C1CSC(=S)N1
Reactant: COc1cc(C=O)cc(CN(C)C)c1O
Agent: NCCC(=O)O
Solvent: CC(=O)O
Product: COc1cc(C=C2SC(=S)NC2=O)cc(CN(C)C)c1O
Yield: 74.5 %

Procedure:
A mixture of 3-[(dimethylamino)methyl]-4-hydroxy-5-methoxybenzaldehyde (2.5 g, 12 mmoles), rhodanine (1.6 g, 12 mmoles), β-alanine (0.6 g, 7 mmoles), and acetic acid (35 ml) is stirred under an inert atmosphere and heated to reflux. After 4 hours the acetic acid is removed by rotary evaporator and the residue dissolved in water (250 ml). The solution is brought to approximate neutrality by addition of saturated aqueous sodium bicarbonate, and stirred for 3 hours. The precipitate is filtered off, rinsed three times with water and dried, then triturated in boiling methanol (100 ml), cooled, filtered off and dried to afford the pure product (2.9 g), mp 198° C. (dec).
Reaction SMILES: [C:1]([C:3]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)([CH3:15])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1Br)#[N:2].[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]([C:3]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)([CH3:15])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[C:32]1[CH:33]=[CH:34][S:30][CH:31]=1)#[N:2]
Reactant: OB(O)c1ccsc1
Reactant: CC(C#N)(COc1cc(F)c(F)cc1Br)NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C#N)(COc1cc(F)c(F)cc1-c1ccsc1)NC(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
120 mg of N-[2-cyano-1-(2-bromo-4,5-difluorophenoxy)-2-propyl]-4-trifluoromethoxybenzamide, 160 mg of thiophene-3-boronic acid and 3 ml of saturated aqueous sodium bicarbonate solution are dissolved in 4 ml of toluene and degassed for 15 minutes using a stream of nitrogen. Subsequently, 9 mg of tetrakis(triphenylphosphine)palladium are added and the mixture is stirred at reflux for 20 h. The mixture is subsequently diluted with ethyl acetate and washed with water and saturated sodium chloride solution. The organic phase is dried with magnesium sulfate, filtered and evaporated. After purifying by means of HPLC, the title compound is obtained with a melting point of 128-30° C.
Reaction SMILES: [F:1][C:2]1[C:3]([I:12])=[C:4]2[NH:10][N:9]=[C:8](N)[C:5]2=[N:6][CH:7]=1.CN(C=O)C.N(OC(C)(C)C)=O.I>O>[F:1][C:2]1[C:3]([I:12])=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1n[nH]c2c(I)c(F)cnc12
Agent: CC(C)(C)ON=O
Agent: I
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cnc2cn[nH]c2c1I
Temperature: 25 °C
Yield: 11.68 %

