Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[N:6]=[N:5][C:4]=1[CH:16]([CH3:18])[CH3:17].[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=2[CH3:36])=[CH:25][CH:24]=1)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:19][O:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:2][C:3]3[N:7]([C:8]4[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=4[Cl:15])[N:6]=[N:5][C:4]=3[CH:16]([CH3:18])[CH3:17])=[CH:31][C:30]=2[CH3:36])=[CH:27][CH:28]=1)=[O:22]
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2C)cc1
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Temperature: 55 °C

Procedure:
To a solution of 5-chloromethyl-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-[1,2,3]triazole (0.1 g, 0.328 mmol) in dimethylformamide (3 mL) is added 4′-hydroxy-2′methyl-biphenyl-4-carboxylic acid methyl ester (0.079 g, 0.326 mmol) and cesium carbonate (0.21 g, 0.646 mmol). The reaction is heated to 55° C. for 2.5 h and is cooled to room temperature. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in 1N hydrochloric acid and ethyl acetate. The layers are separated and the aqueous is extracted again with ethyl acetate. The organic layers are combined and are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4′-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2′-methyl-biphenyl-4-carboxylic acid methyl ester. ES/MS m/e (35Cl/37Cl) 510.2/512.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].Cl.[CH3:13][C:14]1[C:18]([CH2:19][N:20]2[CH:24]=[C:23]([NH2:25])[CH:22]=[N:21]2)=[C:17]([CH3:26])[O:16][N:15]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:25][C:23]1[CH:22]=[N:21][N:20]([CH2:19][C:18]2[C:14]([CH3:13])=[N:15][O:16][C:17]=2[CH3:26])[CH:24]=1)=[O:8])#[N:2]
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)c2cccc(C#N)c2)cn1
Yield: 15 %

Procedure:
Prepared as in Example 4-8 from 3-cyanobenzoic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 15%. MS M+H calculated 322.6, found 322.3.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@@H:17]([CH3:19])[NH:16][C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:29][C:30]1[S:34][C:33]([CH:35]=[CH:36][S:37](Cl)(=[O:39])=[O:38])=[CH:32][CH:31]=1>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][C@@H:17]([CH3:19])[N:16]([S:37]([CH:36]=[CH:35][C:33]4[S:34][C:30]([Cl:29])=[CH:31][CH:32]=4)(=[O:39])=[O:38])[C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: C[C@@H]1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1S(=O)(=O)C=Cc1ccc(Cl)s1
Reaction time: 8 h
Yield: 2.3 %

Procedure:
(3S,5R)-1-(4-Amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (43 mg, 0.123 mmol), minor epimer from EXAMPLE 88, Part D, is taken up in methylene chloride to this is added triethylamine (0.034 ml, 0.25 mmol) followed by 2-(5-chloro-thiophen-2-yl)-ethenesulfonyl chloride (40 mg, 0.16 mmol), EXAMPLE 3. The reaction is stirred overnight, and the crude material is purified by preparative thin layer chromatography (15% methanol/CH2Cl2). The product (1.4 mg, 2.3%) is isolated as a yellow wax. C21H22ClN5O3S2 MS m/z: 492, 494. 1H NMR (CD3OD) δ8.36 (s, 1H); 8.03 (d, 1H, J=7.5 Hz); 7.61 (s, 1H); 7.49-7.44 (m, 2H); 7.19 (d, 1H, J=3.83 Hz); 6.98 (d, 1H, J=3.75 Hz); 6.76 (d, 1H, J=15.1 Hz); 4.86-4.71 (m, 2H); 4.45-4.39 (m, 1H); 4.13-4.09 (m, 1H); 3.64-3.7 (m, 2H); 1.63 (d, 3H, J=7.09 Hz); 1.33 (d, 3H, J=6.80 Hz).
Reaction SMILES: [O-:1][Cr:2]([O:5][Cr]([O-])(=O)=O)(=[O:4])=[O:3].[Na+:10].[Na+].[S:12](=[O:16])(=[O:15])([OH:14])[OH:13]>>[Cr:2]([OH:5])([OH:4])(=[O:3])=[O:1].[S:12](=[O:14])(=[O:13])([OH:16])[O-:15].[Na+:10]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: O=S(=O)(O)O
Agent: [Na+]
Product: O=S(=O)([O-])O
Product: O=[Cr](=O)(O)O

