Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:17]#[N:18])[C:14]=1[O:15][CH3:16])[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.O.[OH-].[Li+].Cl>CO.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:17]#[N:18])[C:14]=1[O:15][CH3:16])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(C#N)c(OC)c(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1c(C#N)cc(C(=O)O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
Methyl 3-t-butyl-5-cyano-4-methoxybenzoate (1.48 g) was dissolved in methanol (20 ml), tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide monohydrate (753 mg) was added to the solution, and then the mixture was stirred at room temperature for 2 hours. To the reaction solution, 10% hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.18 g) as a pale yellow crystal.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][NH:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:5]1[C:4]2[CH:3]=[CH:2][S:1][C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2sccc12
Product: Clc1nccc2sccc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
5H-Thieno[3,2-c]pyridin-4-one (1.0 g, 6.62 mmol) is dissolved in 30 mL of phosphorous oxy chloride. The solution is heated to 100° C. After 4 h, the solution is concentrated. The residue is dissolved in CH2 Cl2. The resulting solution is washed with water and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 40% CH2Cl2 /hexanes to 60% CH2Cl2 /hexanes. The title compound (1.0 g, 5.8 mmol) is obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([N:25]([C:27]4[S:28][CH:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=5)[N:31]=4)[CH3:26])=[C:21]([CH2:23][CH3:24])[N:22]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O>C1COCC1.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([N:25]([C:27]4[S:28][CH:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=5)[N:31]=4)[CH3:26])=[C:21]([CH2:23][CH3:24])[N:22]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1nc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cn2c1N(C)c1nc(-c2ccc(F)cc2)cs1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2c1N(C)c1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (60.0 g, 97 mmol, 1 eq.) in a mixture of THF (750 mL) and MeOH (750 mL) with AcOH (0.279 mL, 4.83 mmol, 0.05 eq.) was added Pd/C (10.3 g, 9.67 mmol, 0.1 eq.). The flask was evacuated and backfilled with argon. Then the reaction was evacuated and backfilled with H2 and stirred at r.t. under atmospheric pressure overnight. The crude product was filtered through a pad of Clarcel and washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was purified to chromatography on silica gel to afford the expected compound.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)[CH:7]=1.O=S(Cl)[Cl:17]>>[Cl:17][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: OCc1cn(-c2ccc(I)cc2)cn1
Reactant: O=S(Cl)Cl
Product: ClCc1cn(-c2ccc(I)cc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound 4-hydroxymethyl 1-(4-iodophenyl)imidazole I-1(0.810 g, 2.70 mmol) was dissolved in SOCl2 (6 mL). The solution was stirred at room temperature for 15 min. It was then concentrated in vacuo. The residue was partitioned between EtOAc and 5% aq. NaHCO3. The organic layer was separated, dried over Na2SO4, concentrated in vacuo to give 4-chloromethyl 1-(4-iodophenyl)imidazole 1-3 as a solid (0.780 g). MS 318.9 and 320.9 (M+H, Cl pattern).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5](Br)[CH3:6])[CH3:2].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:6])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)NCc1ccccc1
Temperature: 20 °C

Procedure:
To a solution of 2-bromo-propionic acid ethyl ester (1 eq.) in MeCN was added benzylamine (0.9 eq.) and potassium carbonate (1.5 eq.). The reaction was refluxed for 4 h then cooled to 20° C. and diluted with EtOAc. The crude was filtered, the filtrate was concentrated under reduced pressure, then purified by chromatography on silica gel (elution with heptane/EtOAc: 7/3) to afford 2-benzylamino-propionic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11](=O)[CH2:12][CH3:13])#[N:2].[OH:15]O.O.[OH-].[Na+]>C(O)C.C(O)(=O)C>[CH2:12]([C:11]1[N:2]=[C:1]([OH:15])[C:3]2[N:7]([CH3:8])[N:6]=[C:5]([CH3:9])[C:4]=2[N:10]=1)[CH3:13]
Reactant: OO
Reactant: CCC(=O)Nc1c(C)nn(C)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1nc(O)c2c(n1)c(C)nn2C
Temperature: 80 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
The above propionamide (18 g, 0.094 mol) is added in portions to a solution prepared by adding 24 ml of 30% hydrogen peroxide to 250 ml of water containing 6 g (0.15 mol) of sodium hydroxide. The mixture is stirred at 80° C. for five hours, cooled and acidified with acetic acid to give 12.7 g (70%) of 5-ethyl-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-ol, mp 220°-222° C. from ethanol.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:17][OH:18])[CH2:3][CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14].[OH:20]O>C(O)(=O)C.O>[CH3:1][C:2]([CH3:19])([CH2:17][OH:18])[CH2:3][CH2:4][CH2:5][CH2:6][S:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:15])([CH3:16])[CH2:13][OH:14])=[O:20]
Reactant: OO
Reactant: CC(C)(CO)CCCCSCCCCC(C)(C)CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(CO)CCCCS(=O)CCCCC(C)(C)CO
Temperature: 25 °C
Reaction time: 22 h
Yield: 104.4 %

