Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH:5]2[C:10](=[O:11])[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6]2)[CH2:26][CH2:25]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C1Nc2ccccc2SC1CCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCC2Sc3ccccc3NC2=O)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 26.6 %

Procedure:
In 10 ml of dimethylformamide were dissolved 1.6 g of 2-(3-chloropropyl)-2H-1,4-benzothiazin-3(4H)-one and 2.55 g of 1-(2-methoxyphenyl)piperazine. The solution was stirred at 100° C. for 1.5 hour. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4, then concentrated under reduced pressure. The concentrate was subjected to a column chromatography on silica-gel (150 g). From the eluate with hexane-acetone (2:1, v/v) was obtained 0.7 g of 2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-2H-1,4-benzothiazin-3(4H)-one as an oily substance. The 3/2 oxalate of this product was obtained as crystals, which were recrystallized from methanol and dichloromethane to give colorless prisms. The yield was 470 mg (13.3%), m.p. 202°-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:19][S:20][C:21](=[N:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])SC.C(N(CC)CC)C>C(#N)C>[CH3:19][S:20][C:21]([N:10]1[CH2:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)=[N:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)(=[O:26])=[O:27]
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Reactant: CSC(=NS(=O)(=O)c1ccc(Cl)cc1)SC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSC(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Yield: 79.7 %

Procedure:
Part A: A stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (12.0 gram, 46.8 mmol), [(4-chlorophenyl)sulfonyl]dithioimidocarbonic acid dimethyl ester (CAS: 13068-12-7) (9.20 gram, 31.1 mmol) and triethylamine (15 ml) in acetonitrile (200 ml) was heated at reflux temperature for 20 hours. An additional portion of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (12.0 gram, 46.8 mmol) was added and the resulting mixture was heated at reflux temperature for another 16 hours. After concentration in vacuo, dichloromethane was added and the resulting solution was washed twice with water and dried over anhydrous Na2SO4. After filtration and evaporation in vacuo the residue was further purified by flash chromatography (diethyl ether/petroleum ether=1/1 (v/v)) to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboximidothioic acid methyl ester (12.5 gram, 80% yield based on [(4-chlorophenyl)sulfonyl]dithioimidocarbonic acid dimethyl ester) as an amorphous solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])(=[O:7])[CH3:6]>>[C:5]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([Cl:3])=[O:13])[CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: CC(=O)Oc1cccc(C(=O)Cl)c1
Yield: 98.5 %

Procedure:
Using the above procedure, reaction of with thionyl chloride (11.1 mL, 15.3 mmol) and 3-acetoxybenzoic acid (2.50 g, 13.9 mmol) gave 511 (2.72 g, 99%) as a colorless oil. This material was used in the next step without additional purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]2=[O:16])=[CH:4][CH:3]=1.[BrH:17]>O>[Br:17][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]1=[O:14]
Reactant: Cc1ccc(C2C(=O)NC(=O)NC2=O)cc1
Reactant: Br
Solvent: O
Product: Cc1ccc(C2(Br)C(=O)NC(=O)NC2=O)cc1
Reaction time: 3 h

Procedure:
To a suspension of 5-(4-Methylphenyl)barbituric Acid (218 mg) in 2 ml of water, kept at 10° C. under stirring, 136 μl of 48% hydrobromic acid are added then 56 μl of brominr are dropped and the stirring is continued for 3 hours. The precipitate which formed is recovered by filtration and washed with water, then it is dried under vacuum to give 270 mg of the product, m.p. 210-213° C.
Reaction SMILES: C([NH:4][C:5]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:14]=1)([CH2:8][OH:9])[CH2:6][OH:7])(=O)C.[OH-].[Na+].Cl>CO>[NH2:4][C:5]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:14]=1)([CH2:6][OH:7])[CH2:8][OH:9]
Reactant: CCCCCCCCCCCOc1cccc(CCCC(CO)(CO)NC(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCOc1cccc(CCCC(N)(CO)CO)c1
Temperature: 0 °C
Yield: 71.4 %

