Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](Cl)(C(C)(C)C)(C)C.N1C=CN=C1.[Si:14]([O:21][CH2:22][CH2:23][C:24]1[CH:25]=[C:26]([CH2:29][C:30]#N)[S:27][CH:28]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(=O)([O-])[O-:33].[K+].[K+]>CN(C=O)C.C1COCC1.O>[Si:14]([O:21][CH2:22][CH2:23][C:24]1[CH:25]=[C:26]([CH2:29][CH2:30][OH:33])[S:27][CH:28]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCc1csc(CC#N)c1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1csc(CCO)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
tert-Butyldimethylsilyl chloride (2.21 g) was added portionwise to a mixture of imidazole (1.00 g) and 2-(4-(2-hydroxyethyl)thiophen-2-yl)acetic acid [Aromatic Intermediate 20, step c] (1.3 g) in DMF (15 mL) at 20° C. over a period of 20 minutes. The resulting solution was stirred at 20° C. for 1 hour. The reaction mixture was diluted with THF (15 mL), cooled in ice-water, and treated with a solution of potassium carbonate (1.35 g) in water (15 mL). This mixture was stirred at 0° C. for 20 minutes. The mixture was partitioned between ethyl acetate and aqueous brine, and the phases separated. The organic layer was washed twice with aqueous brine, dried, filtered and the solvent removed under reduced pressure. The residue was dissolved in THF (40 mL), cooled in an ice bath and treated with borane tetrahydrofuran complex (1M in THF, 21 mL), added dropwise. The resultant solution was stirred at 20° C. for 2 hours. The reaction mixture was quenched by dropwise addition of methanol (10 mL) and the solvents were removed under reduced pressure. The crude product was purified by flash silica chromatography using 17% ethyl acetate in isohexane as solvent. Fractions containing the product were evaporated to dryness to afford the titled compound. Yield 1.25 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]([C:9]([CH2:15][OH:16])=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:7]#[N:8])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C.Cl>COCCOC.C1(C)C=CC=CC=1>[CH3:18][S:19]([O:16][CH2:15][C:9]1[CH:10]=[C:11]([O:12][CH2:13][CH3:14])[C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:17])[C:6]=1[C:7]#[N:8])(=[O:21])=[O:20]
Reactant: CCOc1cc(CO)c(C#N)c(F)c1OCC
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOc1cc(COS(C)(=O)=O)c(C#N)c(F)c1OCC
Temperature: 8 °C
Reaction time: 1 h

Procedure:
3,4-Diethoxy-2-fluoro-6-(hydroxymethyl)benzonitrile (1 g, 4.18 mmol) was dissolved in 1,2-dimethoxyethane (10 mL), and cooled in a constant temperature bath at 8° C. after addition of methanesulfonyl chloride (0.39 mL, 5.02 mmol). Triethylamine (0.76 mL, 5.43 mmol) was added dropwise to this solution at approximately 20° C. or less. After stirring at the same temperature for 1 hour, toluene (5 mL) and 0.5 N hydrochloric acid (2 mL) were added, and this was transferred to a separatory funnel and toluene (5 mL) was used for rinsing. After separation of the solution, sequential washing was carried out with water (4 mL), 10% aqueous sodium hydrogen carbonate solution (4 mL), 10% brine (4 mL), and water (4mL). After the organic layer was evaporated, toluene (4 mL) was added, and water was removed by azeotropic distillation. Toluene (4 mL) was added to the residue and this was used in the next step. HPLC analytical values for the toluene solution: 99.10% (toluene peak is disregarded).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].[Cl-].[Ca+2].[Cl-]>C(O)C.O>[NH2:17][C:15]1[CH:14]=[CH:13][C:3]([O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])=[C:2]([Cl:1])[CH:16]=1
Reactant: N#Cc1cccc(Oc2ccc([N+](=O)[O-])cc2Cl)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(Oc2ccc(N)cc2Cl)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
To a solution of 3-(2-chloro-4-nitrophenoxy)benzonitrile (2.0 g) in ethanol/water (9:1, 40 mL) was added calcium chloride (90%, 449 mg), and the mixture was stirred at 100° C. for 10 min. Reduced iron (90%, 2.7 g) was added at room temperature, and the mixture was stirred at 100° C. for 5 hrs. After the completion of the reaction, the reaction mixture was filtered (celite), and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound (1.25 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[C:33]=2[Cl:42])[CH2:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[ClH:42].[Cl:42][C:33]1[C:34]([C:38]([F:39])([F:40])[F:41])=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:16]([CH2:17][CH:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:15][CH2:14][CH2:13][O:12][C:8]1[CH:7]=[C:6]([NH:5][CH2:4][C:3]([OH:43])=[O:2])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CNc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirring solution of (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamino)-acetic acid methyl ester in THF (6 ml) and water (2 ml) was added lithium hydroxide monohydrate (20 mg, 0.47 mmol) and the mixture was stirred at room temperature for 6 hours. The reaction mixture was acidified with 1 M aqueous HCl (0.5 mL). The aqueous mixture was concentrated in vacuo and the crude material was dissolved in EtOAc. The ethyl acetate solution was washed with brine (1×), dried over sodium sulfate, and filtered. The organic layer was concentrated, and the crude amine was treated with 1 M HCl (Et2O). The resulting precipitate was dried under vacuum to afford the title compound as a solid. MS(ES) m/e 597.4 (M+).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>ClCCl.CN(C)C1C=CN=CC=1.O>[F:21][C:22]1[CH:23]=[C:24]([NH:25][C:12](=[O:14])[CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: Nc1cccc(F)c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccc(-c2ccccc2)cc1)Nc1cccc(F)c1
Temperature: 25 °C