Procedure:
6-Fluoro-7-iodo-1H-pyrazolo[4,3-b]pyridin-3-amine (2.0 g, 7.19 mmol) was combined with DMF (15 mL) and cooled to 0° C. before tert-butyl nitrite (1.709 mL, 14.39 mmol) was added. The reaction mixture was then warmed to room temperature and heated at 85° C. for 4 hours. The reaction mixture was cooled to room temperature and HI solution (1.614 g, 7.19 mmol) in water (57%) was added and heated to 85° C. for another 8 hours. The mixture was cooled, concentrated, to give a residue which was purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 25-45% acetonitrile (containing 10 mM NH4HCO3) in water (containing 10 mM NH4HCO3) to give the title compound. (221 mg, 0.840 mmol, 11.68% yield). MS [M+H] found 264.0.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13]1([SH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH:13]1([S:19][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: SC1CCCCC1
Reactant: CCOC(=O)c1cccc(I)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(SC2CCCCC2)c1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Ethyl 3-iodobenzoate (5.00 g) was dissolve din dioxane (100 mL), and cyclohexanethiol (2.32 mL), N,N-diisopropylethylamine (6.29 mL), Xantphos (2.09 g) and Pd2(dba)3 (1.66 g) were added thereto in that order, and stirred in a nitrogen atmosphere at 100° C. for 7 hours. After left cooled, ethyl acetate was added to it, then washed with water ad saturated brine in that order, and dried with sodium sulfate. The drying agent was removed through filtration, the solvent was evaporated off under reduced pressure, and the residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 25%, gradient) to give the intended compound (5.11 g) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([Cl:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1ccc(-c2cc3c(cc2Cl)OCC3)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)OCC3)cn1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of 5-(6-chloro-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (144) (41 mg, 0.166 mmol) in 2 ml DCM was added 2,6-difluorobenzoyl chloride (42 μl, 2 eq) followed by addition of DIEA (145 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (330 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(6-chloro(2,3-dihydrobenzo[b]furan-5-yl))(2-pyridyl)]carboxamide (145) (52.7 mg, yield: 82.1%, purity>95%) as white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].C(=O)(O)[O-].[Na+].[N:21]([CH2:24][C:25]([O:27]CC)=[O:26])=[C:22]=[O:23].Cl>O>[N+:9]([NH:8][C:7](=[NH:12])[NH:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[NH:1][C:22](=[O:23])[N:21]([CH2:24][C:25]([OH:27])=[O:26])[C:13]1=[O:15])([O-:11])=[O:10]
Reactant: N=C(NCCC[C@H](N)C(=O)O)N[N+](=O)[O-]
Reactant: CCOC(=O)CN=C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N=C(NCCC[C@@H]1NC(=O)N(CC(=O)O)C1=O)N[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
11 g (0.05 mol) of H-Arg(NO2)-OH are dissolved with 4.3 g (0.05 mol) of sodium bicarbonate in 200 ml of water under reflux. At 70° C., 7.1 g (0.055 mol) of ethyl isocyanato-acetate are added dropwise. The mixture is stirred at 70° C. for 1 hour, left to cool and stirred at room temperature overnight, 50 ml of concentrated hydrochloric acid are added, the mixture is concentrated, 20 ml of 50% concentrated hydrochloric acid are added, the mixture is heated under reflux for 1 hour and substantially concentrated, and the precipitated product is filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:35])[C@H:13]([O:14][Si](C)(C)C)[C@@H:12]([O:19][Si](C)(C)C)[C@H:11]([O:24][Si](C)(C)C)[C@@H:10]([CH2:29][O:30][Si](C)(C)C)[O:9]2)=[CH:4][C:3]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH3:45])=[C:39]([F:46])[C:38]=1[F:47].[CH3:48]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:35][CH3:48])[C@H:13]([OH:14])[C@@H:12]([OH:19])[C@H:11]([OH:24])[C@@H:10]([CH2:29][OH:30])[O:9]2)=[CH:4][C:3]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH3:45])=[C:39]([F:46])[C:38]=1[F:47]
Reactant: CS(=O)(=O)O
Reactant: CCOc1ccc(Cc2cc([C@]3(O)O[C@H](CO[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]3O[Si](C)(C)C)ccc2Cl)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.9 %

Procedure:
To a solution of (2S,3R,4S,5R,6R)-2-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyetetrahydropyran-2-ol 23f (0.97 g, 1.3 mmol) in tetrahydrofuran (10 mL) was added a solution of methylsulfonic acid (0.05 mL, 0.65 mmol) in methanol (2 mL) at −70° C. The mixture was warmed up to room temperature and stirred for 16 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate till pH becomes 6-7 and extracted with ethyl acetate (10 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by re-crystallization from a toluene/petroleum ether mixture ((v/v)=1/1, 30 mL) at −5° C. to give the title compound 23g as a pale yellow sticky solid (0.33 g, 54%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]([O:14][CH3:15])[C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:11](=[O:13])[CH:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=2)[O:14][CH3:15])=[CH:20][CH:19]=1)#[N:16]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COc1ccc(C(OC)C(=O)O)cc1O
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)cc1O

Procedure:
(RS)-(3-Hydroxy-4-methoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(3-hydroxy-4-methoxy-phenyl)-2-methoxy-acetamide. White foam.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(Cc1ccc(CCO)cc1)OC(C)C
Reactant: O=C=Nc1cccc(Cl)c1
Product: CC(C)OC(Cc1ccc(CCOC(=O)Nc2cccc(Cl)c2)cc1)C(=O)O

Procedure:
Using ethyl 3-[4-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 3-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: C([O:8][CH2:9][C:10](Cl)=[O:11])C1C=CC=CC=1.[C:13]1([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[OH:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([Si](Cl)(C(C)C)C(C)C)(C)C.N1C=CN=C1>CN(C)C=O.CCCCC>[OH:11][CH2:10][C:9]([O:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8]
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Reactant: O=C(Cl)COCc1ccccc1
Agent: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C(CO)O[C@@H]1CCCC[C@H]1c1ccccc1
Yield: 95 %

Procedure:
To obtain 1c(-), a solution of (-)-(1R,2S)-2-phenyl-1-cyclohexyl hydroxyacetate (851 mg, 3.63 mmol) was prepared through esterification of benzyloxyacetyl chloride with (-)-(1R,2S)-2-phenyl-1-cyclohexanol followed by hydrogenolysis. Then, triisopropylsilyl chloride (840 mg, 4.36 mmol) and imidazole (618 mg, 9.08 mmol) in dimethylformamide (DMF) (1.7 mL) was stirred at room temperature for 12-20 hours. The mixture was poured into pentane (25 mL), and washed with water and brine. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was subjected to a purification on a short silica gel column using hexane/chloroform (3/1) as the eluant to give pure 1c(-) (1.35 g, 95% yield) as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:17]1[CH2:18][CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: c1ccc2c(c1)CCNC2
Solvent: CO
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCc2ccccc2C1

