Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH3:2].[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:35])[C:11]2[O:17][C:16]3[C:18]([Cl:31])=[CH:19][C:20]([NH:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:21][C:15]=3[CH2:14][S:13](=[O:33])(=[O:32])[C:12]=2[CH:34]=1)=[O:7].FC(F)(F)C(O)=O.C([BH3-])#N.[Na+]>CO>[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:35])[C:11]2[O:17][C:16]3[C:18]([Cl:31])=[CH:19][C:20]([N:22]([CH2:1][CH3:2])[CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:21][C:15]=3[CH2:14][S:13](=[O:33])(=[O:32])[C:12]=2[CH:34]=1)=[O:7]
Reactant: CC=O
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCOCC3)cc(Cl)c1O2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCN(CCN1CCOCC1)c1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Acetaldehyde (0.21 mL, 3.80 mmole) was added to a solution of Example 66k (0.370 gm, 0.76 mmol) in dry methanol (15 mL) followed by the addition of trifluoro-acetic acid (0.06 mL, 0.76 mmol). The reaction mixture was stirred at 0° C. for 2 h, allowed to come to room temperature, treated with sodium cyanoborohydride (0.119 g, 1.9 mmol), and stirred overnight. It was concentrated, treated with 10% aqueous sodium bicarbonate solution, water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.3 g, (76.72%); 1H NMR (CDCl3): δ 2.15 (t, 3H, CH3), 2.45-2.55 (m, 6H, 3CH2), 2.70 (s, 3H, CH3), 3.40 (q, 2H, CH2), 3.50 (t, 2H, CH2), 3.70-3.80 (m, 4H, CH2), 3.95 (s, 3H, OCH3), 4.70 (s, 2H, CH2), 6.55 (s, 1H, Ar), 6.70 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.45 (s, 1H, Ar); MS: m/e (CI+) 511 (M—CH3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([Cl:17])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:17][C:16]1[N:15]=[C:14]([CH2:18][CH3:19])[N:11]2[CH2:12][CH2:13][NH:8][CH:9]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][CH:23]=3)[C:10]=12
Reactant: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1nc(Cl)c2n1CCNC2CCc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooled solution of 1-chloro-3-ethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (226 mg; 0.494 mmol) in DCM (5 ml) was added 4N HCl in dioxane (2.5 ml; 10 mmol; 20 eq.). The resulting suspension was further stirred at 0° C. for 10 min., and at rt for 2 h. The volatiles were removed under vacuum and the resulting pale yellow chlorhydrate salt (240 mg) was purified by preparative HPLC in basic conditions leading to the pure product 1-chloro-3-ethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine (89.6 mg; 51%). LC-MS: tR=0.77 min.; [M+H]+=358.36 g/mol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:31]1([CH2:37][NH2:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:31]1([CH2:37][NH:38][C:14]([C:11]2([C:17]3[CH:18]=[C:19]([C:27]([F:29])([F:28])[F:30])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NCC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC1CCCCC1)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3,5-bis-trifluoromethylphenyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.5 mmol; 220.7 mg) in DMF (2 mL) was added cyclohexylmethylamine (0.6 mmol; 0.078 mL), N, N-diisopropyl-N-ethylamine (1 mmol; 0.174 mL) and HBTU (0.6 mmol; 228 mg), and the resulting mixture was stirred at room temperature overnight. The mixture was then purified via reverse phase HPLC. The desired fractions were combined and lyophilized. The resulting residue was dissolved in 1,4-dioxane (3 mL) and a 4N HCl solution in 1,4-dioxane (3 mL) was added. The resulting mixture was stirred for 2 hours at room temperature, then evaporated to yield 4-(3,5-bis-trifluoromethylphenyl)-piperidine-4-carboxylic acid cyclohexylmethylamide as a hydrochloride salt. MS (ESI) m/z 437.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[NH:4][CH2:5][C:6]1[C:7](=O)[NH:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:7]1[C:6]([CH2:5][NH:4][C:3]2[C:2]([Cl:1])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Cl)n1
Temperature: 100 °C
Yield: 22 %

