Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=[O:4].[Si]([O:15][CH2:16][C:17]([CH3:59])([CH3:58])[CH2:18][N:19]1[CH:28]=[C:27]([S:29][CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:43]3[CH:48]=[C:47]([C:49](=[O:54])[NH:50][CH:51]4[CH2:53][CH2:52]4)[CH:46]=[C:45]([F:55])[C:44]=3[CH3:56])[CH:25]=2)[C:20]1=[O:57])(C(C)(C)C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:51]1([NH:50][C:49](=[O:54])[C:47]2[CH:48]=[C:43]([C:24]3[CH:25]=[C:26]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:57])[N:19]([CH2:18][C:17]([CH3:58])([CH3:59])[CH2:16][OH:15])[CH:28]=[C:27]4[S:29]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:4])[C:44]([CH3:56])=[C:45]([F:55])[CH:46]=2)[CH2:53][CH2:52]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(SC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(S(=O)C3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic Acid (1 mL) was added to a solution of tert-butyl 4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfanyl)piperidine-1-carboxylate (Example 59a, 0.06 g) in DCM (2 mL), and the reaction was stirred at room temperature for 30 min. Toluene (10 mL) was added and the volatiles were removed under reduced pressure (repeated 3×). The residue was purified by preparative HPLC (Phenomenex Gemini column using a 95-5% gradient of 0.1% aqueous NH3 in acetonitrile), and after solvent removal and trituration with diethyl ether gave the title compound (0.01 g).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:10][C:11]1[NH:12][C:13](I)=[C:14]([CH2:16][CH3:17])[N:15]=1>CN(C)C=O>[CH3:10][C:11]1[NH:12][C:13]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:14]([CH2:16][CH3:17])[N:15]=1
Reactant: CCc1nc(C)[nH]c1I
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(C)[nH]c1Sc1ccccc1
Temperature: 130 °C
Yield: 64 %

Procedure:
To a solution of 2.24 g of thiophenol (20.3 mmol) in 16 ml of dry dimethylformamide is added 1.4 g of sodium hydride (60% oil suspension: 35 mmol) under ice cooling. Ten minutes later, 3.2 g of 2-methyl-4-ethyl-5-iodoimidazole (13.6 mmol) is added to the mixture, which is heated at 130° C. in a nitrogen atmosphere. Two hours later, the dimethylformamide is evaporated in vacuo. The residue is mixed with dry ice and extracted with methylene chloride. The extract is washed with water, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The crude product is chromatographed on a column of silica gel, eluting with 3% methanol/methylene chloride. The product is recrystallized from ethyl acetate/isopropyl ether to give 1.9 g of 2-methyl-4-ethyl-5-phenylthioimidazole 2. Yield, 64%: mp. 171° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15]C)[N:3]=1.O.Cl>C(O)C>[NH2:1][C:2]1[NH:3][C:4](=[S:15])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: O
Solvent: CCO
Product: N#Cc1c(-c2ccco2)nc(N)[nH]c1=S
Temperature: 25 °C
Yield: 87 %

Procedure:
To a stirred solution of 1.1 g (4.74 mmol) 2-amino-4-(2-furyl)-6-(methylthio)-pyrimidine-5-carbonitrile in 15 ml ethanol under argon was added 1.05 g (14.2 mmol) sodium thiolate and the mixture heated at reflux for 16 h. The reaction mixture was then cooled to room temperature, 20 ml water added, and the mixture made slightly acidic by dropwise addition of concentrated hydrochloric acid. The resulting crystals were collected by filtration, washed with water, and dried in vacuo to afford 0.90 g (87%) 2-amino-4-furan-2-yl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile as a yellow crystalline solid. ES-MS m/e (%): 217 ([M—H]−, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](O[C:33](=O)[CH3:34])OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+].[C:43](O)(=O)[CH3:44]>>[N:1]12[CH2:34][CH2:33][CH:4]([CH2:43][CH2:44]1)[CH:3]([NH:1][C:2]1[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5](=[O:15])[C:4]=3[CH:3]=1)[CH2:2]2
Reactant: Nc1ccc2c(c1)C(=O)c1ccccc1-2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: O=C1c2ccccc2-c2ccc(NC3CN4CCC3CC4)cc21
Reaction time: 0.25 h
Yield: 79 %

