Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([S:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](O)=[O:10])=O)[CH2:3][CH2:2]1.C([N:18](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+].C(P(CCCC)CCCC)CCC>CC(C)=O.O.C1(C)C=CC=CC=1>[CH:1]1([C:4]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=[O:10])[N:18]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccccc1SC(=O)C1CC1
Reactant: CCN(CC)CC
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: O=c1nc(C2CC2)sc2ccccc12
Temperature: -15 °C
Yield: 28 %

Procedure:
2-[(Cyclopropylcarbonyl)thio]benzoic acid (11.11 g, 50 mmol) was suspended in acetone (150 ml). While stirring under ice cooling, triethylamine (5.10 g, 50 mmol) and then ethyl chloroformate (6.68 g, 62 mmol) were dropwise added to the suspension. After stirring at the same temperature for an hour, an aqueous solution (15 ml) of sodium azide (5.00 g, 77 mmol) was dropwise added to the reaction mixture and stirring was continued for further an hour. The reaction mixture was diluted with water and the dilution was extracted with toluene (100 ml×3). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and then filtered. The toluene solution was cooled to about −15° C. and a solution (10 ml) of tributylphosphine (10.50 g, 52 mmol) in toluene was dropwise added to the solution. After completion of the dropwise addition, the reaction temperature was reverted to room temperature and the mixture was heated under reflux for 15 minutes. The reaction solution was concentrated under reduced pressure. The residue was applied to column chromatography using silica gel (300 g) to elute with hexane-ethyl acetate (2:1, v/v). The eluate was recrystallized from ethyl acetate-hexane to give the title compound (2.85 g, 28%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH:3]=1.C([N:22]=[C:23]=[S:24])(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>C1COCC1>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[C:2]([NH:1][C:23]([NH2:22])=[S:24])[NH:6][N:5]=1
Reactant: Nc1cc(-c2ccccc2Cl)n[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)Nc1cc(-c2ccccc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
To a solution of 5-amino-3-(2-chlorophenyl)pyrazole (3.8 g, 19.6 mmol) in THF (150 mL) was added dropwise benzoyl isothiocyanate (2.9 mL, 21.56 mmol). The reaction mixture was stirred at room temperature for 4 hours, then 4 N aqueous solution of NaOH (8 mL) was added, and the reaction mixture was further stirred at room temperature for 17 hours. The reaction mixture was neutralized to pH 7 with 1 N aqueous HCl, and extracted with EtOAc (3×). The combined organic layers were directly purified on silica gel with 0-10% MeOH in CH2Cl2 as eluent to provide 3.47 g (72 % yield) of [5-(2-chloro-phenyl)-2H-pyrazol-3-yl]-thiourea as a tan solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[O:6][C:5](=[O:16])[NH:4]1.N1C=CN=C1.[CH3:22][C:23]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])[CH3:24]>CN(C=O)C>[Si:26]([O:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[O:6][C:5](=[O:16])[NH:4]1)([C:23]([CH3:25])([CH3:24])[CH3:22])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc([C@@H]2OC(=O)N[C@H]2CO)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc([C@@H]2OC(=O)N[C@H]2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.1 %

Procedure:
To a solution of (4S,5S)-4-(hydroxymethyl)-5-(4-methoxyphenyl)oxazolidin-2-one [545435-91-4] (0.68 g, 3.05 mmol) and imidazole (0.249 g, 3.66 mmol) in DMF (10 mL) was added dropwise TBDPSCl (0.97 mL, 3.66 mmol) at 0-5° C. The reaction mixture was allowed to warm to RT and was stirred overnight at RT. The reaction mixture was concentrated and the residual oil was dissolved in TBME and washed with 10% aqueous KHSO4, H2O, saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using EtOAc in heptane from 5% to 50% in order to give the title compound as a white foam (1.62 g, 55%). TLC (heptane/EtOAc 1:1) Rf=0.44; LC-MS: [M+H] 462; Rt 1.36 min; (LCMS method 2). 1H NMR (400 MHz, CDCl3): 7.65 (d, 4H), 7.35-7.60 (m, 6H), 7.24 (d, 2H), 6.92 (d, 2H), 5.24 (d, 1H), 5.20 (br s, 1H), 3.84 (m, 4H), 3.77 (m, 2H), 1.09 (s, 9H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.[CH2:29]([O:31][CH:32]([O:43][CH2:44][CH3:45])[N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][C:34]1=[O:42])[CH3:30]>C1(C)C=CC=CC=1.C1COCC1>[CH2:44]([O:43][CH:32]([O:31][CH2:29][CH3:30])[N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]([C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:34]1=[O:42])[CH3:45]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: CCOC(OCC)N1C(=O)Cc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCOC)c(OC)cc23)c2ccccc21
Reaction time: 2 h
Yield: 72.4 %

