Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([SH:12])[N:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:20]1[CH2:23][CH2:22][CH2:21]1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH:20]2[CH2:23][CH2:22][CH2:21]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: BrC1CCC1
Reactant: CCOC(=O)c1cccc(S)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cccc(SC2CCC2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
After 6-mercapto-pyridine-2-carboxylic acid ethyl ester (0.40 g, 2.18 mmol) was dissolved in CH3CN (9 mL), Cs2CO3(2.667 g, 6.54 mmol) and bromo cyclobutane (0.385 mL, 3.27 mmol) were added thereto, and the mixture was stirred at 50° C. for 18 hours. After the termination of the reaction, the reactant was filtered, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (0.481 g, 92%).
Reaction SMILES: [OH-].[K+].[C:3]([C:5](=[CH:9][C:10]1[CH:15]=CC(OC)=[C:12](OC)[CH:11]=1)[C:6](O)=O)#[N:4].S([CH2:30][N+:31]#[C-])(C1C=CC(C)=CC=1)(=O)=O.Cl.[CH2:34]([CH2:37][O:38][CH3:39])[O:35][CH3:36]>O>[CH3:36][O:35][C:34]1[CH:15]=[C:10]([C:9]2[C:5]([C:3]#[N:4])=[CH:6][NH:31][CH:30]=2)[CH:11]=[CH:12][C:37]=1[O:38][CH3:39]
Reactant: COc1ccc(C=C(C#N)C(=O)O)cc1OC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COCCOC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2c[nH]cc2C#N)cc1OC
Reaction time: 0.5 h
Yield: 92 %

Procedure:
12.62 g (225.0 m mol) of potassium hydroxide was added to 100 ml of dimethoxyethane. The solution was then cooled at a temperature from 0° C. to 10° C., was fed with 11.66 g (50.0 m mol) of alpha-cyano-3,4-dimethoxycinnamic acid, and was stirred for 30 min. at the same temperature. The liquid was then fed dropwise for one hour, at room temperature, with a solution of 10.25 g (52.5 m mol) of tosyl methylisocyanide in 60 ml of dimethoxyethane. When the dropping ended, the mixed liquid was stirred for two hours at room temperature till the reaction completed. Then, to the reaction mixture 70 ml of water was added and neutralized to pH 8 by 10% HCl. From the neutralized mixture, dimethoxyethane was distilled off under reduced pressure, then 800 ml of water was further added thereto, and the mixture was stirred for 30 min. to precipitate crystals. The crystals were then filtered off and washed with water and dried. As the result, 10.50 g of 3-(3,4-dimethoxyphenyl)-4-cyanopyrrole was obtained. Yield 92.0%, Melting point 212°-214° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[O:29][C:30]([CH:33]6OCC[O:34]6)=[CH:31][CH:32]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:38]>C1COCC1>[ClH:38].[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[O:29][C:30]([CH:33]=[O:34])=[CH:31][CH:32]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cn2ncc3cc(Nc4ncnc5ccc(-c6ccc(C7OCCO7)o6)cc45)ccc32)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc5c(cnn5Cc5ccccc5)c4)c3c2)o1
Yield: 91 %

Procedure:
(1-Benzyl-1H-indazol-5-yl)-(6-(5-(1,3)-dioxolan-2-yl-furan-2-yl)-quinazolin-4-yl)amine (2.0 g) and hydrochloric acid (2N, 50 ml) were stirred in THF (20 ml) for 16 hr. The resulting precipitate was filtered, washed with water and dried at 60° C. in vacuo to give the product as a yellow solid (1.80 g, 3.73 g, 91%); δH [2H6]-DMSO 12.30 (1H, s), 9.79 (1H, s), 9.62 (1H, s), 8.85 (1H, s), 8.62 (1H, m), 8.31 (1H, s), 8.19 (1H, m), 8.10 (1H, d), 7.90 (2H, m), 7.78 (2H, m), 7.40 (5H, m), 5.80 (2H, s).
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=[C:9]([CH2:26]O)[N:8]=1)([OH:3])=[O:2].S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[ClH:30].[C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=[C:9]([CH2:26][Cl:30])[N:8]=1)([OH:3])=[O:2]
Reactant: CCCCCCCCCCCCOc1ccc(CO)nc1/C=C/CC(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOc1ccc(CCl)nc1/C=C/CC(=O)O
Product: Cl
Reaction time: 1 h