Procedure:
Thionyl chloride (0.38 ml, 5.0 mmole) was added to an ice water cooled solution of 4-Biphenylacetic acid (0.2 g, 0.9 mmole) in 5 ml dichloromethane, solution allowed to warm to room temperature then heated under reflux for 1 hr, the solvent and excess thionyl chloride was evaporated under vacuum, the oil formed was redissolved in 5 ml dichloromethane followed by addition of 4-Dimethylaminopyridine (0.12 gm, 1.0 mmole) and 3-Fluoroaniline (0.11 gm, 1.0 mmole), stirred at room temperature over night, then the reaction mixture was diluted with 10 ml dichloromethane and 20 ml water, the organic layer washed with 1 N HCl, saturated NaHCO3 solution, and saturated NaCl solution, dried using Na2SO4 and evaporated dryness (0.2 gm, 72%), H1-NMR INOVA-500 (CDCl3) δ 3.805 (s, 2H), 6.815 (t, J=8.5 Hz, 1H), 7.068(d, J=8.0 Hz, 1H), 7.218-7.284(m, 2H), 7.380-7.499(m, 6H) 7.620-7.664(m, 4H). MS (m/z) 306.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH:25]=O>>[CH3:31][O:30][C:28]1[CH:27]=[C:24](/[CH:25]=[C:17](/[C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:16][CH:15]=2)\[C:18]#[N:19])[CH:23]=[C:22]([O:21][CH3:20])[CH:29]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: N#CCc1ccc(OCCCCCCCCO)cc1
Product: COc1cc(/C=C(\C#N)c2ccc(OCCCCCCCCO)cc2)cc(OC)c1
Yield: 68 %

Procedure:
(2Z)-3-(3,5-dimethoxyphenyl)-2-{4-[(8-hydroxyoctyl)oxy]phenyl}prop-2-enenitrile is prepared starting from {4-[(8-hydroxyoctyl)oxy]phenyl}acetonitrile and the commercial 3,5-dimethoxybenzaldehyde according the same procedure following for example 1 in 68% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([CH:15]([C:25]([NH:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[N:33][CH:32]=[CH:31]3)=[O:26])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[OH:8][CH2:9][C:10]1[S:14][C:13]([CH:15]([C:25]([NH:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[N:33][CH:32]=[CH:31]3)=[O:26])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO[Si](C)(C)C(C)(C)C)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 2-(5-((tert-butyldimethylsilyloxy)methyl)thiophen-2-yl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E237) in THF at 0° C. was added TBAF and the solution was stirred for 0° C. for 30 min then warmed to room temperature for 2 h. The compound was poured into EtOAc and washed with NH4Cl(sat), dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 6% MeOH/CH2Cl2) gave pure tert-butyl 2-(5-(hydroxymethyl)thiophen-2-yl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E238).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH:35]1[CH3:43]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH:35]1[CH3:43])=[O:31]
Reactant: CC1Cc2ccccc2C1N
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NC2c3ccccc3CC2C)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-2-methyl-indane
Reaction SMILES: [C:1]1([C:7]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:1]1([C:7]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([S:16]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)(=[O:18])=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
2,2-diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (3.36 g, 9 mmol) was dissolved in methylene chloride (135 ml). Piperidine (1.33 ml, 13.5 mmol) and ethyldiisopropyl amine (2.3 ml, 13.5 mmol) were added at room temperature. The reaction was stirred at room temperature overnight and washed twice with 1N aqueous HCl solution, twice with 1N aqueous NaOH solution and once with brine. The organic layer was dried over sodium sulfate and filtered. The solvent was evaporated and the residue was purified by column chromatography (4/1 hexane/ethyl acetate eluant). The product was suspended in diethyl ether and filtered to yield a white crystalline solid (1.98 g, 52 %). m.p.: 163-164° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([CH:10]2[CH2:12][CH2:11]2)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: OB(O)C1CC1
Reactant: Clc1cnc(I)c(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cnc(C2CC2)c(Cl)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 3,5-dichloro-2-iodopyrazine (2 g), cyclopropylboronic acid (750 mg), tetrakistriphenylphosphine palladium (0) (1.68 g), potassium phosphate (3.09 g), toluene (40 mL), and water (4 mL) was stirred at 110° C. overnight. After leaving to be cooled, the insoluble matter was removed by decantation, followed liquid separation by the addition of ethyl acetate and water. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=98:2) to obtain 3,5-dichloro-2-cyclopropylpyrazine (784 mg) as a colorless oily material.
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[C:9]1([C:15]2[C:19]([CH2:20][CH2:21][CH3:22])=[CH:18][NH:17][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:23]C1C(C2C=CC=CC=2)=NNC=1>>[CH2:8]([CH:2]([N:17]1[CH:18]=[C:19]([CH2:20][CH2:21][CH3:22])[C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:16]1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[CH3:23]
Reactant: CC(Cl)C(=O)N(C)C
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: CCCc1c[nH]nc1-c1ccccc1
Product: CCCc1cn(C(CC)C(=O)N(C)C)nc1-c1ccccc1

