Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12])=[O:3].F[C:14]1C=CC(OC)=C(C(O)(C)C)C=1>>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH3:12])=[C:4]([C:2]([OH:3])([CH3:14])[CH3:1])[CH:9]=1
Reactant: COc1ccc(Cl)cc1C(C)=O
Reactant: COc1ccc(F)cc1C(C)(C)O
Product: COc1ccc(Cl)cc1C(C)(C)O

Procedure:
2-(5-chloro-2-methoxyphenyl)propan-2-ol (m.p. 56° C.) was prepared from 5-chloro-2-methoxyacetophenone following the method described in Example 3 for the preparation of 2-(5-fluoro-2-methoxyphenyl)propan-2-ol.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:10]1[C:11]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=[CH:13]2)(=O)C(C)(C)C.[OH-].[Na+]>O1CCCC1.CO.O>[C:32]([O:31][C@@H:9]([C:10]1[C:11]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([CH:21]([CH3:22])[CH3:23])[CH:14]=[CH:13]2)[CH2:8][OH:7])([CH3:34])([CH3:35])[CH3:33]
Reactant: Cc1cc2nc(C(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(C(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 45 °C
Yield: 96.5 %

Procedure:
To a solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-isopropyl-7-methylquinolin-6-yl)ethyl pivalate (77 mg, 0.156 mmol) in tetrahydrofuran/methanol (2:1, 1 mL) was added 1 M sodium hydroxide (2 mL) and the reaction was heated to 45° C. overnight. The reaction mixture was cooled to room temperature and diluted with water, extracted with ethyl acetate and washed with brine. The organic layer was then dried over sodium sulfate and concentrated, followed by co-evaporation with acetonitrile to give a clear oil (62 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C25H31ClNO2: 412.20. found: 412.96.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:11]([C:9]2[CH:10]=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1cc(F)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2cc(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
66 mg (0.33 mol) of 5-fluoro-1H-indol-7-carboxylic acid, 91 mg (0.30 mmol) of (4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]-amine and 63 mg (0.33 mmol) of EDC.HCl were dissolved in 3 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 7:3) to yield 100 mg (72%) product as a light yellow viscous oil. MS (ISP) 463.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH2:27]([O:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[CH:38]=[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH:36]=[CH:35]2)[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:43]2[CH2:42][CH2:41][N:40]([C:37]3[CH:36]=[CH:35][C:34]4[C:39](=[C:30]([O:29][CH2:27][CH3:28])[CH:31]=[CH:32][CH:33]=4)[CH:38]=3)[CH2:45][CH2:44]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: CCOc1cccc2ccc(N3CCNCC3)cc12
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc2ccc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5-c5ccccc54)CC3)cc12
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A suspension of 0.5 g (1.17 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide, 0.3 g (1.17 mmol) of 1-(8-ethoxy-naphthalen-2-yl)-piperazine and 1 g (7 mmol) of potassium carbonate in 50 ml of dimethylformamide is stirred for 14 hours at 90° C. The reaction mixture is poured onto water and the precipitate is filtered off. The product is purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=3:2).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:8])=[CH:5][C:6]=1[SH:7].[CH2:9]([SH:14])[CH2:10][CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].II>C(OCC)C.O>[CH3:1][C:2]1[O:3][C:4]([CH3:8])=[CH:5][C:6]=1[S:7][S:14][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: Cc1cc(S)c(C)o1
Reactant: CC(C)CCS
Agent: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(SSCCC(C)C)c(C)o1