Procedure:
A suspension of 2-aminofluoren-9-one (400 mg, 2.05 mmol; Aldrich) and anhydrous sodium sulfate (3.0 g, 21 mmol; EM Science) in acetic acid (10 mL) was stirred for 15 min and then treated with sodium triacetoxyborohydride (1.3 g, 6.13 mmol; Aldrich). After stirring overnight, the reaction mixture was basified with saturated aqueous Na2CO3 and extracted with EtOAc (3×). The combined organic phases were concentrated under vacuum and purified by flash chromatography (80 g silica gel, 1-16% gradient of NH4OH-MeOH (1:10) in CH2Cl2) to afford the title compound (492 mg, 1.62 mmol; 79% yield): 1H NMR (300 MHz, CD3OD) δ ppm 7.35-7.47 (m, 3H), 7.33 (d, J=8 Hz, 1H), 7.11 (td, J=7, 2 Hz, 1H), 6.86 (d, J=2 Hz, 1H), 6.70 (dd, J=8, 2 Hz, 1H), 3.57-3.67 (m, 1H), 3.32-3.40 (m, 1H), 2.74-3.00 (m, 4H), 2.60 (ddd, J=14, 5, 1 Hz, 1H), 1.67-2.06 (m, 4H), 1.41-1.55 (m, 1H); MS (DCl/NH3) m/z 305 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:8][CH2:7][CH2:6]1)=[O:4].[S-:9][C:10]#[N:11].[K+]>C(O)C>[S:9]([CH2:2][C:3]([N:5]1[CH2:8][CH2:7][CH2:6]1)=[O:4])[C:10]#[N:11]
Reactant: N#C[S-]
Reactant: O=C(CCl)N1CCC1
Agent: [K+]
Solvent: CCO
Product: N#CSCC(=O)N1CCC1
Reaction time: 4 h

Procedure:
1-(α-Chloroacetyl) azetidine (13 grams; 0.1 mol), potassium thiocyanate (18 grams; 0.18 mol) and ethanol (100 ml) are charged into a glass reaction flask equipped with stirrer and reflux condenser. The reaction mixture is then heated at reflux, with stirring, for a period of about 4 hours. After this time the reaction mixture is cooled and filtered. The filtrate is then stripped of ethanol leaving a residue. The residue is extracted twice with hot benzene and the two benzene extracts are combined. The benzene extract is then evaporated under reduced pressure to yield 1-(α-thiocyanoacetyl) azetidine as a residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N+:34]([O-])=O)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.S1C=CC=C1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[C:29]([NH2:34])=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: Nc1ccccc1NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Yield: 90 %

Procedure:
A mixture of 7 parts of 4-[[1-[(4-fluorophenyl]methyl]-1H-benzimidazol-2-yl]methyl]-N-(2-nitrophenyl)-1-piperidineethanamine, 1 part of a solution of thiophene in methanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 6 parts (90%) of N1 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-1,2-benzenediamine (506).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[CH3:30])(=[O:21])=[O:20])[CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)=[O:4].Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:33]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C(OCC)(=O)C.C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[CH3:30])(=[O:20])=[O:21])[CH:7]=[C:8]([C:36]2[N:35]=[C:34]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:33]=[CH:32][N:37]=2)[CH:9]=1)=[O:4]
Reactant: Clc1ncnc(Nc2ccccc2)n1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cn1S(=O)(=O)c1c(C)cc(C)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ncnc(Nc3ccccc3)n2)cn1S(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 80 °C
Yield: 33.9 %