Procedure:
Potassium bis(trimethylsilyl)amide (48 ml of a 0.5M solution in toluene, 24 mmol) was rapidly added to a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (3.2 g, 11.9 mmol) and 1-diethoxymethyloxindole (4.0 g, 14.9 mmol), (prepared according to Synthesis 1975, 168), in THF (240 ml) at ambient temperature. After 2 hours, the precipitate was filtered off and washed with ether. The filtrate was evaporated. The residue was mixed with the precipitate and partitioned between methylene chloride and water and the organic phase washed with saturated aqueous sodium chloride solution. The organic layer was driied (MgSO4) and the solvent removed by evaporation. The residue was purified by column flash chromatography using methylene chloride/methanol (95/5) as eluent. The purified product was triturated with a mixture of ether and petroleum ether to give 4-(1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (4.03 g, 74%) as a red orange solid.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1)=[O:4].C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl>[CH3:1][C:2]([CH3:22])([CH3:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[C:30](=[O:32])[CH3:31])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)C(=O)Nc1ccccc1C1Cc2ccccc2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2ccccc2CC1c1ccccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice cold solution of 3.5 g 2,2-dimethyl-N-[2-(2,3-dihydro-1H-indol-2-yl)phenyl]propanamide in 35 ml CH2Cl2 was added 8.4 ml triethylamine, followed by dropwise addition of 4.2 ml acetic anhydride. The resulting solution was stirred at room temperature for two hours and then quenched with water. The organic layer was washed successively with 5% aq. HCl, water, saturated NaHCO3 and brine, and dried (MgSO4). Concentration, trituration with hexane and recrystallization from toluene/hexane gave 3.1 g solid, m.p. 184°-186° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>C(#N)C>[CH3:13][N:14]([CH3:16])[CH:15]=[N:10][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8]
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1ccc(Br)s1

Procedure:
To a stirred mixture of 5-bromothiophene-2-sulfonamide (24.2 g, 0.10 mol) in acetonitrile (100 ml) was added dimethylformamide dimethyl acetal (14 ml) in acetonitrile (125 ml) dropwise over 0.5 hour. After an additional 0.5 hour the solvent was removed in vacuo. The residue was treated with water and the solid that precipitated was collected and dried, 28.7 g., m.p. 103°-105° C. Recrystallization from 1-chlorobutane gave material with m.p. 104°-106° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:18]O>>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:18])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1cccc(Br)c1
Yield: 47 %

Procedure:
A solution of trans-3-(3-bromophenyl)-2-propenoic acid (0.405 mol) in methanol (300 ml) was treated with conc. sulfuric acid (6.0 ml) and heated under reflux for 10 h. The cooled mixture was filtered to afford the title compound (46.14 g, 47%) as brilliant white crystals, m.p. 53-55° C. (Found: C, 50.10; H, 3.58; Br; 33.21. C10H9BrO2 requires C, 49.82; H, 3.76; Br, 33.14%); νmax (nujol)/cm−1 1730.5, 1715.0, 1644; δH (270 MHz) 3.81 (3H, s, OCH3); 6.43 (1H, d, 2-H, 3J2,3=16.2 Hz); 7.25 (1H, t, 5′-H, Jo=7.8 Hz); 7.43 (1H, dt, 4′-H, Jo=7.9, Jm=1.0 Hz); 7.50 (1H, dt, 6′-H, Jo=7.9, Jm=1.0 Hz); 7.60 (1H, d, 3-H, 3J3,2=16.2 Hz); 7.66 (1H, t, 2′-H, Jm=1.7 Hz). δc (67.8 MHz) 51.8 (OCH3); 123.0 (3′-C); 133.0 (4′-C); 136.4 (1′-C); 143.1 (3-C); 166.9 (CO2Me). Remaining signals lie in the range 119.3-130.7 ppm; m/z 242.0, 240.0 (46.67, 47.64, M+), 211.0, 209.0 (72.69, 74.00), 182.9, 180.9 (15.67, 16.83), 161.0 (4.19), 130.0 (9.44), 102.1 (100).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([F:32])[CH:38]=3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(F)c1)N1CCN(C2CCC2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-fluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless solid (35%).
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[OH-].[NH4+:16]>O>[NH2:6][C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH2:16])=[O:3]
Reactant: [NH4+]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: O
Product: NC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 59 %