Procedure:
0.64 Grams (0.005 moles) of 2,5-dimethyl-3-furanthiol and 1.04 grams (0.01 moles) of isoamyl mercaptan are dissolved in 12 ml anhydrous diethyl ether. 0.8 Grams (0.0075 moles) of sodium carbonate dissolved in 8 ml water is added with stirring to the reaction mass. 1.9 Grams (0.0075 moles) of iodine dissolved in 6 ml anhydrous diethyl ether is then added dropwise to the reaction mass until the iodine color remains. The reaction mass is then stirred for a period of 30 minutes.
Reaction SMILES: [Br-:1].[K+].N[C@@H:4]([C:9]([OH:11])=[O:10])[CH2:5][CH:6]([CH3:8])[CH3:7].N([O-])=O.[Na+]>S(=O)(=O)(O)O>[Br:1][C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:9]([OH:11])=[O:10]
Reactant: [Br-]
Reactant: CC(C)C[C@@H](N)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)C[C@H](Br)C(=O)O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Potassium bromide (9.5 g., 80 mmol.) was added to a stirred solution of D-leucine (3.0 g., 23 mmol.) in 2.5N sulfuric acid (47 ml.) at room temperature. The reaction mixture was cooled to -10° C. and solid sodium nitrite (2.4 g., 34 mmol.) was added portionwise, maintaining the temperature between -10° and -5° C. After addition was complete, the reaction was stirred for 1 hour and then warmed to room temperature and stirred for another hour. The reaction mixture was then extracted twice with ether, the ether extracts were washed once with water, dried (magnesium sulfate), filtered and evaporated to give 2.7 g. of crude title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]3O[C:15]([NH2:17])=[N:14][N:13]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH2:18][NH2:19]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]3[N:18]([NH2:19])[C:15]([NH2:17])=[N:14][N:13]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(c3nnc(N)o3)CC2)cc1
Reactant: NN
Solvent: O
Product: COc1ccc(C2(c3nnc(N)n3N)CC2)cc1
Temperature: 190 °C
Yield: 47 %

Procedure:
A mixture of 5-[1-(4-methoxyphenyl)cyclopropyl]-1,3,4-oxadiazol-2-amine (0.60 g, 2.6 mmol), and hydrazine (0.64 mL, 20 mmol) in water (2.0 mL) was heated at 190° C. for 3 h. After cooling to RT, the mixture was further cooled with ice-water. The crystalline solid formed was collected by filtration, washed with water, and dried under high vacuum to yield the desired product (300 mg, 47.1%). Analytical LCMS: (M+H)+=246.1.
Reaction SMILES: [CH2:1]([OH:8])[CH:2]1[CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1.[CH2:9](Br)[CH:10]=[CH2:11].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([CH:2]1[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7]1)[O:8][CH2:11][CH:10]=[CH2:9]
Reactant: OCC1CC=CCC1
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOCC1CC=CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a 500 mL round bottom flask equipped with an overhead stirrer, thermometer and a nitrogen inlet were placed 56.085 g (0.5 mol) of distilled 1,2,3,6-tetrahydrobenzylalcohol, 90.75 g (0.75 mol) of allyl bromide, 100 mL of toluene and 30 g (0.75 mol) of sodium hydroxide. The reaction mixture was stirred at room temperature for 15 minutes. Then, 3 g (0.01 mol) of tetra-n-butylammonium bromide was added and the reaction mixture slowly heated to reflux (65° C.) and maintained at that temperature for eight hours. The reaction mixture was cooled and filtered to remove the sodium bromide which precipitated during the reaction. The filtrate was poured into 500 mL of distilled water, the organic layers were separated and the aqueous layer extracted with fresh toluene. The combined organic layers were washed with three 200 mL portions of distilled water and the organic phase was dried over anhydrous sodium sulfate. Then, the excess allyl bromide and toluene were removed using a rotary evaporator and the reaction mixture subjected to vacuum distillation. The clear liquid distillate amounted to 62.32 g (82% recovered yield). Fractional vacuum distillation gave pure CA with a boiling point of 22° C. at 0.05 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:23].[C:25]([O:29][C:30](=[O:36])[NH:31][CH2:32][CH2:33][CH2:34]Br)([CH3:28])([CH3:27])[CH3:26]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][CH2:34][CH2:33][CH2:32][NH:31][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:36])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:23]
Reactant: COC(=O)CC1Cc2ccc(O)cc2N(Cc2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)NCCCBr
Solvent: CC(=O)O
Product: COC(=O)CC1Cc2ccc(OCCCNC(=O)OC(C)(C)C)cc2N(Cc2ccccc2)C1=O