Procedure:
2-Acetamido-2-[3-(3-undecyloxyphenyl)propyl]-1,3-propanediol (1.4 g) was dissolved in 50 ml of methanol and 16.6 ml of a 1N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 3 hours. The mixture was poured into ice water and neutralized with dilute hydrochloric acid. The solvent was distilled away and chloroform was added to the residue for extraction. The chloroform layer was washed and dried. The solvent was distilled away and the residue was recrystallized from diisopropyl ether-hexane to give 0.9 g of 2-amino-2-[3-(3-undecyloxyphenyl)propyl]-1,3-propanediol as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([O:37][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH3:40])[CH3:39])=[O:36])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]([CH3:32])([CH3:33])[O:29][C@@H:28]([CH2:34][C:35]([O:37][C:38]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([CH3:40])[CH3:39])=[O:36])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)OC(C)(C)c2ccccc2)O1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)c2ccccc2)OC(C)(C)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 2-phenylpropan-2-yl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([F:14])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[F:15].C(=O)([O-])[O-].[K+].[K+].[CH:22](B)=[CH2:23]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]([C:2]1[C:11]2[C:6](=[C:7]([F:14])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[F:15])=[CH2:23]
Reactant: COc1cc(F)c2ncc(F)c(Br)c2c1
Reactant: BC=C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1c(F)cnc2c(F)cc(OC)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
4-Bromo-3,8-difluoro-6-(methoxy)quinoline (0.63 g, 2.3 mmol) in DME (26 mL) under argon, was treated with tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.115 mmol) and the mixture stirred at room temperature for 20 minutes. Anhydrous potassium carbonate (0.32 g, 2.3 mmol), water (7 mL), and vinylborane:pyridine complex (see F. Kerins and D O'Shea J. Org. Chem. 2002, 67, 4968-4971) (0.22 g, 0.92 mmol) were added and the mixture was heated at 100° C. for 2 hr. It was cooled, diluted with water and extracted with ether, dried over magnesium sulfate and evaporated to dryness. After work-up the product was chromatographed on silica gel, eluting with 10% methanol in DCM to afford a white solid (0.46 g, 90%). MS (+ve ion electrospray) m/z 221 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH2:7][CH2:8][C:9](=[O:10])[C@@H:4]2[O:3]1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH2:7][CH2:8][C@H:9]([OH:10])[C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@@H]2CCC(=O)[C@@H]2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)O[C@H]2[C@@H](O)CC[C@H]2O1