Procedure:
A mixture of L-phenylalanine methyl ester hydrochloride (6.50 g, 30.1 mmol) and ammonium hydroxide solution (28% in water, 15 mL) in water (60 mL) was stirred at ambient temperature for 64 h. The aqueous layer was extracted with dichloromethane (6×100 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-amino-3-phenylpropanamide as a colorless solid in 59% yield (2.92 g): 1H NMR (300 MHz, DMSO-d6) δ 7.38-7.21 (m, 5H), 7.12 (br s, 1H), 5.44 (br s, 1H), 3.63 (dd, J=9.5, 3.9 Hz, 1H), 3.28 (dd, J=13.7, 3.9 Hz, 1H), 2.72 (dd, J=13.7, 9.5 Hz, 1H), 1.41 (br s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]([C:18](C)(C)[O:19][SiH2]C(C)(C)C)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]([CH2:18][OH:19])[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc(Br)c1)C(C)(C)O[SiH2]C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CO)COc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of Example 273A (3.14 g, 6.8 mmol) in THF (40 mL) was added TBAF (7.14 mL, 7.14 mmol) at rt. The solution was stirred at rt for 1 h and was concentrated. The residual oil was purified by flash chromatography (40-80% EtOAc in hexane) to give the desired product (2.19 g, 93%). MS (DCI) m/z 347, 349 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([Cl:30])=[CH:24][C:23]=2[Cl:31])=[C:5]2[S:11][C:10](/[CH:12]=[CH:13]/[C:14]([O:16]C(C)(C)C)=[O:15])=[CH:9][C:6]2=[N:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[C:4]([NH:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([Cl:30])=[CH:24][C:23]=2[Cl:31])=[C:5]2[S:11][C:10](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:9][C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(/C=C/C(=O)OC(C)(C)C)sc23)c(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Nc2c(C#N)cnc3cc(/C=C/C(=O)O)sc23)c(Cl)cc1Cl
Yield: 92.3 %

Procedure:
A solution of tert-butyl (2E)-3-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2yl)prop-2-enoate (910.8 mg, 1.91 mmol), trifluoroacetic acid (2.18 g, 19.1 mmol) in 27 mL of dichloromethane is stirred at room temparature for 3 days, then concentrated in vacuo. The residue is triturated with ether to provide 741 mg of (2E)-3-(6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl)prop-2-enoic acid as a beige solid, mp >250° C.; 1H NMR (DMSO-d6) δ 3.84 (s, 3H), 6.28 (d, J=16 Hz, 1H), 7.38 (s, 1H), 7.70–7.88 (m, 2H), 7.90 (s, 1H), 8.62 (s, 1H), 9.81 (s, 1H), 12.50 (s, 1H); MS 420.1, 422.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25]([O:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CO[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
90 mg of tert-butyl trans-{4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexyloxy}acetate (0.18 mmol, 1 eq.) are placed in 1 mL of dichloromethane. 0.13 mL of trifluoroacetic acid (1.77 mmol, 10 eq.) is added and the reaction medium is stirred for 18 hours at room temperature. The solvent is evaporated off. The residue is triturated in ethyl acetate and methanol to give 15 mg of trans-{4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexyloxy}acetic acid.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:7]
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Yield: 90.8 %