Procedure:
The title compound is prepared using the procedure of Example 75 and (1-benzyl-7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester in place of 7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)acetic acid and (3-bromopropyl)carbamic acid tert-butyl ester in place of (2-bromoethyl)carbamic acid tert-butyl ester.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:25])(=[O:24])[NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[CH:7]=1.CO>>[O:19]1[C:18]2[CH:22]=[CH:23][C:15]([CH2:14][NH:13][S:12]([C:8]3[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:26])=[O:2])[CH:11]=[CH:10][CH:9]=3)(=[O:25])=[O:24])=[CH:16][C:17]=2[O:21][CH2:20]1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1
Solvent: CO
Product: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2ccc3c(c2)OCO3)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-{3-[(benzo[1,3]-dioxol-5-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid methyl ester (0.47 g, 1.25 mmol) in methanol (6 ml) 1N NaOH solution (3.75 ml, 3.75 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5. The title compound was obtained as a white solid (0.39 g, 87%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:20]([C:24]1[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH:26][N:25]=1)([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:20]([C:24]1[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:26]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[N:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: OB(O)c1ccc2ncccc2c1
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.5 %

Procedure:
Quinolin-6-ylboronic acid (0.34 g, 2.0 mmol) was dissolved in CH2Cl2 (30 mL) and pyridine (1 mL) with MS (activated 4 Å) and stirred at RT for 6 hours. Ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (0.39 g, 2.0 mmol) and copper(II) acetate (0.36 g, 2.0 mmol) were added and the reaction was stirred at RT for 3 days open to air. The reaction mixture was filtered through a pad of Celite®, the filtrate was concentrated in vacuo and purified by silica gel chromatography to obtain ethyl 3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazole-5-carboxylate (0.21 g, 33% yield). MS (ESI) m/z: 324.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:37]=[CH:36][C:24]([CH2:25][NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1.[Cl-].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([CH:9]=[O:10])=[C:6]([N:26]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:37][CH:36]=2)[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[N:7]=1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(N)nc(Cl)c2C=O)cc1
Reaction time: 1.25 h

Procedure:
2-Amino-4,6-dichloro-5-pyrimidine carbaldehyde (0.50 g; 2.60 mmol) was stirred in dry DCM (5 ml). Triethylamine (0.263 g; 2.60 mmol) and di(4-methoxybenzyl)amine (0.669 g; 2.60 mmol) were added and the reaction stirred at r.t for 1.25 h. the reaction was worked up by addition of further DCM (50 ml) and extraction with saturated sodium chloride solution (3×50 ml). The organic layer was washed with water (50 ml), dried (MgSO4) and evaporated yielding a yellow foam (0.957 g; 2.32 mmol; 89.2%).
Reaction SMILES: Br[C:2](Br)=[CH:3][C@@H:4]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C@@:5]([O:11][CH3:12])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9].[Mg].CCCCCC>C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][C@@H:4]([C@@:5]([O:11][CH3:12])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9])[C:3]#[CH:2]
Reactant: CCCC[C@@](C)(OC)[C@@H](C=C(Br)Br)OC1CCCCO1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#C[C@@H](OC1CCCCO1)[C@@](C)(CCCC)OC

Procedure:
A solution of (3R,4R)l,l-dibromo-3-tetrahydro-pyranyloxy-4-methoxy-4-methyl-l-octene (240 mg; 0.58 mmol) in THF (2 ml) is added dropwise to a refluxing mixture of activated magnesium turnings (activated with I2, 183 mg, 0.75 mmol) in THF (1 ml). The mixture is refluxed for 1 h, hexane (5 ml) is added and the suspension is filtered through a short path of silica gel. The filter cake is washed with ether and the solvent is removed in vacuo. The alkyne (3R,4R)3-tetrahydropyranyloxy-4-methoxy-4-methyl-l-octyne is purified by column chromatography on silica gel, eluting with 5% EtOAc in petroleum ether, to afford (3R,4R)3-tetrahydropyranyloxy-4-methoxy-4-methyl-l-octyne.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[CH:13]=[CH:12][NH:11][C:10]=12>CC(O)=O.[Fe]>[NH:11]1[C:10]2=[C:5]([O:4][C:3]3[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:2]=3[F:1])[N:6]=[CH:7][CH:8]=[C:9]2[CH:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
To a solution of 260 (100 mg, 0.36 mmol) in AcOH (4 mL) at 90° C., was added iron powder (102 mg, 2.1 mmol). The reaction mixture was vigorously stirred for 10 min, cooled, filtered through a Celite pad and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (1:1), to afford title compound 261 (87 mg, 99% yield) as an off-white solid. MS (m/z): 244.1(M+H) (found).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4](S)[N:3]=1>CO.[Ni]>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:2]([OH:1])=[N:3][CH:4]=[N:5][C:6]=1[CH3:13]
Reactant: COC(=O)Cc1c(C)nc(S)nc1O
Agent: [Ni]
Solvent: CO
Product: COC(=O)Cc1c(C)ncnc1O