Procedure:
13.6 g (43 mmol) of crude 5-(2,6-dichloroanilinomethyl)-2-methylthio-3H-pyrimidin-4-one was treated with 120 ml of phosphorus oxychloride and the mixture heated at 100° C. for 15 minutes then cooled. The mixture was evaporated and cautiously partitioned between 200 ml of ethyl acetate and 200 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography on silica gel eluting with diethyl ether/isohexane in a ratio of 1:9 to give 3.2 g (22%) of 4-chloro-5-(2,6-dichloroanilinomethyl)-2-methylthiopyrimidine as a pale yellow oil. [Mass spectrum (ESI) MH+ =334].
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].[C:8](O)(=O)[CH3:9].O>C1(C)C=CC=CC=1>[CH:3]([C@H:2]1[CH2:6][O:7][C:8]([CH3:9])=[N:1]1)([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](N)CO
Reactant: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=N[C@@H](C(C)C)CO1
Reaction time: 24 h
Yield: 77.8 %

Procedure:
20 g (0.194 mol) valinol are dissolved with 11.64 g (0.194 mol) acetic acid in 60 ml toluol and cooked for 24 h under reflux in the water separator. After cooling the solution is extracted with 10% hydrochloric acid. The aqueous phase is neutralized with 40% sodium hydroxide solution and extracted with diethyl ether. The organic phase is dried via Na2SO4 and the solvent removed. Distillation (112° C.) produces 19.2 g (78%) 4-(S)-isopropyl-2-methyloxazoline as a colourless oil.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]2)=[CH:4][N:3]=1.[S:45]1[C:49]2[CH:50]=[CH:51][C:52]([NH2:54])=[CH:53][C:48]=2[N:47]=[CH:46]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]3[C:2]([NH:54][C:52]4[CH:51]=[CH:50][C:49]5[S:45][CH:46]=[N:47][C:48]=5[CH:53]=4)=[N:3][CH:4]=[C:5]([CH2:34][N:35]4[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]4)[CH:6]=3)[N:9]=2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2scnc2c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc4scnc4c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
A mixture of 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 128; 60.0 mg, 0.097 mmol) and benzo[d]thiazol-5-amine (29.0 mg, 0.193 mmol)(Maybridge, Trevillet, UK) in THF (1.0 mL) at 0° C. was treated with LiHMDS (1.0 M in THF, Aldrich, St. Louis, Mo.) (483 μL, 0.483 mmol) dropwise via syringe. The reaction was stirred at 0° C. for 15 min, then was quenched with sat. aq. NH4Cl (3 mL). The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with a gradient of 10-35% EtOAc in DCM with 1% MeOH to give N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)benzo[d]thiazol-5-amine (51.0 mg, 0.068 mmol, 70.3% yield) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 9.16 (1H, br. s.); 8.99 (1H, s); 8.40-8.54 (2H, m); 7.84 (1H, d, J=8.8 Hz); 7.58 (1H, d, J=8.6 Hz); 7.12-7.25 (4H, m); 6.77-6.92 (4H, m); 4.93 (2H, s); 4.89 (2H, s); 4.15 (2H, s); 3.79 (12H, d, J=18.0 Hz); 3.35-3.51 (2H, m); 2.87-2.97 (2H, m); 2.85 (3H, s); 2.69 (3H, s). m/z (ESI, positive ion) 752 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17]>C(Cl)Cl>[CH2:20]([O:19][C:15](=[O:18])[CH2:16][CH2:17][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:21]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)CNCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CCN(CC(=O)OCC)Cc1ccccc1
Yield: 76.3 %