Procedure:
2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-(hydroxymethyl)pyridine (250 mg, 0.662 mmol) was dissolved in dry toluene (10 mL) under an argon atmosphere and cooled to 0∞C. Thionyl chloride (0.50 mL, 6.85 mmol) was slowly added and the solution was stirred at 0∞C. for 30 minutes followed by 1 h at room temperature. The solvent and excess thionyl chloride were removed at reduced pressure. The crude hydrochloride salt was then used directly in the next step without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[C:13]4[C:19]5[C:32]([CH2:33][CH2:34][C:12]4=[CH:11][C:10]=3[CH:9]=[N:8]2)=[C:31]([O:35][CH3:36])[C:30]2[C:29](=[O:37])[C:28]3[C:23](=[CH:24][C:25]([OH:40])=[C:26]([CH3:39])[C:27]=3[OH:38])[C:22](=[O:41])[C:21]=2[C:20]=5[OH:42])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[C:46]([O:48][CH3:49])=[O:47].C(O)(=O)C>O>[C:1]1([N:7]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[C:13]4[C:19]5[C:32]([CH2:33][CH2:34][C:12]4=[CH:11][C:10]=3[CH:9]=[N:8]2)=[C:31]([O:35][CH3:36])[C:30]2[C:29](=[O:37])[C:28]3[C:23](=[CH:24][C:25]([O:40][C:46]([O:48][CH3:49])=[O:47])=[C:26]([CH3:39])[C:27]=3[OH:38])[C:22](=[O:41])[C:21]=2[C:20]=5[OH:42])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Cl
Reactant: COc1c2c(c(O)c3c1C(=O)c1c(cc(O)c(C)c1O)C3=O)-c1c(cc3cnn(-c4ccccc4)c(=O)c3c1O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Oc1cc2c(c(O)c1C)C(=O)c1c(OC)c3c(c(O)c1C2=O)-c1c(cc2cnn(-c4ccccc4)c(=O)c2c1O)CC3
Yield: 84 %

Procedure:
A solution of 281.2 mg (0.5 mmol) of 2-phenyl-10,12,15,16-tetrahydroxy-8-methoxy-11-methyl-9,14-dioxo-6,7,9,14-tetrahydronaphthaceno[1,2-g]phthalazin-1-one (5) in 2 m of 2 M sodium hydroxide solution is diluted with 5 m of water. This solution is equilibrated at 5° C. and, while stirring, 2 m of methyl chloroformate are added. The mixture is subsequently stirred at room temperature for 30 min and then neutralized with acetic acid. The precipitated product is filtered off with suction to obtain 260 mg of the product. The yield is 84% of theory.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:21])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]([F:20])([F:19])[F:18])[CH:9]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH:24]1([CH2:23][N:6]2[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:9][N:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][C:17]([F:20])([F:18])[F:19])[C:7]2=[O:21])[CH2:26][CH2:25]1
Reactant: BrCC1CC1
Reactant: CC(C)Cc1cn(-c2ccccc2OC(F)(F)F)c(=O)[nH]1
Product: CC(C)Cc1cn(-c2ccccc2OC(F)(F)F)c(=O)n1CC1CC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 4-isobutyl-1-(2-trifluoromethoxy-phenyl)-1,3-dihydro-imidazol-2-one (obtained in example 44, 60 mg) by alkylation with bromomethylcyclopropane (35 mg). 3-Cyclopropylmethyl-4-isobutyl-1-(2-trifluoromethoxy-phenyl)-1,3-dihydro-imidazol-2-one was obtained as a light yellow oil (11 mg). MS (ESI): 355.2 (MH+).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[C:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)C(Cl)=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:37]([N:39]1[C:51]2[CH:50]=[CH:49][C:48]([NH2:52])=[CH:47][C:46]=2[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH3:38]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11](=[O:13])[CH:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:8]([C:18]([NH:52][C:48]2[CH:49]=[CH:50][C:51]3[N:39]([CH2:37][CH3:38])[C:40]4[C:45]([C:46]=3[CH:47]=2)=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, staring from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 43% purity by LC/MS. MS(ESI+): m/z=571.2.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[C:10]([N:16]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][C@H:18]([OH:20])[CH3:19])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1.N1C=CC=CC=1>ClCCl>[CH2:21]([N:16]([CH2:17][C@H:18]([OH:20])[CH3:19])[C:10]1[C:9]([NH:8][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=[C:12]([Br:15])[N:11]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C[C@@H](O)CN(Cc1ccccc1)c1nc(Br)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Br)nc1N(Cc1ccccc1)C[C@@H](C)O
Temperature: 40 °C
Yield: 55.7 %

