Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:28])[N:25]([CH3:27])[CH3:26])=[CH:20][C:19]=4[Cl:29])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1.[C:31]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:28])[N:25]([CH3:27])[CH3:26])=[CH:20][C:19]=4[Cl:29])[CH3:31])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C(=O)c1ccc(NC(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To solution of 8-bromo-N-(2-chloro-4-(dimethylcarbamoyl)phenyl)-4,5-dihydro-benzo[b]thieno[2,3-d]oxepine-2-carboxamide (29.0 g, 57.3 mmol), Cs2CO3 (37.40 g, 114.7 mmol) in DMF (600 mL), CH3I (30 mL, 479.8 mmol) was slowly added. The reaction mixture was stirred at room temperature overnight. Concentration removed about 200 mL of DMF, and then water (100 mL) was added to the mixture. The resulting precipitate was filtered, washed with water, dried to give 8-bromo-N-(2-chloro-4-(dimethylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (29.50 g, yield: 99%). ESI-MS: 519.4. 1H NMR (DMSO-d6, 400 MHz): δ7.72-7.68 (m, 2H, ArH), 7.52-7.49 (m, 1H, ArH), 7.30-7.20 (m, 3H, ArH), 6.76 (s, 1H, ═CH), 4.19 (s, 2H, CH2), 3.29 (s, 3H, CH3), 3.00 (s, 3H, CH3), 2.96 (s, 2H, CH2), 2.93 (s, 3H, CH3).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.CC([O-])(C)C.[K+].[CH2:18]([OH:22])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([O:22][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH2:11])[N:3]=1)[CH2:19][CH2:20][CH3:21]
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: CCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCOc1nc(N)c2nc[nH]c2n1
Temperature: 170 °C
Yield: 70 %

Procedure:
2-chloroadenine (1.53 g, 9.03 mmol) was divided among three microwave vials (10-20 mL), each containing 1-butanol (10 mL) and t-BuOK (5 mL, 1M in THF). Each vial was heated to 170° C. for 40 minutes. The three reaction mixtures were combined, the solvent was removed by rotary evaporation and the product was purified on flash column eluting 10% methanol in ethylacetate. Evaporation of solvent gave 1.33 g (70%) of 2-butoxy-9H-purin-6-amine (6) as an off white solid. 1H NMR (DMSO) δ, 0.919 (t, 3H), 1.39 (m, 2H), 1.62 (m, 2H), 4.09 (t, 2H), 6.00 (s, 2H), 7.44 (s, 1H). LCMS: m/z for C9H13N5O++H observed 208.1 at 1.34 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[N:12]3)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[N:12]2)(=[O:29])=[O:28]
Reactant: OC(c1ccccc1)c1ccc2nccnc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(c1ccccc1)c1ccc2nccnc2c1
Yield: 100 %

Procedure:
To a stirred and cooled (0° C.) mixture of 12 parts of intermediate 3, namely α-phenyl-6-quinoxalinemethanol, 213 parts of dichloromethane and 15.4 parts of N,N-diethylethanamine was added a solution of 8.8 parts of methanesulfonyl chloride in 26.6 parts of dichloromethane under nitrogen atmosphere. After stirring overnight at room temperature, the reaction mixture was evaporated, yielding 54 parts (100%) of α-phenyl-6-quinoxalinemethanol methanesulfonate (ester) as an oily residue (interm. 4).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].[C:28](Cl)(=[O:30])[CH3:29]>C1COCC1>[C:28]([O:18][C:17]1[C:9]([Br:8])=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH:12]=[CH:11]2)(=[O:30])[CH3:29]
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)c(O)ccc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
Triethylamine (0.29 g, 2.8 mmol) was added to a solution of 4-bromo-1-(phenylsulfonyl)-1H-indol-5-ol (Intermediate 21, 0.67 g, 1.9 mmol) and acetyl chloride (0.22 g, 2.8 mmol) in THF (10 mL). The mixture was stirred for 10 minutes at room temperature and evaporated. The residue was partitioned between DCM and saturated aqueous NaHCO3. The reaction mixture was washed with saturated aqueous NaHCO3, and the organic phase was dried (MgSO4) and evaporated to give the title compound (0.6 g) as a red solid. MS m/z 394/396 [M+H]+.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.[NH2:14][C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.C([OH:24])C>>[OH:24][C:16]1([CH3:21])[CH:17]=[CH:18][CH:19]=[CH:20][CH:15]1[N:14]=[CH:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:2]=1
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: Cc1ccccc1N
Reactant: CCO
Product: CC1(O)C=CC=CC1N=Cc1cccc2ccccc12
Temperature: 70 °C