Procedure:
Ethyl N-benzylglycinate (0.1295 mol, 1 eq), ethyl acrylate (0.142 mol, 1.1 eq) and 155 μL of Triton™ B (available from Sigma-Aldrich, St. Louis, Mo.) were combined at room temperature under N2. The mixture was then heated to reflux overnight. An aliquot was removed and NMR spectrum was taken of the crude material. The product was present plus both starting materials. The excess of the ethyl acrylate was removed under vacuum at 10 mmHg (60° C. water bath). The crude amber oil that resulted was dissolved in 50 mL of CH2Cl2 and was charge onto a Biotage™ 75L cartridge and eluted with the following gradient 0.5% by volume acetone in hexanes, 1% (1200 mL), 1.5% (1200 mL) and 2.5% (3600 mL). The fractions containing the desired product were combined and concentrated to a colorless oil which was dried under high vacuum for 2 hours to afford 29 g (76%) of product (I-4a). 1H NMR spectrum (CDCl3) and LC/MS (294) were consistent with the compound I-4a.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6](Cl)=[O:7].[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>CCOCC>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: OCc1ccccc1
Reactant: O=C(Cl)C1CCCO1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)C1CCCO1
Reaction time: 0.67 h

Procedure:
Tetrahydrofuroyl chloride (15.0 g, 112 mmol) was added dropwise to a cold solution of benzyl alcohol (10.9 g, 101 mmol) and pyridine (20.0 g, 253 mmol) in Et2O (200 mL). The solution was stirred at 0° for 40 minutes, then filtered to remove the side product pyridine hydrochloride. The filtrate was washed with 0.1M HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), and then dried over MgSO4. Filtration and evaporation of the solvent gave a yellow oil, which was distilled. Benzyl tetrahydrofuroate was obtained as a colorless oil (21.1 g), b.p. 118° to 120° at 0.5 mm Hg. Microanalysis calc'd for C12H14O3 (206.2): C, 69.89; H, 6.84; O, 23.27; Found: C, 69.62; H, 6.89.
Reaction SMILES: O[C:2]1([C:14]([O:16][CH3:17])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOCC>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH2:5][CH2:4][CH:3]=[C:2]2[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:8]=1
Reactant: COC(=O)C1(O)CCCc2ccc(OC)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)C1=CCCc2ccc(OC)cc21

Procedure:
A solution of 1-hydroxy-7-methoxytetralin-1-yl-carboxylic acid, methyl ester (0.5 g; 2.1 mmol; see Example 1(i) above) in toluene (5 mL) was added to a refluxing solution of p-TsOH (0.6 g; 3.2 mmol) in toluene (10 mL), and the resultant mixture was refluxed for 45 minutes. After cooling, the reaction mixture was diluted with ether, washed with water and NaHCO3/aq, dried with Na2SO4 and concentrated. Yield 392 mg (85%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([OH:34])=[CH:23][N:22]=3)[C:5]=2[CH3:35])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:43][CH2:44][N:45]([CH3:47])[CH3:46].CC(=O)CC>CN(C=O)C>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:11]([F:20])=[CH:12][C:13]([O:17][CH2:18][CH3:19])=[CH:14][C:15]=3[F:16])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)[C:24]([O:34][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])=[CH:23][N:22]=3)[C:5]=2[CH3:35])[CH2:3][CH2:2]1
Reactant: CN(C)CCCl
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(O)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCN(C)C)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Temperature: 50 °C

Procedure:
80 mg of 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol 2-2-1 (0.048 mmol, 1.0 eq) were dissolved in 1.9 mL of dry DMF and 33.5 mg potassium carbonate (0.24 mmol, 5.0 eq) and 10.5 mg 2-chloro-N,N-dimethylethanamine (0.073 mmol, 1.5 eq) were added. The reaction mixture was stirred over night at 50° C. Then butan-2-one was added and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The purification of the residue by flash chromatography and HPLC provided 10 mg (0.02 mmol, 37%) of analytically pure target compound.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH3:13].CN([CH:25]=[O:26])C>C1COCC1>[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[CH:25]=[O:26])[CH3:13]
Reactant: CCOc1cccc(F)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1cccc(F)c1C=O
Temperature: -65 °C
Reaction time: 0.42 h