Procedure:
Disclosed is an improvement on a process in which sodium chromate is reacted with sulfuric acid to produce sodium bichromate and sodium sulfate, and the sodium bichromate is reacted with sulfuric acid to produce chromic acid and sodium bisulfate. In the improvement, the sodium sulfate and sodium bisulfate are reacted with hydrogen chloride to produce sulfuric acid, which is recycled, and sodium chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].Cl[CH:11]([CH3:15])[C:12]([OH:14])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C@H:11]([C:12]([OH:14])=[O:13])[CH3:15])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CC(Cl)C(=O)O
Product: C[C@H](Nc1cc(F)cc(F)c1)C(=O)O

Procedure:
Using the procedure set forth in U.S. Pat. No. 3,598,859 and Example Q above, N-(3,5-difluorophenyl)alanine was prepared using 3,5-difluoroaniline (Aldrich) and 2-chloropropionic acid (Aldrich).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2].C(N(CC)CC)C.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:31][CH:32]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)Nc2ccccc2N)c1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2)cc1
Reaction time: 20 h
Yield: 87.5 %

Procedure:
To a solution of N1-(3-cyanobenzoyl)-1,2-benzenediamine (500 mg, 2.1 mmol), triethylamine (0.44 mL, 3.2 mmol) in methylene chloride (100 mL) was added 4-tert-butylbenzoyl chloride (0.41 mL, 2.1 mmol). After stirring for 20 hours, the reaction mixture was concentrated in vacuo. Chromatography (silica gel, 20% ethyl acetate/80% hexanes) yielded 730 mg (87%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[N:12][C:11]=2[Cl:17])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][O:27][CH2:28][C:29](O)=[O:30].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:17][C:11]1[N:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:9]([NH:8][C@H:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][C:29](=[O:30])[CH2:28][O:27][CH3:26])[CH2:3][CH2:4]1)=[O:18]
Reactant: COCC(=O)O
Reactant: N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
N-(cis-4-Aminocyclohexyl)-2-chloro-5-fluoronicotinamide (837 mg, 2.72 mmol) and triethylamine (1.14 ml, 8.15 mmol) were dissolved in dimethylformamide (20 ml) and 2-methoxy acetic acid (208 μl, 2.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (573 mg, 2.99 mmol) and 1-hydroxybenzotriazole (404 mg, 2.99 mmol) were added. The reaction was stirred under nitrogen at room temperature for 18 h then partitioned between water and ethyl acetate. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting using dichloromethane:methanol (96:4 to 91:9) as eluant to give 2-chloro-5-fluoro-N-{cis-4-[(methoxyacetyl)amino]cyclohexyl}nicotinamide (550 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[CH:33][NH:34]2)=[CH:30][CH:29]=1.[H-].[Na+].[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1.O>C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[CH:33][N:34]2[S:47]([C:44]2[CH:43]=[CH:42][C:41]([O:40][CH3:39])=[CH:46][CH:45]=2)(=[O:49])=[O:48])=[CH:30][CH:29]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc4cc[nH]c4c3)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(S(=O)(=O)n2ccc3ccc(-c4c(N)ncnc4N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