Procedure:
A mixture of 113 mg of 4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.32 mmol), 244 mg of glycine (3.2 mmol), and 6.4 ml of a 0.5 N solution of sodium methoxide in methanol (3.2 mmol) was refluxed for 24 h with stirring. Then the solvent was evaporated in vacuo, the residue dissolved in 25 ml of water and the resulting solution was washed twice with 50 ml of ethyl acetate. The pH of the solution was subsequently adjusted to about 3 by addition of concentrated hydrochloric acid and the resulting slurry was extracted twice with 25 ml of ethyl acetate. The combined extracts were dried over MgSO4 and evaporated in vacuo. 103 mg of the title compound were obtained; 1H NMR (DMSO-d6): δ=9.32 (t, 1H), 8.74 (s, 1H), 8.19 (d, 1H), 7.94 (d, 1H), 7.45 to 7.65 (m, 6H), 4.02 (d, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([Cl:30])=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[Cl:30][C:19]1[N:20]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:22]2[S:23][C:15]([CH:14]=[C:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:16][C:17]=2[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2sc(C=C3CCNCC3)cc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
To a suspension of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethylene)-piperidine-1-carboxylic acid tert-butyl ester (0.85 g) in dichloromethane (10 mL) at room temperature was added hydrogen chloride (2 mL of a 2.0 M solution in diethyl ether). The reaction mixture was stirred at room temperature for 16 h and then reduced in vacuo. The residue was redissolved in dichloromethane (10 mL) and washed with saturated sodium carbonated solution (2×10 mL) and brine (10 mL), dried (MgSO4) and reduced in vacuo to give 2-chloro-4-morpholin-4-yl-6-piperidin-4-ylidenemethyl-thieno[3,2-d]pyrimidine (0.53 g).
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].C(#N)C.O[CH:12]([C:31]1[CH:43]=[CH:42][C:34]([O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:33]([CH3:44])[CH:32]=1)[CH2:13][CH2:14][C:15]1[S:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH3:30]>C1CCCCC1>[CH2:40]([O:39][C:37](=[O:38])[CH2:36][O:35][C:34]1[CH:42]=[CH:43][C:31]([CH2:12][CH2:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH3:30])=[CH:32][C:33]=1[CH3:44])[CH3:41]
Reactant: CCOC(=O)COc1ccc(C(O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CC#N
Product: CCOC(=O)COc1ccc(CCCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 21 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of trimethylsilylchloride (0.15 ml), sodium iodide (0.175 g) and acetonitrile (0.061 ml) was added a solution of ethyl [4-(1-hydroxy-3-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}propyl)-2-methylphenoxy]acetate (intermediate 12, 0.096 g) in cyclohexane (1 ml). The reaction mixture was stirred at 21° C. for 18 hours and then refluxed for 2 hours. The reaction mixture was partitioned between water and ethyl acetate; the aqueous layer separated and extracted twice more with ethyl acetate. The organic solutions were combined and were dried with brine and over magnesium sulfate and concentrated. The product isolated after evaporation of the solvent was further purified by flash chromatography using cyclohexane: ethyl acetate (7:1) as eluent to give the title compound as a pale yellow gum.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:20])([F:19])[C:5]1[N:9]2[CH2:10][CH2:11][NH:12][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:8]2=[CH:7][CH:6]=1.[CH:21]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=1[O:34][CH3:35])([CH3:23])[CH3:22].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl.O>[CH:21]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:16]2[CH2:15][CH2:14][C:13]3([NH:12][CH2:11][CH2:10][N:9]4[C:5]([C:4]([F:3])([F:19])[F:20])=[CH:6][CH:7]=[C:8]34)[CH2:18][CH2:17]2)=[O:30])=[CH:27][C:26]=1[O:34][CH3:35])([CH3:23])[CH3:22]
Reactant: FC(F)(F)c1ccc2n1CCNC21CCNCC1
Reactant: COc1cc(C(=O)O)ccc1OC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: COc1cc(C(=O)N2CCC3(CC2)NCCn2c(C(F)(F)F)ccc23)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.5 %

Procedure:
To a stirred solution of 6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]dihydrochloride (475 mg, 1.43 mmol), 4-isopropoxy-3-methoxy-benzoic acid (361 mg, 1.72 mmol) and 1-hydroxybenzotriazole (232 mg, 1.72 mmol) in CH2Cl2 (5.5 mL) at ambient temperature was added 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (266 mg, 1.72 mmol) followed by 4-methylmorpholine (786 μL, 7.15 mmol). The mixture was stirred for 16 h at room temperature. The mixture was poured into water and was extracted with EtOAc (3×). The organics were combined, washed with 0.1 N HCl, 1N NaOH, water, brine, dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (0-100% ethyl acetate/hexanes) to give (4-isopropoxy-3-methoxy-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone (623 mg, 96%). ESI-MS m/z calc. 451.2, found 452.3 (M+1)+; Retention time: 1.30 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J=1.9 Hz, 1H), 6.98 (dd, J=8.2, 1.9 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.54 (d, J=3.7 Hz, 1H), 5.93 (d, J=3.8 Hz, 1H), 4.56 (dd, J=12.2, 6.1 Hz, 1H), 4.52 (s, 1H), 3.94 (s, 2H), 3.88 (s, 3H), 3.69 (s, 1H), 3.47 (s, 2H), 3.27 (s, 2H), 1.87 (s, 4H), 1.38 (d, J=6.1 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9][CH2:8][C:6]=2[N:7]=1.O.C(O)(=O)C>CC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncc2c(n1)CCNC2
Yield: 80 %

Procedure:
2-Amino-5,6,7,8-tetrahydro-6-triphenylmethylpyrido-[4,3-d]pyrimidine (80 mg, 0.20 mmol) was mixed with water (0.5 ml) and acetic acid (0.5 ml) and heated on a steam bath for 5 minutes. Addition of acetone provided a homogeneous mixture. Removal of solvents gave an oil, which was purified by flash column chromatography (eluant: 89:10:1 chloroform:methanol:concentrated ammonium hydroxide) to provide the title product (24.3 mg, 0.16 mmol, 80% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[OH:39][CH:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[OH:39][CH:40]1[CH2:44][CH2:43][N:42]([CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:6][C:7](=[O:31])[C:8]2[CH:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[O:26][CH:27]=[CH:28][C:29]=4[CH3:30])=[O:24])[CH:17]=3)[CH:11]=[N:10][CH:9]=2)[CH2:41]1
Reactant: OC1CCNC1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCN3CCC(O)C3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3-hydroxypyrrolidine were converted to the title compound.