Procedure:
Using the procedure of Example 1, but substituting 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide and 3-phenyl-4-propylpyrazole for 4-methyl-3-phenylpyrazole, there was obtained α-ethyl-N,N-dimethyl-3-phenyl-4-propylpyrazole-1-acetamide, m.p. 63°-65.5° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:54]/[O:55][CH3:56])/[C:12]([NH:14][CH:15]2[C:52](=[O:53])[N:17]3[C:18]([C:36]([O:38]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:37])=[C:19]([C:22]4[C:25](=[O:26])[C:24](=[O:27])[C:23]=4[O:28]CC4C=CC=CC=4)[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1.C1(OC)C=CC=CC=1>[N+](C)([O-])=O.C(Cl)Cl.Cl>[NH2:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:54]/[O:55][CH3:56])/[C:12]([NH:14][CH:15]2[C:52](=[O:53])[N:17]3[C:18]([C:36]([OH:38])=[O:37])=[C:19]([C:22]4[C:23](=[O:28])[C:24](=[O:27])[C:25]=4[OH:26])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OCc4ccccc4)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(c3c(O)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Reaction time: 2 h
Yield: 7.7 %

Procedure:
A solution of aluminum chloride (82 mg, 0.612 mmol) in nitromethane (1 mL) was added rapidly to a stirred, cooled (ice/H2O bath) solution of diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(2-benzyloxy-3,4-dioxo-1-cyclobutenyl)-3-cephem-4-carboxylate (50 mg, 0.068 mmol) and anisole (66 mg, 0.612 mmol) in CH2Cl2 (1 mL). The mixture was stirred with cooling for 0.33 hr and then for 2 hrs at ambient temperatures. The solution was cooled and diluted with dilute aqueous hydrochloric acid to precipitate a solid which was collected and discarded. The aqueous filtrate was washed with ethyl acetate. The aqueous layer was applied to a Michel-Miller HPLPLC column (22×130 mm) containing Partisil Prep 40 ODS-3. The column was eluted with a mixture of H2O-acetonitrile-acetic acid (90:10:0.5). The appropriate fractions were combined and the organic solvents removed. Lyophilization of the aqueous solution afforded the title compound (2.5 mg, 7.7 % yield) as a bright yellow solid.
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14].C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[C:1]1([C@H:7]([CH3:11])[C:8]([NH:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](C(=O)NNC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
EDC (734 mg) was added to a solution of (S)-(+)-2-phenylpropionic acid (CAS #7782-24-3, 500 mg), tert-butyl carbazate (CAS #870-46-2, 440 mg) and HOBT (517 mg) in DMF (7.5 ml), and the reaction solution was stirred at room temperature for eight hours. Ethyl acetate and a sodium bicarbonate solution were added to the reaction solution, and the organic layer was separated. The organic layer washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Ethyl acetate and heptane were added to the resulting residue, and the precipitated solid was collected by filtration to obtain 482 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1.[NH2:20][OH:21].[OH-].[K+].CO>C1COCC1>[OH:21][NH:20][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1
Reactant: NO
Reactant: COC(=O)C=CC=CCSc1ccc(N(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ccc(SCC=CC=CC(=O)NO)cc1
Temperature: 0 °C
Yield: 43.1 %