Procedure:
In a 10 mL flask was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (1.0 equivalent, 0.34 mmol, 149 mg), (4-chloro-[1,3,5]triazin-2-yl)-phenyl-amine (1.1 equivalent, 0.37 mmol, 78 mg), tetrakistriphenylphosphine palladium (0.2 equivalent, 0.07 mmol, 80 mg), sodium carbonate (1 mL, 2 N), methanol (1 mL) and benzene (5 mL). The resulting mixture was heated at 80° C. for 2 hours then diluted in ethyl acetate and washed with water, brine. The organic layer was dried over sodium sulfate then concentrated under vacuum. The crude mixture was then purified by prep HPLC to afford 55 mg of the title compound. HPLC, Rt=8.8 min, FIA, ES+=478.1.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][CH3:7])=[S:5])[NH2:3].N1C=CC=CC=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24](Cl)=[O:25]>O>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]([NH:3][N:2]([CH3:1])[C:4]([NH:6][CH3:7])=[S:5])=[O:25]
Reactant: CNC(=S)N(C)N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Solvent: O
Product: CNC(=S)N(C)NC(=O)c1ccc2ccccc2c1

Procedure:
To a stirred solution of 2,4-dimethylthiosemicarbazide (2.39 g, 2.00×10-2 mole) and pyridine (20 ml) was added dropwise 2-naphthoyl chloride. (3.89 g, 2.04×1031 2 mole) After stirring at room temperature for 48 hours the reaction was evaporated to dryness, affording a beige solid which was treated with H2O (100 ml). Filtration of the aqueous mixture gave the desired compound as a beige product, 5.47 g (100%). If pure 1-(2-naphthoyl)-2,4dimethylthiosemicarbazide is desired, the crude product is purified by crystallization.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]1([NH:13][NH:14][C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22][CH3:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[ClH:25].C1(O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:7]1([NH:13][N:14]=[C:15]([Cl:2])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:25])[C:17]=2[S:22][CH3:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CSc1ccccc1C(=O)NNc1ccccc1
Reactant: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: Oc1ccccc1
Product: CSc1c(Cl)cccc1C(Cl)=NNc1ccccc1

Procedure:
A mixture consisting of 21.9 g. (0.105 mole) phosphorus pentachloride, 150 ml. of carbon tetrachloride, and 25.83 g. (0.100 mole) o-(methylthio)benzoic acid 2-phenylhydrazide (prepared in Part A above) was heated at the reflux temperature until evolution of hydrogen chloride ceased. The reaction mixture was chilled in an ice-bath, and a suspension of 31.5 g, (0.335 mole) phenol in 50 ml. carbon tetrachloride was added. After removing the carbon tetrachloride by evaporation under reduced pressure, the resulting triphenylphosphate solution of the desired product was poured through a column of silica gel. Elution was effected with a mixture consisting of 1 part benzene and 1 part Skellysolve B. After removing the solvents from the eluate by evaporation under reduced pressure, 2.0 g. of residue was obtained. Recrystallization from petroleum ether gave an o-(methylthio)-chlorobenzoyl chloride phenylhydrazone having a melting point at 65° to 66.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][NH2:11].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][NH:11][C:13](=[O:12])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1ccc(Br)c(CN)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COc1ccc(Br)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of 1-(2-bromo-5-methoxyphenyl)methanamine (3.2 mmol) in DCM (15 mL) was added BOC2O (3.2 mmol). The reaction mixture was allowed to stir at rt overnight and then concentrated. The residue was purified by column chromatography to give tert-butyl (2-bromo-5-methoxybenzyl)carbamate (3.1 mmol, 95%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:20](=O)([O-])[O-].[K+].[K+].CI>O1CCOCC1>[CH3:20][N:10]1[C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=[C:9]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [K+]
Solvent: CI
Solvent: C1COCCO1
Product: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Temperature: 40 °C
Yield: 38 %