Procedure:
To a solution of 6-(5,5-dimethyl-6-hydroxy-hexyl-sulfanyl)-2,2-dimethyl-hexan-1-ol 5.1 g, 17.5 mmol) in glacial acetic acid (25 ml) was added hydrogen peroxide (50 wt. % in water; 1.20 g; 17.5 mmol). The reaction mixture was stirred at rt for 22 h, then diluted with water (200 ml), and extracted with chloroform (2×150 ml). The combined organic phases were subsequently washed with saturated NaHCO3 solution (3×100 ml) and saturated NaCl solution (100 ml), dried over MgSO4, concentrated in vacuo, and dried in high vacuo to give crude product (5.60 g; 105%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ ppp=3.29 (AB, 2 H, J=12.2); 3.27 (AB, 2 H, J=12.2); 2.70 (m, 4 H); 2.48 (s br, 2 H); 1.76 (m, 4 H); 1.44 (m, 4 H); 1.30 (4 H); 0.87 (s, 6 H); 0.86 (s, 6H). 13C NMR (75 MHz, CDCl3) δ ppp=76.80; 71.39; 52.20; 38.08; 35.15; 24.21; 24.03; 23.66; 23.26. Calcd. for C16H35SO3 (MH+): 307.2307, found 307.2309.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10](OS(C(F)(F)F)(=O)=O)[N:9]=2)=[CH:4][CH:3]=1.[CH3:29][NH:30][S:31]([CH3:34])(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].C(OCCCC)(=O)C>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([N:30]([CH3:29])[S:31]([CH3:34])(=[O:33])=[O:32])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CNS(C)(=O)=O
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(OS(=O)(=O)C(F)(F)F)nc1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 123.5 °C
Yield: 78 %

Procedure:
In a 50 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 3.0 g (7 mmol.) of 4-(4-fluorophenyl-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine, 1.13 g (10.5 mmol.) of N-methylmethanesulfonamide, 1.45 g (10.5 mmol.) of potassium carbonate (available from Wako Junyaku Co., Ltd., special grade), and 14 mL of butyl acetate. The mixture was heated to 122-125° C. for 3 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the reaction mixture were added 10 mL of water and 7 mL of acetone, and the organic liquid portion was separated. The organic liquid portion was washed with a saturated aqueous sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (5:1, volume ratio)). There was obtained 2.1 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine as a white crystalline product. The yield was 78% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine).
Reaction SMILES: I[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[I:14]C1C=CC([N+]([O-])=O)=CC=1C(O)=O>>[I:14][C:4]1[CH:3]=[CH:2][C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1I
Product: NC(=O)c1cc([N+](=O)[O-])ccc1I

Procedure:
2-iodo-5-nitro-benzamide was synthesized by the method previously described for 4-iodo-5-nitro-benzamide using 2-iodo-5-nitro benzoic acid (Chemica Alta Ltd., Edmonton, Alberta, Canada) as the starting material.
Reaction SMILES: [C:1]([CH:3]1[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH:4]1[N:13]1[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[C:15]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:14]1)#[N:2].C1COCC1.Cl>CCOC(C)=O>[C:1]([CH:3]1[CH2:12][CH2:11][C:6](=[O:7])[CH2:5][CH:4]1[N:13]1[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[C:15]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:14]1)#[N:2]
Reactant: N#CC1CCC2(CC1n1cc(C(N)=O)c(Nc3ccccc3)n1)OCCO2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CC1CCC(=O)CC1n1cc(C(N)=O)c(Nc2ccccc2)n1
Temperature: 75 °C