Procedure:
3.44 g (20.0 mmol) of 2-hydroxy-1-naphthaldehyde was dissolved in 50 ml ethanol under heating, and 2.14 g (20.0 mmol) of o-toluidine was added. After stirring under reflux at 70° C. for 1 hour, completion of the reaction was confirmed by TLC. The solution was concentrated with an evaporator to about 30 ml, whereupon a crystal was formed, which was filtered by Kiriyama funnel. Drying under reduced pressure at 25° C. for 24 hours gave 2-hydroxy-1-naphthylmethylidene-2-methylaniline (hereinafter, also referred to as “HNOT”) as a yellow crystal (4.24 g, 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH3:34][C@@H:35]1[CH2:40][NH:39][CH2:38][C@H:37]([CH3:41])[NH:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:39]2[CH2:38][C@H:37]([CH3:41])[NH:36][C@H:35]([CH3:34])[CH2:40]2)=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)O)c1C)C(=O)N2
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)N3C[C@@H](C)N[C@@H](C)C3)c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[5-(2,6-dimethyl-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.26 mmol), (2R,6S)-2,6-dimethyl-piperazine (37 mg, 1.2 eq.), HOBt (50 mg, 1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMF (0.2 M) was stirred at rt for overnight. The reaction was concentrated, diluted with DCM, washed with water, filtered and concentrated to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C@@H:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([Cl:30])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7]1.CN1CCOCC1.[C:42](Cl)(=[O:45])[CH2:43][CH3:44]>C(Cl)Cl>[Cl:30][C:22]1[CH:21]=[C:20]([C@@H:13]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]([NH:11][C:8]2[CH:9]=[CH:10][N:6]([CH2:5][C:4]3[CH:32]=[CH:33][CH:34]=[C:2]([NH:1][C:42](=[O:45])[CH2:43][CH3:44])[CH:3]=3)[N:7]=2)=[O:31])[CH:25]=[CH:24][C:23]=1[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CCC(=O)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(N)c3)n2)cc1Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
N-[1-(3-Amino-benzyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide prepared in example 58 (110 mg, 0.22 mmol) was dissolved in methylene chloride (2 mL) and N-methyl-morpholine (26 μL, 0.24 mmol) was added. Propionyl chloride (19 μL, 0.22 mmol) was added and the reaction stirred at 25° C. for 30 min. The reaction was concentrated in vacuo to give a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-propionylamino-benzyl)-1H-pyrazol-3-yl]-propionamide (75 mg, 61%) as a white powder: ESI-LRMS m/e calcd for C28H33ClN4O4S [M+] 556.19, found 557.27 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.19 (m, 2H, CH2), 1.23 (t, J=7.5 Hz, 3H, CH3), 1.41-1.92 (m, 8H, 4×CH2), 2.15-2.27 (m, 1H, CH), 2.36 (m, 2H, NCOCH2), 3.25 (s, 3H, SO2CH3), 3.56 (t, J=7.75 Hz, 1 H, CH), 5.09 (s, 2H, NCH2), 6.68 (d, J=2.0 Hz, 1H, Ar), 6.86 (d, Jo=7.8 Hz, 1H, Ar), 7.18-7.23 (m, 1H, Ar), 7.24 (s, 1H, NH), 7.30 (d, J=2.0 Hz, 1H, Ar), 7.33-7.42 (m, 2H, Ar), 7.44 (d, Jo=8.2 Hz. 1H, Ar), 7.58 (s, 1H, Ar), 8.04 (d, Jo=8.2 Hz. 1H, Ar), 8.05 (brs, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[CH3:16][O:17][C:18]1[CH:28]=[CH:27][C:21](/[CH:22]=[CH:23]/[C:24]([Cl:26])=O)=[CH:20][CH:19]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:26].[F:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:24](/[CH:23]=[CH:22]/[C:21]3[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:28][CH:27]=3)=[N:15][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)ccc1Nc1ccccn1
Reactant: COc1ccc(/C=C/C(=O)Cl)cc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: COc1ccc(/C=C/c2nc3cc(F)ccc3n2-c2ccccn2)cc1