Procedure:
Added to a solution of 500 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 in 1.5 ml of dioxane, are 330 mg of potassium carbonate and 150 ml of methyl iodide. The reaction mixture is heated at 40° C. for 16 minutes, and then cooled to ambient temperature. The suspension is filtered through sintered glass and then rinsed with dioxane and the filtrate is concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane, acetonitrile and methanol (98/01/01, 96/02/02, then 90/05/05 V/V/V). 200 mg of ethyl [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1.[C:17](=O)([O:20]C)[O:18][CH3:19]>C1COCC1>[CH3:19][O:18][C:17](=[O:20])[CH2:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([Cl:9])[CH:15]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: COC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccnc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A solution of LDA (1.8M in THF/heptane/ethyl benzene, 223 ml, 401 mmol) was added slowly to a stirred solution of 2-chloro-4-methylpyridine (17.5 ml, 200 mmol) in dry THF (1 L) under N2, such that the internal temperature <−70° C. After 1 hour at this temperature, dimethyl carbonate (40 ml, 475 mmol) was added. After 30 minutes the reaction was transferred to a cold bath at −40° C., and then allowed to warm slowly to 0° C. After 1 hour at 0° C. the reaction was quenched with saturated aqueous NH4Cl (250 ml). The mixture was partitioned between EtOAc/H2O. The aqueous layer was extracted with EtOAc (×2). The combined extracts were washed with brine (×1), then dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with 10-25% EtOAc/isohexane to give the ester (27.8 g, 75%) as a pale yellow liquid. 1H NMR (400 MHz, CDCl3) δ: 3.63 (2H, s), 3.73 (3H, s), 7.17 (1H, dd, J 5.1, 1.4), 7.28 (1H, s), 8.34 (1H, d, J 5.1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][S:25][CH2:26][C@H:27]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:3](=[O:23])[NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:1][C@@H:2]([CH2:24][S:25][CH2:26][C@H:27]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:3](=[O:23])[NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OCCCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCC(=O)O)OCCCCCCCCCCCC

Procedure:
A solution of (15R,19R)-tert-butyl 15-amino-19-(dodecyloxy)-14-oxo-4,7,10,21-tetraoxa-17-thia-13-azatritriacontan-1-oate in 1:1 TFA/DCM (0.1 M) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated en vaccuo. The crude mixture was purified by reverse phase high performance liquid chromatography (HPLC) with C4 column eluting with a gradient of 40-100% MeCN/10 mM NH4OAc (95:5) in 10 mM NH4OAc (pH 9) to give the title product as a white solid after lyophilizing. 1H NMR (DMSO-d6): δ 8.04 (t, 1H), 7.36 (s, 1H), 5.04 (d, 2H), 3.58 (t, 2H), 3.19-3.50 (m, 20H), 2.77 (dd, 2H), 2.59 (dd, 2H), 2.40 (t, 2H), 1.43-1.48 (m, 4H), 1.21-1.28 (m, 36H), 0.85 (t, 6H). LRMS [M+H]=735.6.
Reaction SMILES: C(OC([CH2:6][CH2:7][NH:8][CH:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])[CH:10]([CH3:16])[C:11]([O:13]CC)=O)=O)C.CC(C)([O-])C.[K+].C(O)C>C1(C)C=CC=CC=1.O>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][CH:9]1[CH:10]([CH3:16])[C:11](=[O:13])[CH2:6][CH2:7][NH:8]1
Reactant: CCOC(=O)CCNC(Cc1ccccc1OC)C(C)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccccc1CC1NCCC(=O)C1C
Temperature: 70 °C