Procedure:
To a vial containing 1-(8-cyano-1,4-dioxaspiro[4.5]dec-7-yl)-3-(phenylamino)-1H-pyrazole-4-carboxamide (Example #2-4, 37 mg, 0.10 mmol) was added THF (0.38 mL), and 1N aqueous HCl (0.13 mL). The resulting mixture was heated to 75° C. for 5.5 hours. The reaction mixture was allowed to cool to ambient temperature and was diluted with EtOAc. The layers were separated and the organic layer was washed with water, saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was dissolved in DMSO and purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and lyophilized to afford the title compound as a 1:1 mixture of cis and trans isomers.
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([OH:18])[CH:9]=[CH:10][C:11]=2[O:15][CH2:16][CH3:17])[S:4]1(=[O:6])=[O:5].[Na].[C:20]1([N:26]2[C:30]([SH:31])=[N:29][N:28]=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([N:26]2[C:30]([S:31][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[C:8]([OH:18])[CH:9]=[CH:10][C:11]=4[O:15][CH2:16][CH3:17])[S:4]3(=[O:6])=[O:5])=[N:29][N:28]=[N:27]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCOc1ccc(O)c2c1C(=O)N(CCl)S2(=O)=O
Agent: [Na]
Solvent: CCO
Product: CCOc1ccc(O)c2c1C(=O)N(CSc1nnnn1-c1ccccc1)S2(=O)=O
Yield: 88 %

Procedure:
By the method of part F of Example 45 condensation of 2-chloromethyl-4-ethoxy-7-hydroxysaccharin (1.95 g) and 1-phenyltetrazol-5-thiol sodium salt (1.5 g, reaction time about 8 hours) and purification of part of the product (2.5 g., 88% yield) from ethanol gave 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-hydroxysaccharin, mp 178°-180° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([F:8])[CH2:5][N:4]1[C:9]([NH:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([NH2:23])=[O:22])[CH:13]=1)=[O:10].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].C(N(CC)CC)C.O>C(Cl)Cl>[C:28]1([O:27][C:25](=[O:26])[NH:1][CH2:2][C@@H:3]2[CH2:7][C@@H:6]([F:8])[CH2:5][N:4]2[C:9](=[O:10])[NH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21](=[O:22])[NH2:23])[CH:13]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC[C@@H]1C[C@@H](F)CN1C(=O)Nc1cn(C(N)=O)c2ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)n1cc(NC(=O)N2C[C@H](F)C[C@H]2CNC(=O)Oc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-[((2S,4R)-2-aminomethyl-4-fluoro-pyrrolidine-1-carbonyl)-amino]-indole-1-carboxylic acid amide (50 mg, 0.157 mmol, prepared as described in Scheme B11) and phenyl chloroformate (22 μL, 0.17 mmol) in CH2Cl2 (0.5 mL), was added triethylamine (24 μL, 0.17 mmol) and the resulting suspension was stirred at RT under nitrogen overnight. The mixture was poured into water and extracted with CH2Cl2 (×2). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19×50 mm, eluent: 20% to 100% CH3CN in H2O in 15 min, CH3CN and H2O containing 0.1% HCOOH, flow: 20 mL/min) to give after lyophilization of the purified fractions the desired material. Rf, TLC (EtOAc)=0.45; MS (LC-MS): 440 [M+H]+, 901.3 [2M+Na]+; tR (HPLC conditions f): 1.77 min.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][S:18][CH3:19])=[CH:11][N:10]=2)=CC=1>FC(F)(F)C(O)=O>[CH3:19][S:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[N:14][C:9]([NH2:8])=[N:10][CH:11]=1
Reactant: COc1ccc(CNc2ncc(OCCSC)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CSCCOc1cnc(N)nc1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 32.5 %

Procedure:
N-(4-Methoxybenzyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (172.4 mg) was dissolved in trifluoroacetic acid (3 mL) at room temperature, and the solution was stirred at 60° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative silica gel thin layer chromatography (chloroform: methanol=15:1) to obtain 5-[2-(methylthio)ethoxy]pyrimidin-2-amine (34 mg, 18% in 2 steps) as colorless amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](Cl)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:22][S:23]([O-:25])=[O:24].[Na+].C(OCC)(=O)C.O>CS(C)=O>[CH3:1][O:2][C:3](=[O:21])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:23]([CH3:22])(=[O:25])=[O:24])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 83.3 %