Procedure:
Free base of the titled compound was prepared from 4-fluoro-2-amino-N-(2-pyridyl)aniline and (E)-4-methoxycinnamoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/ethanol to give the titled compound.
Reaction SMILES: [O:1]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H-].[Na+]>>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:33][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(Oc1ccccc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)(Oc1ccccc1)C(=O)OCC
Yield: 62.1 %

Procedure:
Reaction and post-treatment were carried out according to Reference example 12(a) using 2.81 g of diethyl phenoxymalonate, 2.59 g of 4-benzyloxybenzyl chloride and 530 mg of sodium hydride (55% oil suspension) to obtain 3.10 g of the desired compound as a syrup.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1)(=[O:4])=[O:3].[H][H]>CCO.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[N:7][CH:8]=1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(N)cn1
Yield: 33.2 %

Procedure:
A solution of the product from Step 2 (0.374 g, 1.72 mmol) in 95% EtOH (90 ml) was treated with 0.5 g of 10% palladium-on-carbon catalyst and hydrogenated at atmospheric pressure. The reaction was stopped when the theoretical amount of hydrogen had been consumed. The mixture was filtered through celite and the solid was extracted with warm (2:1) MeOH--CH2 cl2. The combined extracts and filtrate were concentrated and the residue was crystallized from MeOH to give 0.107 g of the titled product, mp 199°-202° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[NH2:16].N1C=CC=CC=1.[C:24](Cl)(Cl)=[O:25].[C:28]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:32][C:31]([CH2:34][OH:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[NH:16][C:24]([O:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:33][CH:32]=1)=[O:25])=[O:17]
Reactant: COC(=O)c1cc(-c2ccccc2)ccc1N
Reactant: O=C(Cl)Cl
Reactant: OCc1ccc(-c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(-c2ccccc2)ccc1NC(=O)OCc1ccc(-c2ccccc2)cc1
Temperature: 90 °C

Procedure:
To a solution of methyl-5-phenyl-2-aminobenzoate (0.40 g, 1.76 mmol) and pyridine (0.285 mL, 3.52 mmol) in toluene (7 mL) at room temperature under argon was added 20% phosgene in toluene (1.32 mL, 2.55 mmol) and the mixture was heated at 90° C. for 1 h. The mixture was filtered, and the filtrate was concentrated to dryness. The crude material was dissolved in toluene (10 mL), biphenyl-4-methanol (0.270 g, 1.46 mmol) and DMAP (0.018 g, 0.146 mmol) were added and the mixture was heated at 90° C. for 18 h. The solvent was evaporated to dryness to give 0.51 g of 4-(biphenyl-4-ylmethoxycarbonylamino)-biphenyl-3-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8]O)[N:3]=1.S(Cl)([Cl:12])=O>ClCCl>[ClH:12].[Cl:12][CH2:8][N:4]1[C:5]([CH3:7])=[CH:6][C:2]([CH3:1])=[N:3]1
Reactant: Cc1cc(C)n(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C)n(CCl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.63 g of 3,5-dimethyl-1H-pyrazole-1-ylmethanol was dissolved to 25 ml of dichloromethane. 1.2 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 0.93 g of 1-(chloromethyl)-3,5-dimethyl-1H-pyrazole hydrochloride.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:3]1>[Pd].C(O)C>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5]1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)O1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CN(c2ccc(N)cc2)C[C@H](C)O1
Temperature: 50 °C
Reaction time: 6 h
Yield: 61.6 %