Procedure:
210 g (0.6 mol) of ethyl 3-(2-ethoxycarbonylethyl)-amino-4-(2-methoxyphenyl)-2-methylbutanoate 14 are dissolved in 3 1 toluene and first about 100 mL of a solvent/water mixture are entrained. The mixture is cooled to about 70° C., combined with 80 g (0.7 mol) of potassium tert-butoxide and heated for 30 minutes to 105° C., while the ethanol formed is distilled off. Then the mixture is left to cool and the solvent is eliminated in vacuo. The residue is combined with 400 mL of ethanol and 200 mL of 40% sodium hydroxide solution and refluxed for 3 h. The alcohol is eliminated in vacuo and the aqueous phase is extracted three times with 400 mL of diethylether (ether). The combined organic phases are dried over magnesium sulfate, and the solvent is eliminated in vacuo. Yield 109 g (78%) oil.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[I:8][C:9]1[CH:10]=[C:11]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[NH2:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[I:8][C:9]1[CH:10]=[C:11]([NH:12][C:1]([CH3:2])=[CH:4][C:5](=[O:7])[CH3:6])[CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=1
Reactant: Nc1cc(I)cc(C(F)(F)F)c1
Reactant: CC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=C(C)Nc1cc(I)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
1.38 g (13.8 mmol) Acetylacetone, 3.95 g (13.8 mmol) 3-iodo-5-trifluoromethyl-aniline, and 0.1 g (1.6 mmol) 4-toluenesulfonic acid are dissolved in 150 ml toluene. The reaction mixture is refluxed for 7 h with a Dean-Stark trap to remove water. After cooling down to room temperature, the suspension is filtered. The solid is purified by recrystallisation from ethanol.
Reaction SMILES: O1CCNC1=O.C([C@@H]1COC(=O)N1[C:20](=[O:44])[C@H:21]([C@H:24]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:31]=1)[O:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH3:23])C1C=CC=CC=1>>[CH:38]1([CH2:37][O:36][C:32]2[CH:31]=[C:30]([C@H:24]([O:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C@H:21]([CH2:22][CH3:23])[CH2:20][OH:44])[CH:35]=[CH:34][CH:33]=2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: CC[C@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O[Si](C)(C)C)c1cccc(OCC2CCCCC2)c1
Agent: O=C1NCCO1
Product: CC[C@H](CO)[C@@H](O[Si](C)(C)C)c1cccc(OCC2CCCCC2)c1

Procedure:
Oxazolidinone cleavage of (R)-4-benzyl-3-((S)-2-((R)-(3-(cyclohexylmethoxy)phenyl)(trimethylsilyloxy)methyl)butanoyl)-oxazolidin-2-one following the method described in Example 45 gave (R)-2-((R)-(3-(cyclohexylmethoxy)phenyl)-(trimethylsilyloxy)methyl)butan-1-ol as colorless oil. Yield (0.273 g, 21%). 1H NMR (400 MHz, DMSO-d6) δ 7.17 (t, J=7.6 Hz, 1H), 6.73-6.80 (m, 3H), 4.64 (d, J=6.5 Hz, 1H), 4.19 (t, J=5.1 Hz, 1H), 3.41-3.47 (m, 1H), 3.32-3.37 (m, 1H), 1.58-1.79 (m, 6H), 1.48 (m, 1H), 0.99-1.26 (m, 7H), 0.76 (t, J=7.6 Hz, 3H), −0.06 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C=O)C>[ClH:25].[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([Cl:25])=[O:21])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)Cl
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 510 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid in dichloromethane were added 0.30 ml of oxalyl dichloride and one drop of DMF under ice-cooling, followed by stirring at room temperature for 30 minutes, and the solvent was evaporated under reduced pressure to obtain 603 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid chloride hydrochloride.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH2:36][C:37]([NH2:39])=[O:38]>>[NH2:39][C:37](=[O:38])[CH2:36][CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:31]1[CH:30]=[CH:29][C:28]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)=[O:7])=[O:18]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCCC(N)=O
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCCC(N)=O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and 3-aminopropanamide, the title compound was obtained in 71% purity by HPLC. MS(ESI+): m/z=409.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH:8]([CH3:13])[N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[CH3:20]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[CH2:9][CH:8]([CH3:13])[N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1
Reactant: CC(=O)N(C)C
Reactant: CC1CC(=O)Nc2cnc(Cl)nc2N1C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC1CC(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.28 g (0.001 mole) of (rac)-2-chloro-9-cyclopentyl-8-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 2 mL of N,N-dimethylacetamide and 0.093 mL (0.0015 mole) of iodomethane at 0 degrees was added 0.06 g (0.0015 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 10 mL of water was added. The precipitate collected by filtration to give 0.278 g of (rac)-2-chloro-9-cyclopentyl-5,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-3) as an yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)nc23)CC1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.012 mL (0.053 mMol) 2-fluoro-4-trifluoromethylbenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.