Procedure:
1.6M Butyl lithium in hexane (24 ml, 38.4 mmol) was added slowly (0.5 h) to a solution of 1-ethoxy-3-fluorobenzene (5.0 g, 35.7 mmol) in 100 ml of dry THF at -65° C. under nitrogen. The solution was stirred at -65° C. for 25 min. DMF (5.22 g, 71.4 mmol) was added dropwise to the solution. The mixture was allowed to warm to room temperature. 300 ml of ice was poured to this mixture and it was extracted with diethyl ether. Diethyl ether was washed with brine, dried over Na2SO4 and evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 10:100) to give 2-ethoxy-6-fluorobenzaldehyde.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10](=[O:12])[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]=[C:26]=[O:27])=[O:17])[CH3:14].O>CN(C=O)C>[CH2:13]([O:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][C:10]1=[O:12])=[O:27])=[O:17])[CH3:14]
Reactant: CCOC(=O)CCCCCCCN=C=O
Reactant: O=c1[nH]cc(-c2ccccc2)o1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCNC(=O)n1cc(-c2ccccc2)oc1=O
Reaction time: 24 h

Procedure:
16.1 g (0.1 mol) of 5-phenyl-4-oxazolin-2-one are dissolved in 100 ml of absolute DMF and 25.6 g (0.12 mol) of ethoxycarbonylheptyl isocyanate are added. The mixture is stirred for 24 hours at 50°-60° C., water is added and the oily/crystalline precipitate which is formed is separated, washed with water and dried in vacuo at room temperature. The crude product is recrystallised from ethanol.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[S:9][C:8]([C:10]([O:12]CC)=[O:11])=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>CO.O>[F:16][C:2]([F:1])([F:15])[C:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: CCOC(=O)c1ccc(C(=O)C(F)(F)F)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C(=O)C(F)(F)F)s1

Procedure:
Ethyl 5-(trifluoroacetyl)thiophene-2-carboxylate was hydrolysed with LiOH (2.1 eq.) in MeOH/H2O (1:1) at RT for 48 h. The mixture was concentrated under reduced pressure and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give the title compound as white solid. MS (ES) C7H3F3O3S requires: 224, found: 243 (M+H2O+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:17][C:18](=[O:24])[C:19]([O:21]CC)=[O:20])[CH:6]=[C:7]([NH:9][C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[CH:8]=1)#[N:2].[OH-].[Na+]>>[C:1]([C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:16])[C:11]([OH:13])=[O:12])[CH:6]=[C:5]([NH:17][C:18](=[O:24])[C:19]([OH:21])=[O:20])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(=O)Nc1cc(C#N)cc(NC(=O)C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc(NC(=O)C(=O)O)cc(NC(=O)C(=O)O)c1

Procedure:
A solution of 1.51 gram (0.0045 mole) of diethyl N,N'-(5-cyano-m-phenylene)dioxamate in 10 ml. of 5% sodium hydroxide solution is stirred for 25 minutes and filtered. To the filtrate is added dilute hydrochloric acid. The resulting precipitate is removed by filtration; weight 0.86 grams. M.P. 230° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13]OS(C)(=O)=O)=[CH:7][CH:6]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(O)C>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:9][CH:10]=1
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCOS(C)(=O)=O)cc1
Reactant: C1COCCN1
Solvent: CCO
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCN2CCOCC2)cc1
Yield: 95.1 %