Procedure:
(3 aR,6aR)-2,2-dimethyldihydro-3 aH-cyclopenta[d][1,3]dioxol-4(5H)-one (1-2) (2.75 g, 17.6 mmol, 1 equiv) was dissolved in methanol (166 mL) and sodium borohydride (1.0 g, 26.4 mmol, 1.5 equiv) was added portion wise at 0° C. Upon disappearance of the starting material as monitored by LC-MS analysis, water was added and the mixture was concentrated. The aqueous phase was extracted with DCM (3×100 mL), the combined organics were dried (Na2SO4), and the solvent was removed to afford (3AS,4S,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (1-3) as a colorless oil that did not require further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[NH:16][CH:15]=[C:14]([I:17])[C:6]=2[N:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:9]=1.Cl[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:20][CH2:19][N:16]1[C:5]2[C:4]([Cl:3])=[N:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[N:7][C:6]=2[C:14]([I:17])=[CH:15]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCOCc1ccccc1
Reactant: CCCCc1nc(Cl)c2[nH]cc(I)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c2c(n1)c(I)cn2COCc1ccccc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
Sodium hydride (0.338 g, 60% in oil, 14.08 mmol) was added portionwise to a stirred solution of 4-chloro-7-iodo-2-butyl-5H-pyrrolo[3,2-d]pyrimidine (2.19 g, 6.53 mmol) in DMF (30 mL) cooled in an ice-bath. After 30 minutes benzyl chloromethyl ether (1.13 mL, 1.278 g, 8.16 mmol) was added and the reaction stirred at room temperature. The reaction mixture was quenched with water and the resultant mixture partitioned between ethyl acetate (150 mL) and water (150 mL). The organic phase was washed with water then saturated aqueous sodium chloride solution, dried (Na2SO4), filtered and evaporated. The sample was dissolved in dichloromethane and purified by chromatography on silica (100 g) using a gradient of 0-100% ethyl acetate-cyclohexane over 30 minutes. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (2.82 g).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]([OH:12])=O)[CH2:6][CH:5]([CH3:13])[O:4]1.[NH2:14][C@@H:15]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17]>>[CH2:35]([O:34][CH2:33][C@H:15]([NH:14][C:10](=[O:12])[CH2:9][N:7]1[CH2:6][CH:5]([CH3:13])[O:4][CH:3]([CH3:2])[CH2:8]1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC1CN(CC(=O)O)CC(C)O1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CC1CN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC(C)O1
Yield: 25.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2,6-dimethylmorpholino)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 265, (2S)-3-(benzyloxy)-2-(2-(2,6-dimethylmorpholino)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (11.1 mg, 25.9%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.20 (s, 1H), 7.98 (d, 1H), 7.60 (d, 2H), 7.27-7.32 (m, 5H), 7.19-7.23 (m, 2H), 6.98-7.04 (m, 4H), 4.69-4.71 (m, 1H), 4.52 (s, 2H), 3.71-3.77 (m, 2H), 3.54-3.5 (m, 2H), 2.93-3.03 (m, 2H), 2.74 (dd, 2H), 1.73-1.80 (m, 2H), 1.00 (dd, 6H). MS (EI) for C30H34FN3O5. found 536.6 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:16]=[N:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][C:23]=2[CH:24]=1>>[Br:14][C:15]1[CH:16]=[N:17][C:18]2[CH2:19][CH2:20][N:21]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH2:22][C:23]=2[CH:24]=1
Reactant: Brc1cnc2c(c1)CNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ncc(Br)cc2C1
Yield: 62 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Bromo-5,6,7,8-tetrahydro-[1,6]naphthyridine to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: Fc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 61.8 %

Procedure:
A suspension of 0.207 g (1 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 0.173 g (1.2 mmol) of 3-fluorobenzyl chloride and 0.276 g (2 mmol) of potassium carbonate in 10 ml of dimethylformamide is stirred at 60° C. for 24 hours. The reaction mixture is subsequently cooled and is poured into a mixture of ice-cold water and of ethyl acetate. After settling, the organic phase is separated and then it is washed with two times 50 ml of water and then with 50 ml of a saturated sodium chloride solution. The solution is dried over magnesium sulfate and is filtered, and then the filtrate is concentrated under reduced pressure. 0.195 g of an oil is obtained, which oil is used as is in the following stage.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([CH:19]1O[CH:20]1[CH2:21][O:22][CH2:23][CH:24]1[O:42][CH:25]1CCCCCCCCCCCCCCCC)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCC>O1CCCC1>[CH2:21]([O:22][CH2:23][CH:24]([OH:42])[CH2:25][NH:2][CH3:1])[CH2:20][CH2:19][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCCC1OC1COCC1OC1CCCCCCCCCCCCCCCC
Reactant: CN
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(O)CNC

Procedure:
A cooled mixture of 15.5 g of methylamine, 50 cc. of tetrahydrofurane and 15 g of hexadecyl-2.3-epoxypropylether is heated to 60° C. for 2 hours in an autoclave, cooled and evaporated in a vacuo. The residue is purified by column chromatography (silicic acid gel//chloroform/methanol).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[C:4](O)=[O:5].B.O>O1CCCC1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO
Temperature: 75 °C
Yield: 93.8 %