Procedure:
Acetic anhydride (0.623 mL, 6.60 mmol) was added to a solution of crude (R)-1-((3-amino-6-bromopyridin-2-yl)(benzyl)amino)propan-2-ol (2.22 g, 6.60 mmol) and pyridine (1.60 mL, 19.8 mmol) in dichloromethane (60 mL). The reaction mixture was then heated to 40° C. for 39 h. The reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in toluene (ca. 100 mL), which was then concentrated under reduced pressure in order to remove residual pyridine. The crude product was purified by column chromatography on silica gel (eluting with 2:1 dichloromethane-ethyl acetate followed by 3:2 dichloromethane-ethyl acetate) to afford (R)-N-(2-(benzyl(2-hydroxypropyl)amino)-6-bromopyridin-3-yl)acetamide (1.39 g, 56% yield). MS (ESI, pos. ion) m/z 378, 380 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:27][C:28]([OH:30])=[O:29]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:27][C:28]([OH:30])=[O:29])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Reactant: O=C(O)CBr
Product: O=C(O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid gave the title compound.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([OH:18])=O)[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:20]([C:23]1[CH:36]=[CH:35][C:26]([CH2:27][O:28][C:29]([NH:31][CH2:32][CH2:33][SH:34])=[O:30])=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>C1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:34][CH2:33][CH2:32][NH:31][C:29]([O:28][CH2:27][C:26]2[CH:35]=[CH:36][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)=[O:30])=[O:18])[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
1.00 9 (3,48 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-carboxymethyl-2-azetidinone and 1.07 g (4.8 mmole) of 2-(p-nitrobenzyloxycarbonyl-amino)ethanethiol were dissolved in 20 ml of benzene. To this solution were added 861 mg (4.18 mmole) of dicyclohexylcarbodiimide and 10 mg (0.082 mmole) of 4-dimethylaminopyridine, at room temperature with stirring. The mixture was stirred for 2 hours, after which the insolubles which had formed were filtered off and the resulting filtrate was concentrated to dryness by evaporation under reduced pressure, The residue was purified by column chromatography through 40 g of silica gel, to give 1.59 g (yield 87%) of the desired product as an oil from the fractions eluted with a 1:1 volume mixture of benzene and ethyl acetate.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH2:28][N:29]([CH3:42])[S:30]([C:33]1[S:34][C:35]([Cl:41])=[C:36]([N+:38]([O-])=O)[CH:37]=1)(=[O:32])=[O:31]>>[Cl:41][C:35]1[S:34][C:33]([S:30](=[O:32])(=[O:31])[N:29]([CH2:28][CH2:27][OH:26])[CH3:42])=[CH:37][C:36]=1[NH:38][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)=[N:6][C:7]=12)=[O:14]
Reactant: CN(CCO)S(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(CCO)S(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-methyl-amide (example B.21) according to general procedure II.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([N:16]1[CH2:21][CH2:20][C@@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][C@H:17]1[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[C:11]#[C:12][C:13]([CH3:15])=[CH2:14])C1C=CC=CC=1>CO.[Ni]>[OH:8][CH2:9][C@H:10]([N:16]1[CH2:21][CH2:20][C@@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][C@H:17]1[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=1)[CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15]
Reactant: C=C(C)C#C[C@H](COCc1ccccc1)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [Ni]
Solvent: CO
Product: CC(C)CC[C@H](CO)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of methyl {(2S,4R)-1-{(1R)-1-[(benzyloxy)methyl]-4-methylpent-4-en-2-yn-1-yl}-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Example 28, 1.4 g, 2.80 mmol) in MeOH (15 ml) was hydrogenated over Raney nickel (˜1 g) at 50 psi on the Parr overnight at room temperature. MS showed mostly desired product, but still some alkene. Extra Raney nickel (˜1 g) was added and the hydrogenation was continued for a further 5 hours. MS showed the reduction to be almost complete. The catalyst was removed by filtration, washing with MeOH. The filtrate was evaporated. The residue was partitioned between DCM and water. The aqueous layer was extracted with DCM (×3). The combined extracts were dried (Na2SO4), filtered and evaporated to give the alkane (1.16 g) as an oil. This material was used without further purification. A solution of benzyl ether (above, 1.16 g, 2.294 mmol) in acetic acid (25 ml) was hydrogenated at 50 psi over 10% palladium on carbon (150 mg, 0.141 mmol) on the Parr at room temperature overnight. The catalyst was removed by filtration—washing with MeOH. The filtrate was evaporated—azeotroping with PhMe (×2). The residue was partitioned between DCM and saturated aqueous NaHCO3. The aqueous layer was extracted with DCM (×3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, 10-20-40% EtOAc/isohexanes) to give the alcohol. (795 mg) as an oil. This material was hydrolysed with NaOH in MeOH to give {(2S,4R)-1-[(1R)-1-(hydroxymethyl)-4-methylpentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetic acid, M/Z 402 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([CH2:12][CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:12][CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:14][CH:15]=2)=[CH:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCC(Oc1ccc(O)cc1)C(=O)NC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(Oc1ccc(OCc2ccc(C#N)cc2)cc1)C(=O)NC