Procedure:
To a solution of 6-(4-dimethylamino-phenylsulfanyl)-hexa-2,4-dienoic acid methyl ester (0.556 g, 2.0 mmol) in distilled THF (10 mL) containing aqueous hydroxylamine (50%, 1.21 mL, 18.4 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 2.8 mL, 2.8 mmol) over a period of 30 minutes. After stirring the mixture at 0° C. for an additional hour, distilled water (10 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The solution was then extracted with ethyl acetate (2×50 mL), and the combined extracts were dried over anhydrous MgSO4, and evaporated to dryness. The solid residue was recrystallised from ethyl acetate to give the title compound (0.24 g, 43%) as a white solid.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[N:5][C:6]([Cl:19])=[CH:7][CH:8]=2)[CH:3]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:26]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[N:27]1.C([O-])([O-])=O.[Na+].[Na+]>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>[Cl:19][C:6]1[N:5]=[C:4]2[CH:3]=[C:2]([C:30]3[N:26]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][O:20]4)[N:27]=[CH:28][CH:29]=3)[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:9]2=[CH:8][CH:7]=1
Reactant: Clc1cccc(Cn2c(Br)cc3nc(Cl)ccc32)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1cccc(Cn2c(-c3ccnn3C3CCCCO3)cc3nc(Cl)ccc32)c1
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-5-chloro-1-(3-chlorobenzyl)-1H-pyrrolo[3,2-b]pyridine (1.3 g, 3.3 mmol, from Step 2), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 g, 3.9 mmol, Aldrich), and Na2CO3 (1.7 g, 16 mmol) in 1,2-dimethoxyethane (40 mL) and water (6 mL) was degassed by a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol, Strem) was added, and the reaction was heated to reflux for 35 minutes. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc three times. The combined extracts were dried over sodium sulfate, filtered, and concentrated. Flash chromatography, eluting with a gradient from 0-30% EtOAc in hexanes afforded product as a light yellow oil (0.87 g, 56%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>CN(C=O)C.O>[OH:1][CH2:2][CH2:3][N:4]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: BrCc1ccccc1
Reactant: CCCCOc1ccc(S(=O)(=O)NCCO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc(S(=O)(=O)N(CCO)Cc2ccccc2)cc1
Reaction time: 16 h
Yield: 69 %

Procedure:
Part A: To a solution of 15.11 g (55 mmol) of N-(2-hydroxyethyl)-4-(n-butoxy)benzenesulfonamide from Example 2 in 100 mL of anhydrous DMF, was added 22.9 g (165 mmol) of powdered potassium carbonate and then 10.3 g (60 mmol) of benzyl bromide. After 16 hours, ethyl acetate and water was added, the organic layer separated and washed 3×s with brine, dried with sodium sulfate, filtered and stripped to afford 20.7 g of crude product. This was recrystallized from ethyl acetate/hexane to afford 13.8 g of the desired N-(hydroxyethyl)-N-(phenylmethyl)-4-(n-butoxy)benzenesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][NH:11][C:12]2([C:17]([O:19]C)=O)[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH2:23]([O:25][C:26](=[O:29])[CH2:27][NH2:28])[CH3:24].CC(O)=O.[BH3-]C#N.[Na+]>CO>[F:8][C:6]1[CH:5]=[C:4]([CH:9]2[N:28]([CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:29])[C:17](=[O:19])[C:12]3([CH2:13][CH2:14][CH2:15][CH2:16]3)[NH:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)CN
Reactant: COC(=O)C1(NCC(=O)c2cc(F)cc(F)c2)CCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CN1C(=O)C2(CCCC2)NCC1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of methyl 1-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}cyclopentanecarboxylate from Step A (10.0 g, 33.6 mmol), glycine ethyl ester hydrochloride (46.9 g, 336 mmol), and AcOH (5.78 mL, 101 mmol) in MeOH (300 mL) was stirred at ambient temperature for 10 min. NaCNBH3 (2.54 g, 40.4 mmol) was added and the pH of the mixture was checked and adjusted to pH ˜5 as necessary by addition of AcOH. The reaction mixture was heated to 50° C. for 18 h then allowed to cool. The reaction mixture was carefully quenched with saturated aqueous NaHCO3 (250 mL) and then extracted with CH2Cl2 (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=353 (M+1).