Procedure:
2,6-Dimethyl-3-nitrobenzoic acid (10 g) was dissolved in 100 ml of dry tetrahydrofuran and 165 ml of 1M borane in tetrahydrofuran added. The mixture was heated to 75° C. for 4 hr. The mixture was cooled to room temperature and the excess reagent slowly decomposed with water and the solvent evaporated. The residue was treated with ethyl acetate, washed with 1M hydrochloric acid, then with water, dried, and evaporated to give 8.71 g of (2,6-dimethyl-3-nitro-phenyl)-methanol, mp 94.5-96.1° C. ##STR124##
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[H-].[Na+].CI.[C:19](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:12][C:11]([O:10][C:8]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][O:4][CH3:19])=[O:9])([CH3:14])[CH3:13]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
In a DMF solution containing 2.00 g of Boc-Ser-OH, 0.86 g of sodium hydride (60% oily suspension) was added under ice cooling and the resultant mixture was stirred for 30 min. To the resultant solution, 0.72 ml of methyl iodide was added and the resultant solution was stirred for 3 hr. The reaction mixture was neutralized with citric acid and evaporated under reduced pressure. The obtained residue was redissolved in ethyl acetate, and the solution was washed with 5% aqueous citric acid solution and saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography (chloroform:methanol=10:1) and crystallized as its DCHA salt from n-hexane to give 0.79 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][NH2:26])=[O:24].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:26][NH:25][C:23](=[O:24])[C:22]2[CH:27]=[CH:28][CH:29]=[C:20]([F:19])[CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(F)c2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (2 g, 7.44 mmol) and 3-Fluorobenzohydrazide (1.26 g, 8.19 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (1.0 g, 7.44 mmol), TEA (1.56 mL, 11.16 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (2.14 g, 11.16 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) followed by water (80 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (2.75 g, 91%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.84 (br s, 2H), 7.79-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.58-7.51 (m, 2H), 7.41-7.35 (m, 1H), 6.68 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.79 (br s, 1H), 4.42-4.36 (m, 1H), 4.14-4.10 (m, 1H), 2.36 (s, 3H) and 1.36 (d, J=6.5 Hz).
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH2:2][CH3:3].[CH2:18]([N:25]=[C:26]=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[CH2:18]([NH:25][C:26]([N:4]([CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[CH2:1][CH2:2][CH3:3])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C(=O)NCc1ccccc1)C1CCNCC1

Procedure:
The title compound was prepared by the reaction of 4-(N-(prop-1-yl)amino)-1-tert-butoxycarbonylpiperidine (from Example 17, Step A) with benzyl isocyanate, followed by treatment of the product with 50% TFA in CH2Cl2 to remove the tert-butoxycarbonyl group, affording the title compound. ESI-MS: 276.1 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[C:8]([CH:9](O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:7][N:6]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:5]=2)[CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([C:4]2[C:8]([CH:9]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=3)[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:7][N:6]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COc1ccc(-n2cc(C(O)CC(C)C)c(C3CC3)n2)cc1
Product: COc1ccc(-n2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C3CC3)n2)cc1
Yield: 12 %

Procedure:
Using 1-[3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]-3-methylbutan-1-ol (0.5 g) synthesized in Example 44(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.33 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (80 mg, 9%) was obtained as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].Cl>CO.O>[C:20]([O:19][C:17]([C:5]1([C:3]([OH:4])=[O:2])[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)C1(C(=O)OC(C)(C)C)CCc2cccc(OC)c2C1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cccc2c1CC(C(=O)O)(C(=O)OC(C)(C)C)CC2

Procedure:
The methyl ester from Example 33B was dissolved in a mixture of MeOH (10 mL) and water (2.0 mL) followed by addition of LiOH monohydrate (1.9 g, 45 mmol). The mixture was stirred for 18 hours after which 10% HCl was added until pH=4 was achieved. This mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried with MgSO4, filtered, concentrated under reduced pressure to provide the titled compound (4.3 g).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH3:30][N:29]([CH3:31])[CH2:28][CH2:27][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1
Reactant: CN(C)CCCl
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OCCN(C)C)cc(C)c21
Temperature: 90 °C

Procedure:
To the mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (200 mg, 0.8 mmol) in 15 ml DMF was added Cs2CO3 (782 mg, 2.4 mmol), followed by 2-chloro-N,N-dimethylethanamine hydrochloride (116 mg, 0.81 mmol). The mixture was heated to 90° C. for 6 h and quenched by ice water (20 mL). The resulting mixture was extracted with EtOAc (3×20 ml) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was used directly in next step reaction without further purification.