((S)-2-(1-((6-Amino-5-(1H-indol-6-yl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (126 mg, 0.26 mmol) was added to a suspension of sodium hydride (14 mg, 0.37 mmol, 60% dispersion in mineral oil) at 0° C. After 30 min., 4-methoxybenzene-1-sulfonyl chloride was added dropwise. After 10 min. the reaction was let to warm to room temperature. After 1 h the crude was poured over a mixture of ice and water. Ethyl acetate was added and the organic phase was washed with water and brine. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (50-100% hexane/Ethyl acetate) to give 75 mg (42% yield). Purity 97%.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[O:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=3)[CH:21]=2)[NH:16][N:15]=1.[OH:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36].O>CN(C=O)C>[OH:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:28]([C:26]1[O:27][C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[NH2:13])=[CH:24][CH:25]=1)=[O:30]
Reactant: NCc1cccc(O)c1
Reactant: Nc1n[nH]c2ccc(-c3ccc(C(=O)O)o3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1n[nH]c2ccc(-c3ccc(C(=O)NCc4cccc(O)c4)o3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
144 mg (0.75 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) are added to a solution of 146 mg (0.60 mmol) of 5-(3-amino-1H-indazol-5-yl)furan-2-carboxylic acid and 73.9 mg (0.60 mmol) of 3-hydroxybenzylamine in 1 ml of DMF, and the mixture is stirred at room temperature for 4 hours. Water is added to the reaction mixture, which is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated, and the residue is purified by preparative HPLC, giving N-3-hydroxybenzyl-5-(3-amino-1H-indazol-5-yl)furan-2-carboxamide (“62”) as yellowish solid, ESI 349.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([CH3:28])[CH:27]=1)[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][CH3:17])=[CH:27][C:26]=3[CH3:28])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(C)c2c(c1)CCN2
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 156-158° C.; 1H NMR (300 MHz, CDCl3): δ 6.87 (s, 1 H), 6.65 (d, J=1.8 Hz, 1 H), 6.57 (d, J=2.2 Hz, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 4.10-4.02 (m, 1 H), 3.77 (s, 3 H), 3.02 (t, J=7.7 Hz, 2 H), 2.05 (s, 3 H), 1.93-1.73 (m, 2 H), 1.06-0.99 (m, 1 H), 0.95-0.87 (m, 3 H), 0.80-0.73 (m, 1 H), 0.55-0.44 (m, 2 H), 0.34-0.23 (m, 1 H); HRMS (ESI) calcd for C20H25N3O2Cl (M+H)+: 374.1635; found m/z 374.1634.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]([CH:13]=1)=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH3:28])=[C:9]2[C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1)=[O:30])=[O:4].O.[OH-].[Li+]>O1CCOCC1.O>[C:40]([O:39][C:37]([N:34]1[CH2:33][CH2:32][N:31]([C:29]([C:9]2[N:8]3[C:12]([CH:13]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7]3)=[C:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10]=2[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[CH3:28])=[O:30])[CH2:36][CH2:35]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)c1ccn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(C(=O)O)ccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
The compound of step 5 (0.159 g, 0.27 mmol) was dissolved in 2 ml of dioxane, and a solution of lithium hydroxide hydrate (0.034 g, 0.82 mmol) in 0.8 ml water was added. The solution was stirred at 50° C. overnight. The solvents were then evaporated under reduced pressure, the residue was dissolved in 6 ml of water and acidified to pH 1 with 1 N hydrochloric acid. The product was filtered off, dissolved in EA and the solution washed with brine. The organic phase was dried over sodium sulfate, filtered and evaporated to give 0.139 g of the title compound as a light-brown powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][CH2:6][C:5]([CH2:10][CH3:11])([CH2:8][OH:9])[CH2:4][O:3]1.[H-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>O1CCCC1>[CH2:15]([O:9][CH2:8][C:5]1([CH2:10][CH3:11])[CH2:4][O:3][C:2]([CH3:12])([CH3:1])[O:7][CH2:6]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: CCC1(CO)COC(C)(C)OC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(COCc2ccccc2)COC(C)(C)OC1
Reaction time: 1 h