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-butyramide with 4-bromomethyl-benzonitrile in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(4-cyano-benzyloxy)-phenoxy]-N-methyl-butyramide as a white solid; MS: m/e=325 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:8]=[O:9]>[Ag]=O.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:8]([OH:1])=[O:9])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [OH-]
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: O=[Ag]
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)O)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Sodium hydroxide (12g.; 0.3m) was dissolved in 200 ml. of water, silver oxide (11.6g.; 0.05m) added and the resulting mixture warmed to 50°C, 3-methoxy-4-benzyloxybenzaldehyde (12.1g; 0.05m) added in one portion and the mixture heated to 60°C with stirring for 1 hour, stirred 18 hours at room temperature, filtered and acidified to give the acid which was recrystallised from glacial acetic acid, m.p. 172°-3°C.
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=1)[O:13][CH:12]([C:23]([F:26])([F:25])[F:24])[C:11]([C:27]([OH:29])=[O:28])=[CH:10]2.[OH-].[NH4+:31]>CCOC(C)=O>[NH2:31][S:2]([C:20]1[CH:21]=[CH:22][C:17]([C:15]2[CH:16]=[C:7]([Cl:6])[CH:8]=[C:9]3[C:14]=2[O:13][CH:12]([C:23]([F:26])([F:24])[F:25])[C:11]([C:27]([OH:29])=[O:28])=[CH:10]3)=[CH:18][CH:19]=1)(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)C1=Cc2cc(Cl)cc(-c3ccccc3)c2OC1C(F)(F)F
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(-c2cc(Cl)cc3c2OC(C(F)(F)F)C(C(=O)O)=C3)cc1
Reaction time: 1 h

Procedure:
Chlorosulfonic acid (5 mL) was cooled to −20° C. and 6-chloro-8-phenyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid prepared as in U.S. Pat. No. 6,271,253 B1 Example 129, Step 2 (61.7 mg, 0.174 mmole) was added as a solid. The bright orange mixture was then added dropwise to a cold ammonium hydroxide solution, EtOAc was added and the mixture was stirred for 1 h. The EtOAc layer was separated, washed with H2O, aqueous NH4Cl, dried over Na2SO4, concentrated in vacuo and triturated with hexanes to give the product: 1H NMR (CD3OD/400 MHz) 7.95 (d, 2H, J=8.6 Hz), 7.81 (s, 1H), 7.66 (d, 2H, J=8.6 Hz), 7.46 (d, 1H, J=2.6 Hz), 7.42 (d, 1H, J=2.6 Hz), 5.80 (q, 1H, J=7.0 Hz); ESHRMS m/z 431.9945 (M−H, C17H10ClF3NO5S, Calc'd 431.9915).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]([NH2:38])([CH2:23][C:24]#[C:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:27]=3)[C:19]([O:21]C)=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.COC1C=CC(B(O)O)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([C:18]([NH2:38])([CH2:23][C:24]#[C:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:27]=3)[C:19]([OH:21])=[O:20])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C(N)(CC#Cc1cccc(N2CCOCC2)c1)S(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)C(N)(CC#Cc3cccc(N4CCOCC4)c3)C(=O)O)cc2)cc1