Procedure:
A mixture of cis-2,6-dimethyl-4-(4-nitrophenyl)morpholine (Intermediate 68, 8.0 g) and 10% palladium on carbon (800 mg) in ethanol (100 mL) was stirred under an atmosphere of hydrogen at 50° C. for 6 h. The mixture was filtered and the filtrate was concentrated by evaporation to give the title compound (4.3 g, 100%) as an oil which subsequently solidified; 1H NMR δ (CDCl3): 6.79 (2H, d), 6.65 (2H, d), 3.81 (2H, m), 3.25 (2H, d), 2.33, (2H, t), 1.23 (6H, d); MS m/e MH+: 207.
Reaction SMILES: O.[O:2]=[CH:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[C:14]([OH:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([OH:24])=[O:23])([C:18]([OH:20])=[O:19])[OH:17].[NH3:27].[SiH4]>O>[C:14]([O-:26])(=[O:25])[CH2:15][C:16]([CH2:21][C:22]([O-:24])=[O:23])([C:18]([O-:20])=[O:19])[OH:17].[NH4+:27].[NH4+:27].[NH4+:27].[O:2]=[CH:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: N
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [SiH4]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [NH4+]

Procedure:
Aqueous triammonium citrate-dextrose (1:6) binders were prepared by the following general procedure: Powdered dextrose monohydrate (915 g) and powdered anhydrous citric acid (152.5 g) were combined in a 1-gallon reaction vessel to which 880 g of distilled water was added. To this mixture were added 265 g of 19% aqueous ammonia with agitation, and agitation was continued for several minutes to achieve complete dissolution of solids. To the resulting solution were added 3.3 g of SILQUEST A-1101 silane to produce a pH˜8-9 solution (using pH paper), which solution contained approximately 50% dissolved dextrose monohydrate and dissolved ammonium citrate solids (as a percentage of total weight of solution); a 2-g sample of this solution, upon thermal curing at 400° F. for 30 minutes, would yield 30% solids (the weight loss being attributed to dehydration during thermoset binder formation). Where a silane other than SILQUEST A-1101 was included in the triammonium citrate-dextrose (1:6) binder, substitutions were made with SILQUEST A-187 Silane, HYDROSIL 2627 Silane, or Z-6020 Silane. When additives were included in the triammonium citrate-dextrose (1:6) binder to produce binder variants, the standard solution was distributed among bottles in 300-g aliquots to which individual additives were then supplied.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=2)[C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+:23]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)[C:3]=1[C:4]([O-:6])=[O:5].[Na+:23]
Reactant: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)O)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)[O-])n1
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
1.7 g of 2-chloro-6-[(4,6-dimethoxy-2-pyrimidinyl)thio]benzoic acid dissolved in 10 ml of tetrahydrofuran was gradually dropwise added to a suspension of 0.2 g of 60% sodium hydride in 20 ml of tetrahydrofuran. The mixture was reacted under stirring for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure. Isopropyl ether was added to the residue, and a solid was collected by filtration. The solid was dried to obtain 1.8 g of the desired compound as white powder.
Reaction SMILES: [B]1OC2C(=CC=CC=2)O1.[F:10][C:11]([F:41])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:12](=[O:34])/[CH:13]=[CH:14]/[C@H:15]1[CH2:20][CH2:19][O:18][C:17](=[O:21])[N:16]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]>C1(C)C=CC=CC=1>[F:41][C:11]([F:10])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH:12]([OH:34])/[CH:13]=[CH:14]/[C@H:15]1[CH2:20][CH2:19][O:18][C:17](=[O:21])[N:16]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]
Reactant: CC(C)OC(=O)CCCCCCN1C(=O)OCC[C@@H]1/C=C/C(=O)C(F)(F)c1ccccc1
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)CCCCCCN1C(=O)OCC[C@@H]1/C=C/C(O)C(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of catecholborane (107 mg) in toluene (1 mL) was added (S)-2-methyl-CBS-oxaborolidine (1M in toluene, 0.89 mL) under N2 at −78° C. and the mixture was stirred at the temperature for 1 h. Isopropyl 7-{(4R)-4-[(1E)-4,4-difluoro-3-oxo-4-phenylbut-1-en-1-yl]-2-oxo-1,3-oxazinan-3-yl}heptanoate (200 mg) in toluene (2 mL) was added via a cannula slowly and the mixture was stirred for an additional hour and quenched with 1N HCl. The mixture was allowed to warm to room temperature and extracted with DCM (2×). The organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography (80–100% ethyl acetate/hexanes) to give the title compound. MS (+ESI): m/z 454 (M+1)+.
Reaction SMILES: [Cl:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[N+](C1C=CC([O:38][C:39](=O)[O:40][CH2:41][C:42]2[O:43][C:44](=[O:48])[O:45][C:46]=2[CH3:47])=CC=1)([O-])=O>CN(C=O)C>[CH3:47][C:46]1[O:45][C:44](=[O:48])[O:43][C:42]=1[CH2:41][O:40][C:39]([N:19]1[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:24][CH:18]1[C:16](=[O:17])[NH:15][CH:3]([CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1)[CH:2]([Cl:1])[CH3:28])=[O:38]
Reactant: Cc1oc(=O)oc1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCC1CCNC(C(=O)NC(C(C)Cl)C2OC(SC)C(O)C(O)C2O)CC1
Solvent: CN(C)C=O
Product: CCCC1CCC(C(=O)NC(C(C)Cl)C2OC(SC)C(O)C(O)C2O)N(C(=O)OCc2oc(=O)oc2C)CC1
Reaction time: 16 h
Yield: 33.6 %