Procedure:
2,2-Dimethyl-5-ethyl-5-hydroxymethyl-1,3-dioxane (10 g.) was added to a stirred suspension of sodium hydride (2.4 g., 50% dispersion in oil) in dry tetrahydrofuran (80 ml.) The mixture was refluxed with stirring for one hour. Benzyl chloride (9.2 ml.) was added and the mixture was refluxed with stirring for three hours. the mixture was poured into water and the aqueous mixture was extracted with ether. The ethereal extract was washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. 5-Benzyloxymethyl-2,2-dimethyl-5-ethyl-1,3-dioxane was obtained as a pale brown oil (15 g.) and was used without further purification.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].[H-].[Na+].Br[CH2:17][C:18]1[C:19]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=2[S:21][CH:22]=1.O>CN(C=O)C.C(OCC)(=O)C>[Cl:27][C:25]1[CH:24]=[CH:23][C:20]2[S:21][CH:22]=[C:18]([CH2:17][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]3=[O:13])[C:19]=2[CH:26]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(Cc2csc3ccc(Cl)cc23)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
To a solution of 1-isopropenylbenzimidazolone (0.3 g, 1.72 mmol) in DMF (5 mL) was added 60% NaH (0.1 g, 2.6 mmol). The reaction mixture was stirred at room temperature for 15 min and added 3-(Bromomethyl)-5-chlorobenzo[b]thiophene (0.54 g, 2.07 mmol). The reaction mixture was heated to 65° C. and stirred at that temperature for 2 h. When the reaction was complete, the mixture was treated with water. The mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC to afford 0.53 g (87%) of the desired product.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH:24]([CH3:26])[CH3:25])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].[CH:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[C:37]([C:38]([O:40][CH3:41])=[O:39])[C:30]=12)=O>ClCCCl.C(O)(=O)C>[CH3:25][CH:24]([CH3:26])[C@@H:16]([NH:15][CH2:27][C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[C:37]([C:38]([O:40][CH3:41])=[O:39])[C:30]=12)[C:17](=[O:18])[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)[C@@H](N)C(=O)N1CCCC1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)N3CCCC3)C(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
A mixture of sodium triacetoxyborohydride (139 mg, 0.657 mmol) and (R)-2-amino-3-methyl-1-(pyrrolidin-1-yl)butan-1-one (84 mg, 0.493 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (100 mg, 0.329 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (128 mg, 85%). [M+H] calc'd for C24H34N4O5, 459; found, 459.6.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C:11]1([CH2:24][C:25]([CH3:27])=[CH2:26])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:28]O.[OH-].[Na+].O>C1COCC1>[CH2:1]([O:8][CH2:9][O:10][C:11]1([CH2:24][CH:25]([CH3:27])[CH2:26][OH:28])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)CC1(OCOCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(CO)CC1(OCOCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-((benzyloxy)methoxy)-4-(2-methylallyl)piperidine-1-carboxylate (3.05 g, 8.1 mmol) in THF (50 mL) was added BH3 solution in THF (32 mL, 1 mol/L, 32.4 mmol), and the mixture was stirred at room temperature for 16 hrs. Then 30% H2O2 solution (30 mL) and 10% sodium hydroxide solution (50 mL) were added slowly to the mixture, and the mixture was stirred for another 2 hrs. The mixture was then treated with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by a standard method to give the product (1.97 g). LC-MS: m/z 394.5 (M+H)+
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]2([C:23](OC(C)(C)C)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)(O)=[O:2].O.[OH:31][N:32]1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:48][C:49]([F:62])([F:61])[O:50][C:51]1[CH:60]=[CH:59][C:54]([C:55](=[N:57]O)[NH2:56])=[CH:53][CH:52]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[OH:31][NH:32][C:23]([C:17]1([S:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][C:1]3[O:2][N:57]=[C:55]([C:54]4[CH:59]=[CH:60][C:51]([O:50][C:49]([F:62])([F:61])[F:48])=[CH:52][CH:53]=4)[N:56]=3)=[CH:13][CH:12]=2)(=[O:15])=[O:16])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)=[O:24]
Reactant: NC(=NO)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)C1(S(=O)(=O)c2ccc(OCCCC(=O)O)cc2)CCOCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NO)C1(S(=O)(=O)c2ccc(OCCCc3nc(-c4ccc(OC(F)(F)F)cc4)no3)cc2)CCOCC1
Reaction time: 2 h
Yield: 88.9 %