Procedure:
To a stirred solution of (R)-tert-butoxycarbonylamino-[4-(2-methanesulfonyloxy-ethoxy)-phenyl]-acetic acid methyl ester (50 mg, 0.12 mmol) in ethanol (1 mL) was added morpholine (0.043 mL, 0.49 mmol) at room temperature. The reaction mixture was refluxed for 1 hour. The solvent was evaporated and the crude product was purified by chromatography over silica gel eluted with 1:1 v/v hexanes/ethyl acetate to give (R)-tert-butoxycarbonylamino-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetic acid methyl ester (45 mg, 92% yield) as a colorless oil.
Reaction SMILES: C([O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][C:8]([CH:9]=[O:10])=[C:7](Br)[C:6]=1[O:16][CH3:17])(=O)C.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([OH:20])=[O:19]>>[CH:9]([C:8]1[C:7]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:18]([OH:20])=[O:19])[CH:26]=2)=[C:6]([O:16][CH3:17])[C:5]([OH:4])=[C:12]([O:13][CH3:14])[CH:11]=1)=[O:10]
Reactant: COc1cc(C=O)c(Br)c(OC)c1OC(C)=O
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: COc1cc(C=O)c(-c2cccc(C(=O)O)c2)c(OC)c1O

Procedure:
6′-Formyl-3′-hydroxy-2′,4′-dimethoxy-biphenyl-3-carboxylic acid was prepared from 4-acetoxy-2-bromo-3,5-dimethoxybenzaldehyde (Example 162, step a) and 3-carboxyphenyl boronic acid using the protocol described in Example 145, step a. Mass Spectrum 288 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][NH2:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24](OCC)=[O:25])[N:23]=2)[CH:20]=1>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24]([NH:13][CH2:12][C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:11])[F:9])=[C:2]([F:1])[CH:3]=3)=[O:25])[N:23]=2)[CH:20]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Product: O=C(NCc1ccc(C(F)(F)F)c(F)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (3-fluoro-4-(trifluoromethyl)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:21]=[N:20][CH:19]=[C:18](Cl)[N:17]=1>CS(C)=O>[CH2:1]([O:8][C:18]1[CH:19]=[N:20][CH:21]=[C:16]([Cl:15])[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Clc1cncc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Clc1cncc(OCc2ccccc2)n1

Procedure:
Benzylalcohol (500 μL, 7.83 mmol) and potassium tert-butoxide (222.4 mg, 1.82 mmol) in anhydrous DMSO (1 mL) were reacted with 2,6-dichloropyrazine (149.7 mg, 1.00 mmol) as described in Example 19B to afford the title compound. MS (DCI/NH3) m/z 221 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[N:28]([CH2:29][C:30](=[O:38])[NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:27]2[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:26]=2[N:25]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:23][C:24]3[N:28]([CH2:29][C:30](=[O:38])[NH:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:27]4[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:26]=4[N:25]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc2c(c1)nc(CCl)n2CC(=O)NC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3nc4cc(C#N)ccc4n3CC(=O)NC3CCCCC3)cc2)CC1
Yield: 95.5 %

Procedure:
A solution of 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (8.21 g), 2-chloromethyl-1-(cyclohexylcarbamoylmethyl)-5-cyanobenzimidazole (9.29 g) and diisopropylethylamine (9.8 ml) in dimethylformamide (93 ml) was stirred at 60° C. for 14 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. To the obtained residue were added ethyl acetate and hexane and the precipitated solid was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give the title compound (15.726 g).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][CH3:31])[N:19]=2)=[C:9]1[CH3:32])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:30]([N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:33])=[O:5])[C:9]=2[CH3:32])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:29])=[O:28])[CH3:31]
Reactant: CCN1N=C(c2c(C)n(CC(=O)OC(C)(C)C)c3ccc(F)cc23)c2ccccc2S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CCN1N=C(c2c(C)n(CC(=O)O)c3ccc(F)cc23)c2ccccc2S1(=O)=O

Procedure:
[3-(2-Ethyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid tert-butyl ester (61 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.09 (d, 1H), 7.91 (t, 1H), 7.84 (t, 1H), 7.48 (d, 1H), 7.42 (dd, 1H), 6.97 (m, 2H), 4.52 (s, 2H), 3.96 (q, 2H), 2.21 (s, 3H), 1.39 (t, 3H) ppm. MS calculated for C20H18FN3O4S—H: 414, observed: 414.