Procedure:
The title compound from example 47 (54 mg, 0.12 mmol) was dissolved in dry DMF (5 mL), then solid KHCO3 (25 mg, 0.25 mmol) and carbonic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester 4-nitro-phenyl ester (40 mg, 0.14 mmol prepared as described in F. Sakamoto, et. al, Chem. Pharm. Bull. 1984, 32 (6), 2241-2348) were added. The resulting mixture was stirred for 16 h, and the solvents were removed under reduced pressure, then the residue was purified by chromatography on silica with 5% MeOH/DCM to provide the title compound (24 mg, 33%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[S:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH3:25])(=[O:28])=[O:27]
Reactant: CCCCCCCC(=O)NCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)NCCCCCCOS(C)(=O)=O
Yield: 107.2 %

Procedure:
To a solution of 2.00 g (7.37 mmol) of N-(6-hydroxyhexyl)caprylamide and 1.23 ml of triethylamine in 50 ml of methylene chloride was added 0.68 ml (8.84 mmol) of methanesulfonyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was washed with hexane to obtain 2.54 g of the desired compound (98.6%, colorless powder), mp: 62.0°-63.0° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14].C(O)(=O)C>C1(C)C=CC=CC=1.C(OC(C)C)(C)C>[CH3:14][C:13]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([CH3:9])=[CH:11][CH:12]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NCc1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Product: Cc1ccc(C)n1Cc1ccccc1
Yield: 92.3 %

Procedure:
A mixture of benzylamine (10.7 g, 0.10 mol) and 2,5-hexanedione (11.4 g, 0.10 mol) and acetic acid (2.5 mL, 0.04 mol) in 50 mL toluene was heated at reflux under a Dean-Stark trap for 0.75hr. The resulting mixture was concentrated in vacuo to provide a viscous oil. The oil was dissolved in several volumes of isopropyl ether, then the solution was washed with 10% aqueous hydrochloric acid. The ether solution was dried and concentrated in vacuo to provide 2,5-dimethyl-1-benzylpyrrole (17.1 g, 92%) as a thick oil which eventually crystallized. The product was chromatographically homogenous and displayed an NMR spectrum consistent with its assigned structure. ##STR15## Preparation of Ethyl 2,5-Dimethyl-1-benzylindol-3-oyl-acetoacetate (I-3, a representative Friedel-Crafts acylation reaction):