Procedure:
Part A. In dry equipment under nitrogen, 4-[[4-(3carboxypropoxy)phenyl]sulfonyl]tetrahydro-2H-pyran-4-carboxylic acid, 1,1-dimethylethyl ester (2.57 g, 6.0 mmol, prepared as in Example 7) was dissolved in dry N,N-dimethylformamide (12 mL), and the remaining reagents were added to the solution in the following order: 1-hydroxybenzotriazole hydrate (1.13 g, 8.4 mmol), triethylamine (1.0 mL, 7.2 mmol), 4-(trifluoromethoxy)benzamidoxime (1.58 g, 7.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.73 g, 9.0 mmol). After 2 hr at 35° C., the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, saturated sodium bicarbonate solution, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography using ethyl acetate/hexanes afforded 3.05 g (81%) of the desired product as a clear glass. ESMS m/z=631 [M+Na]+.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:7]([CH3:15])=[N:8][N:9]([CH2:12][CH:13]=[CH2:14])[C:10]=1[CH3:11])C.CO.[OH-].[Na+]>O>[CH3:15][C:7]1[C:6]([CH2:5][C:4]([OH:16])=[O:3])=[C:10]([CH3:11])[N:9]([CH2:12][CH:13]=[CH2:14])[N:8]=1
Reactant: C=CCn1nc(C)c(CC(=O)OCC)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCn1nc(C)c(CC(=O)O)c1C
Yield: 48 %

Procedure:
5 grams of 3,5-dimethyl-1-allyl-pyrazol-4-acetic acid-ethyl ester were mixed with 25 milliliters methanol and 10 milliliters water. The mixture was heated to the boiling temperature and held there while 11.3 milliliters 2n aqueous sodium hydroxide were added dropwise at such rate, that the pH of 10 was maintained. The reaction mixture thus obtained was worked up by the procedure described in Example (1b). 21. grams 3,5-dimethyl-1-allyl-pyrazol-4-acetic acid melting at 139°-140° C. were obtained representing a yield of 48%.
Reaction SMILES: CS(C)=O.[H-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>C(OCC)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:15]#[N:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CC1(c2ccc(Cl)cc2)CCOCC1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Into a round-bottom flask under argon fitted with an addition funnel and thermometer was added anhydrous dimethylsulfoxide (60 mL) and sodium hydride (1.17 g, 48.8 mmol, 95%). Then a solution of (4-chlorophenyl)acetonitrile (3.37 g, 22.2 mmol) and 2-bromoethyl ether (90%, 3.41 mL, 24.4 mmol) in diethyl ether (15 mL) was added slowly, while maintaining the reaction temperature at 20–30° C. The reaction mixture was maintained at room temperature for overnight. The reaction mixture was carefully quenched with water (50 mL) and then extracted with hexane (3×100 mL). The organic extracts were combined, washed with water (3×75 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to give a pale yellow oil. The oil was purified by column chromatography on silica gel using hexane/ethyl acetate (80:20) to give 4.7 g of 4-(4-chlorophenyl)tetrahydropyran-4-carbonitrile, as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 2.00–2.15 (m, 4H); 3.89 (dt, 2H, J1=12.6 Hz, J2=3 Hz); 4.05–4.11 (m, 2H); 7.37–7.45 (m, 4H); 13C NMR (CDCl3, 300 MHz): δ 36.66 (2C), 41.51, 64.98 (2C), 121.40, 127.03, 129.37, 134.31, 138.46.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[C:7]([O:11]C)[C:8]=1[CH2:9][CH3:10].B(Br)(Br)Br>>[CH2:9]([C:8]1[C:7]([OH:11])=[CH:6][C:5]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[OH:2])[CH3:10]
Reactant: CCc1c(OC)cc(C=Cc2ccccc2)cc1OC
Agent: BrB(Br)Br
Product: CCc1c(O)cc(C=Cc2ccccc2)cc1O
Yield: 91 %

Procedure:
This material was synthesized from 1-(3,5-dimethoxy-4-ethylphenyl)-2-phenylethene and BBr3 in 91% yield by the same method as described in example 6.