Procedure:
A suspension of methyl (4-hydroxy-2-mercapto-6-methyl-5-pyrimidinyl)-acetate (160 g, 0.75 mol) and Raney-Nickel in water (1.51) is refluxed for 16 hours. The reaction mixture is filtered and the filtrate concentrated under reduced pressure to 1/10 of the original volume. Filtration of the precipitate and drying gives methyl(4-hydroxy-6-methyl-5-pyrimidinyl)-acetate in form of colorless crystals (116 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][NH2:22])=O)=[CH:17][N:16]=1.Cl.[C:26](N)(=[NH:28])[CH3:27]>CN(C=O)C.C(OC(=O)C)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]2[NH:28][C:26]([CH3:27])=[N:22][N:21]=2)=[CH:17][N:16]=1
Reactant: CC(=N)N
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)[nH]1
Temperature: 120 °C
Yield: 20.2 %

Procedure:
A mixture of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid hydrazide (300 mg, 0.6 mmol) and acetamidine hydrochloride (87 mg, 0.9 mmol) in DMF (6 mL) was heated at 120° C. for 2 h. A second portion of acetamidine hydrochloride (174 mg, 1.8 mmol) was added. After 8 h the mixture was cooled to room temperature and diluted with ethylacetate (40 mL). The mixture was filtered and the filtrates collected and washed with water (3×10 mL) and brine (10 mL) then dried over sodium sulfate, filtered and concentrated. Purification by chromatography (SiO2, 0-5% dichloromethane:methanol=100:0 to 95:5) followed by purification by HPLC (acetonitrile:water=2:8) gave the title compound (42 mg, 20%) as a white solid. MS: m/e=348.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[CH2:17](I)[CH2:18][CH3:19]>C1COCC1.[OH-].[Na+]>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[N:10]([CH2:17][CH2:18][CH3:19])[C:9](=[O:14])[CH2:8][CH2:7]3
Reactant: CCCI
Reactant: O=C1CC[C@@H]2c3ccc(Cl)cc3CC[C@H]2N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN1C(=O)CC[C@@H]2c3ccc(Cl)cc3CC[C@H]21
Reaction time: 22 h

Procedure:
A 2.35 g portion of (4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was slurried in 40 mL of THF and 5 mL of 50% aqueous sodium hydroxide, and 3.4 g of propyl iodide was added. The mixture was heated to about 60° and the mixture was stirred at that temperature for about 22 hours. Workup was carried out by separating the organic layer and evaporating it to dryness, and adding water and ethyl acetate. The organic layer was separated, washed twice with water, dried, filtered and evaporated under vacuum to obtain 710 mg of white crystalline product, found to be of about 90% purity. It was then purified by silica gel flash chromatography, eluting with ethyl acetate, to obtain 510 mg of purified product, m.p. 110°-11° of 98.98% purity, by HPLC, eluting with 1.1 acetonitrile:aqueous buffer (5% ammonium acetate) and monitoring at 220 nanometers.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].CC(O)(C)C.[CH3:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][N:32]3[C:40]4[CH2:39][CH2:38][NH:37][CH2:36][C:35]=4[C:34]([C:41]4[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=4)=[N:33]3)[CH2:25][CH2:24]2)[C:15]1=[O:51].C(N(CC)CC)C>C(Cl)Cl.CO.C(Cl)Cl>[CH3:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][N:32]3[C:40]4[CH2:39][CH2:38][N:37]([S:2]([NH2:5])(=[O:4])=[O:3])[CH2:36][C:35]=4[C:34]([C:41]4[CH:42]=[CH:43][C:44]([C:47]([F:49])([F:50])[F:48])=[CH:45][CH:46]=4)=[N:33]3)[CH2:25][CH2:24]2)[C:15]1=[O:51]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cn1c(=O)n(C2CCN(CCCn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCNC4)CC2)c2ccccc21
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: CO
Product: Cn1c(=O)n(C2CCN(CCCn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCN(S(N)(=O)=O)C4)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 108.3 %