Procedure:
Prepared analogously to Example 1.1.c. from 1 g (3.622 mmol) of 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 1.36 mL (10.87 mmol) of 1,2,3,4-tetrahydroisoquinoline. Yield: 1.4 g (77% of theory); C18H20N2O4 (M=328.36); calc.: molecular ion peak (M+H)+: 329; found: molecular ion peak (M+H)+: 329; Rf value: 0.7 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C.[C:29]1([CH3:44])[CH:34]=[CH:33][C:32]([S:35]([O:38][C@H:39]([CH3:43])[C:40](Cl)=[O:41])(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[C:29]1([CH3:44])[CH:30]=[CH:31][C:32]([S:35]([O:38][C@H:39]([CH3:43])[C:40]([N:1]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[CH2:3][C@H:2]2[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[O:41])(=[O:36])=[O:37])=[CH:33][CH:34]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CC2=C(CCCC2)N1
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)N2C3=C(CCCC3)C[C@H]2C(=O)OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
Introduce into a reactor 200 g of benzyl (2S)-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate and 1.5 litres of dichloromethane, and then bring the temperature of the reaction mixture to 0° C. and add 201 ml of diisopropylethylamine, followed by 202 g of (1R)-2-chloro-1-methyl-2-oxoethyl p-toluenesulphonate. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water. The solution of benzyl (2S)-1-[(2R)-2-{p-toluenesulphonyloxy}propionyl]-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate so obtained is used as it is in the following Step.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:14]#[N:15]>C(Cl)(Cl)(Cl)Cl.CCOCC.[W].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:19][C:18]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[O:10][CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C#N)ccc1C
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C#N)ccc1CBr
Yield: 65 %

Procedure:
N-Bromosuccinimide (3.2 g.) and benzoyl peroxide (0.005 g.) were added to a solution of 3-methoxy-4-methylbenzonitrile (2.65 g.) in dry carbon tetrachloride (90 ml.). The mixture was heated to reflux for 15 minutes using a 250 watt tungsten lamp. The cooled reaction mixture was diluted with petrolum ether (b.p. 60°-80° C., 90 ml.), insoluble material removed by filtration, and the filtrate evaporated. The solid residue was recrystallized from a mixture of dichloromethane and petroleum ether to give 4-bromomethyl-3-methoxybenzonitrile (W) (2.64 g., 65%) as a white solid, m.p. 87°-91° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([S:17][CH3:18])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1.O>[CH3:18][S:17][C:4]1[N:3]=[C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(Nc2ccccc2)c(C=O)c(-c2ccccc2)n1
Yield: 69.8 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-6-phenylamino-pyrimidine-5-carbaldehyde (300 mg, 1.07 mmol) in dioxane (21 mL) and H2O (7 mL) was added anhyd K2CO3 (443 mg, 3.21 mmol, 3 eq) followed by phenylboronic acid (196 mg, 1.6 mmol, 1.5 eq). The reaction mixture was degassed and tetrakis(triphenylphophine)palladium (61 mg, 0.053 mmol, 0.05 eq) was added. The reaction mixture was then heated under reflux for 24 h and cooled 23°, the layers were separated, EtOAc (50 mL), followed by H2O (10 mL), was added, the organic layer was separated, washed with satd aq NaCl, dried (MgSO4) and filtered. The yellow solution was then evaporated. Product was purified by column chromatography or by crystallization from 10 mL of isopropanol:H2O (2:1) to give 240 mg (70% yield) of pure 2-methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde. 1H-NMR δ 2.60 (s, 3H), 7.22 (m, 1H), 7.35-7.81 (m, 9H), 9.89 (s, 1H), 11.31 (br s, 1H), LC MS (m/e)=322 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][C@H:5]1[O:7][C@@H:6]1[CH2:8][OH:9].O(O)O.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[S:21]([CH:5]([CH2:4][CH:3]([O:10][CH3:11])[O:2][CH3:1])[CH:6]([OH:7])[CH2:8][OH:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Sc1ccccc1
Reactant: COC(C[C@H]1O[C@@H]1CO)OC
Agent: OOO
Product: COC(CC(Sc1ccccc1)C(O)CO)OC

Procedure:
The epoxy alcohol (2R,3R) 3-(2,2-dimethoxyethyl)oxiranemethanol is reacted with thiophenol in the presence of a metal catalyst to obtain 3-thiophenoxy-5,5-dimethoxy pentane-1,2-diol: ##STR15##