Procedure:
A solution of 2-(4-chloro-3-nitrophenyl)-3-cyclopentyl-propionic acid methyl ester (1.00 g, 3.21 mmol) and sodium methanesulfinate (0.36 g, 3.53 mmol) in dimethyl sulfoxide (3 mL) was heated at 130° C. for 5 h. The black reaction mixture was then poured over ice (20 g), resulting in the formation of a brown sticky substance. The resulting mixture was then treated with ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid methyl ester (0.95 g, 84%) as a yellow gel: FAB-HRMS m/e calcd for C16H21NO6S (M+H)+ 356.1169, found 356.1175.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:44])[F:43])[CH:36]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: FC(F)(F)c1cccc(-c2cccc(Br)n2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(C(F)(F)F)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(3-trifluoromethyl-phenyl)-pyridine.
Reaction SMILES: [F:1][C:2]1[N:6]2[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1.Cl.[NH:26]1[CH2:29][CH:28]([C:30]2[NH:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[N:31]=2)[CH2:27]1>>[F:1][C:2]1[N:6]2[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][N:26]4[CH2:27][CH:28]([C:30]5[N:31]=[C:32]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=6)[NH:33][N:34]=5)[CH2:29]4)=[CH:13][CH:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Reactant: O=Cc1ccc(-c2nc3ncc(F)n3cc2-c2ccccc2)cc1
Agent: Cl
Product: Fc1cnc2nc(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)c(-c3ccccc3)cn12
Yield: 57.6 %

Procedure:
This compound was prepared in analogy by reacting 90 mg (0.28 mmol) 4-(3-fluoro-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde with 93 mg (0.34 mmol) 2-(5-azetidine-3-yl-[1,2,4]triazol-3-yl)-pyridine hydrochloride salt according to the procedure in example 1. After four and a half hours the reaction mixture was worked up and purified in the usual way as described in example 1. 81 mg of the desired product were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[C:32](Br)[CH:31]=[CH:30][N:29]=1>>[NH2:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:26])[CH3:9])=[CH:4][CH:3]=2)[CH:31]=[CH:30][N:29]=1
Reactant: Nc1cc(Br)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccnc(N)c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 2-amino-4-bromopyridine in Step 4. LC-MS Method 2 tR=0.951, m/z=432; 1H NMR (CDCl3) 1.26-1.40 (m, 1H), 1.48 (d, 3H), 1.59-1.63 (m, 1H), 1.83-1.95 (m, 2H), 2.09-2.20 (m, 1H), 2.21-2.37 (m, 2H), 2.86 (m, 1H), 3.50 (m, 2H), 4.54-4.75 (s, 2H), 5.62 (m, 1H), 6.56 (s, 1H), 6.71 (d, 1H), 6.90 (d, 2H), 7.21-7.33 (m, 7H), 8.00 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].Br[CH2:31][CH2:32][CH:33]([Cl:35])C.[C:36](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:35][CH2:33][CH2:32][CH2:31][CH2:36][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:21])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1O
Reactant: CC(Cl)CCBr
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}-(phenyl)methanone (500 mg), 1-bromo-3-chlorobutane (668 mg), and potassium carbonate (896 mg) were suspended in N,N-dimethylformamide (20 ml), and the suspension was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (584 mg, yield 95%).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17]O)=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[C:5]1([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][Cl:3])=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCc1ccc(C#Cc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(C#Cc2ccccc2)cc1

Procedure:
Thionyl chloride, 7 ml., is added dropwise to a stirred solution of 6.0 g. (0.0288 mole) of 4-(phenylethynyl) benzyl alcohol in 100 ml. of dry chloroform at room temperature and the mixture is stirred for 6 hours. Solvent is evaporated under reduced pressure and at a temperature below 50°. The residue is freed from traces of thionyl chloride by dissolution in dry benzene and evaporation under reduced pressure. This process is repeated and the residual solid product is purified by sublimation in vacuo; m.p. 61.5°-63.5°C.
Reaction SMILES: [CH:1]1([N:7]([P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([N:7]([P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=[S:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOP(=O)(OCC)N(C=O)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)N(C=S)C1CCCCC1

Procedure:
A mixture of 0.359 g (1.4 mmol) of N-(cyclohexyl)diethylphosphonoformamide, 0.276 g (0.7 mmol) of Lawesson Reagent in 10 ml toluene was refluxed for 5.5 h. The resulting mixture was subjected to VLC (vacuum liquid chromatography) using gradient eluants [from 5% ethyl acetate in petroleum ether to ethyl acetate/petroleum ether (40:60) to give N-cyclohexyl diethylphosphonothioformamide as a yellow solid, 0.327 g (85.8%, isolated yield). NMR (CDCl3): 3P −1.66. 1H, 1.18–2.01 (m, 16H), 4.17 (m, 4H), 4.34 (m, 1H), 8.89 (br. s, 1H).