Procedure:
To a solution of chlorosulfonyl isocyanate (0.018 mL, 0.209 mmol) in CH2Cl2 (0.150 mL) was added 2-methyl-2-propanol (0.020 mL, 0.209 mmol) and the solution was stirred at room temperature for 15 min. This solution was then added dropwise to a solution of 1-methyl-3-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-1,3-dihydro-benzoimidazol-2-one (75 mg, 0.139 mmol) and triethylamine (0.039 mL, 0.279 mmol) in CH2Cl2 (0.4 mL). An additional 0.15 mL of CH2Cl2 was used to transfer all of the material to the reaction mixture. The reaction mixture was allowed to stir overnight. Column chromatography (silica, 2-10% MeOH/CH2Cl2) gave 93 mg (93%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.24. MS (electrospray): calculated for C34H42F3N7O5S, 718.3 ([M+H]+); m/z found, 718.3.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].[CH2:20]([N:27]1[CH:31]=[C:30]([CH:32]=O)[C:29]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(COC)OC.CO>[CH2:20]([N:27]1[CH:31]=[C:30]([CH2:32][C:10]#[N:11])[C:29]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cn(Cc2ccccc2)nc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: N#CCc1cn(Cc2ccccc2)nc1OCc1ccccc1
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
A solution of p-toluenesufonylmethylisocyanide (10.3 g) in dimethoxyethane (50 ml) was added to a mixture of potassium t-butoxide (11.2 g) and dimethoxyethane (50 ml) at −78° C., and the mixture was stirred for 5 minutes. A solution of 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (14.6 g) in dimethoxyethane (50 ml) was added to the mixture. After stirring at the same temperature for 1 hour, the mixture was stirred for 1 hour while raising the temperature. Methanol (150 ml) was added to the mixture, which was refluxed for 1 hour. After cooling, the reaction solution was poured into saturated aqueous ammonium chloride solution, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 1-benzyl-3-benzyloxy-1H-pyrazol-4-ylacetonitrile (13.1 g, yield 86%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:44])[C@@H:15]([O:41][CH2:42][CH3:43])[C@@H:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([O:28][CH2:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]([CH3:40])([CH3:39])[CH3:38])[O:34][C:35]=2[CH3:36])=[CH:20][CH:19]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:44])[C@@H:15]([O:41][CH2:42][CH3:43])[CH2:16][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([O:28][CH2:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]([CH3:40])([CH3:38])[CH3:39])[O:34][C:35]=2[CH3:36])=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(C(C)(C)C)oc2C)c2ccccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc(OCCc2nc(C(C)(C)C)oc2C)c2ccccc12)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 4 h

Procedure:
0.267 g of the above prepared (S)-4-benzyl-3-((2S,3R)-3-{4-[2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-ethoxy-3-hydroxy-propionyl)-oxazolidin-2-one (0.444 mmol) was dissolved in 1.4 ml of trifluoroacetic acid, treated at 0° with 0.353 ml of triethylsilane (5 eq.) and then kept for 4 h at 0°, when TLC indicated the disappearance of starting material. The reaction mixture was then poured onto crashed ice/AcOEt/NaHCO3, the organic layer washed with water (pH of aq. phase˜8), dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=65/35) delivered 0.237 g of the title compound as white foam.