Procedure:
Methyl 2-{[4′-methoxy-(1,1′-biphenyl)-4-yl]-sulfonyl}-amino-5-(3-morpholino-phenyl)-pent-4-ynoate: The starting sulfonamide 5b (367 mg, 0.66 mmol) is converted to the title compound with 4-methoxyphenylboronic acid (151 mg. 1.14 mmol) as described. for compound 3b. The crude product is adsorbed onto silica and then eluted through a column of flash silica with Hexanes:EtOAc (4:1 to 1:1) to give a pale orange-yellow, foamy solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:12][CH:13]([C:19]1([CH3:24])OCC[O:20]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:12][CH:13]([C:19](=[O:20])[CH3:24])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:11]
Reactant: CCOC(=O)C(CN1C(=O)c2cccc(O)c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(CN1C(=O)c2cccc(O)c2C1=O)C(C)=O

Procedure:
Ethyl 2-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (121 mg, 31%) in the same manner as described in the above example 6 (20) from ethyl 3-(4-hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.46 g, 1.46 mmol) and p-toluenesulfonic acid monohydrate (50 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: C(O[C:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])=O)C.CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[C:37]([O:41][C:42](=[O:45])CBr)([CH3:40])([CH3:39])[CH3:38].[OH-].[Na+]>C1COCC1.CCOCC>[C:37]([O:41][C:42](=[O:45])[CH2:4][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
A solution of 2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid ethyl ester (3 g, 14.78 mmol) (N. Meanwell et al, J. Org. Chem, 1995, 60(6), 1565-82) in THF (100 ml) was treated with BTPP(5.4 ml, 17.74 mmol) followed by t-butylbromoacetate (2.4 ml, 16.3 mmol) and the mixture was stirred for 30 minutes. The solution was diluted with ether and washed with water, dired over MgSO4 and concentrated. The residue was dissolved in MeOH (30 ml) and treated with NaOH (10 N, 3 ml, 30 mmol) and stirred for 1 h at 23° C. The solvent was removed and the residue diluted with ether and washed with 1N HCl, saturated NaCl dried over MgSO4 and concentrated. The residue was purified by flash chromatography to give 1.84 g (50%) (2-oxo-2,3-dihydro-benzoimidazol-1-yl)-acetic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[C:9]([N:17]1[CH:21]=[C:20]([CH2:22][OH:23])[N:19]=[CH:18]1)[CH:8]=2)[CH3:2].CN(C)C=O>C(O)C.[Pd]>[NH2:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[N:17]1[CH:21]=[C:20]([CH2:22][OH:23])[N:19]=[CH:18]1)[N:6]=[C:5]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:4]([O:3][CH2:1][CH3:2])=[N:13]2
Reactant: CCOC(=O)c1nc2cc(-n3cnc(CO)c3)c([N+](=O)[O-])cc2nc1OCC
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2cc(-n3cnc(CO)c3)c(N)cc2nc1OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 3-ethoxy-7-(4-(hydroxymethyl)imidazole-1-yl)-6-nitroquinoxaline-2-carboxylate&Asteriskpseud;A (2.00 g, 5.16 mmol) in ethanol (200 ml) was added 10% palladium on carbon (200 mg), and the mixture was stirred for 4 hours at room temperature under hydrogen atmosphere (4 atm, 392 KPa). After completion of reaction, N,N-dimethylformamide was added to the reaction mixture to dissolve the precipitated crystals and then catalyst was filtered off using celite. By distilling off solvent, 1.89 g of title compound were obtained as yellow powder. The yield was quantitative.