Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH:16]2[CH:14]([O:15]2)[CH2:13]1.[H][H]>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH:16]2[CH:14]([O:15]2)[CH2:13]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(F)c(N2CC3OC3C2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(N2CC3OC3C2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10% Palladium on carbon (0.02 g) was added to 3-(2,6-difluoro-4-nitro-phenyl)-6-oxa-3-aza-bicyclo[3.1.0]hexane (0.2 g, 0.83 mmol) dissolved in ethyl acetate (8.0 mL). The flask was charged with hydrogen gas and the mixture was stirred at room temperature for 3 h. The reaction mixture was filtered through celite and the solvent removed to get the title compound which was used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].O[CH2:25][C:26]1[NH:31][C:30](=[O:32])[NH:29][C:28](=[O:33])[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:25][C:26]2[NH:31][C:30](=[O:32])[NH:29][C:28](=[O:33])[CH:27]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(O)cc2)c(C)c1
Reactant: O=c1cc(CO)[nH]c(=O)[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3cc(=O)[nH]c(=O)[nH]3)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
A mixture of N-(2,4-dimethylphenyl)-4-hydroxy-N-isobutylbenzenesulfonamide (33 mg, 0.099 mmol), 6-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (17.1 mg, 0.12 mmol) and triphenylphosphine (26 mg, 0.099 mmol) was dissolved in tetrahydrofuran (THF) (0.6 mL) and treated with diisopropyl diazene-1,2-dicarboxylate (DIAD) (25 uL, 0.13 mmol). The vessel was capped and stirred at 20° C. for 2 days. Additional 6-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (17.1 mg, 0.12 mmol) and diisopropyl diazene-1,2-dicarboxylate (DIAD) (30 uL, 0.156 mmol) were added and reaction stirred for further 18 hours. The reaction was then filtered and purification attempted by mass directed autoprep (ammonium carbonate modifier), but this failed to isolate clean material. Purification successfully achieved by mass directed autoprep (formic acid modifier), to provide the required product, 1.1 mg. LCMS [LCMS1] Rt 1.13 min, m/z (ES+) 458 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)(=[O:23])=[O:22].F[C:35](F)(F)[C:36]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH2:35]([O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)(=[O:23])=[O:22])[CH:4]=2)=[CH:10][CH:11]=1)[CH3:36]
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cccc(C(F)(F)F)c3)c2)cc1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cccc(C(F)(F)F)c3)c2)cc1

Procedure:
4-[4-Chloro-3-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=497.1 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 3-trifluoromethyl-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3C(=O)C4=CC=CC=C4C3=O)[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.O.NN>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2=CCN(CCCCN3C(=O)c4ccccc4C3=O)CC2)cc1
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1ccc(C2=CCN(CCCCN)CC2)cc1
Yield: 150.1 %

Procedure:
A solution of N-[4-{4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl]phthalimide (0.98 g), hydrazine hydrate (0.17 g) in methanol (10 ml) was stirred under reflux for 4 hours. After evaporation of the solvent, the crude residue was mixed with chloroform and 1N sodium hydroxide. The chloroform layer was separated, dried over magnesium sulfate and evaporated to give an oil of 4-[4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl]butylamine (0.96 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH:26]=[CH:25]3)=[C:17]([NH:29][CH:30]3[CH2:35][CH2:34][N:33](CC4C=CC=CC=4)[CH2:32][CH2:31]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.O.[Pd]>[C:1]([O:5][C:6](=[O:43])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH:26]=[CH:25]3)=[C:17]([NH:29][CH:30]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(NC3CCN(Cc4ccccc4)CC3)c3ncn(C4C=CCC4)c3n2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(NC3CCNCC3)c3ncn(C4C=CCC4)c3n2)CC1

Procedure:
Add to a solution of trans-{4-[6-(1-benzyl-piperidin-4-ylamino)-9-cyclopent-2-enyl-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (8c, 1.0 mmol) in 40 mL of methanol, a suspension of Pd black (0.5 wt %) in a small amount of water. Then add a solution of ammonium formate (2.2 mmol) in 10 mL of water, and heat at a gentle reflux overnight. Remove the catalyst by filtration through Celite® and concentrate the filtrate. Dissolve the residue in DCM and extract with water. Remove the white precipitate by filtration through a pad of Celite®, wash the filtrate with brine, dry over sodium sulfate and filter. Concentrate the filtrate and purify the residue on silica gel (50 g) using DCM:methanol (4:1) to give trans-{4-[9-cyclopent-2-enyl-6-(piperidin-4-ylamino)-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (9c).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CN1CCOCC1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:31])=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:12][C:2]([F:1])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:31])=[C:26]([CH:30]=2)[C:27]([OH:29])=[O:28])=[O:9])=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a suspension of 4-(trifluoromethyl)benzoic acid (1.0 g, 5.3 mmol) in DCM (20 mL) were added CDMT (1.1 g, 6.3 mmol) and NMM (2.3 mL, 21 mmol). The mixture was stirred at RT for 30 min under an argon atmosphere. 5-amino-2-chlorobenzoic acid (1.4 g, 7.9 mmol) was added and the mixture stirred at RT for additional 2 h. The reaction mixture was poured into saturated NaHCO3 solution and then extracted with DCM. The organic layer was dried (Na2SO4), filtered and the filtrate concentrated to afford the title compound (1.6 g, 88%) as a cream solid.
Reaction SMILES: [CH3:1][C:2]1[N:19]=[C:5]2[N:6]([CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[OH:12])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:20].[H-].[Na+].[CH3:23]I>C1COCC1>[CH3:1][C:2]1[N:19]=[C:5]2[N:6]([CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:12][CH3:23])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:20]
Reactant: Cc1nc2n(CC(O)c3ccccc3)cccc-2c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(Cn1cccc2c(C)c(C)nc1-2)c1ccccc1
Yield: 65 %

Procedure:
A solution of 2,3-dimethyl-7-(2-phenyl-2-hydroxyethyl)pyrrolo[2,3-b]pyridine (as the base) (266 mg, 1.0 mmol) in 25 ml dry THF was deaerated and treated with 55% NaH dispersion in oil (48 mg, 1.1 mmol) for 30 min. Methyl iodide (62 μl, 1.0 mmol) was added and allowed to react for 50 min. The solvent was evaporated and the residue partitioned between 100 ml CH2Cl2 and 20 ml 5% NaOH. The organic layer was dried over MgSO4 and evaporated. The residue was chromatographed (silica, CH2Cl2 saturated with NH3). Pure fractions were pooled and evaporated leaving a gum which partly crystallized. Trituation with diethyl ether furnished 207 mg (65%) pure title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8](O)=[O:9].S(Cl)([Cl:14])=O>>[CH3:11][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([Cl:14])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1CC(=O)O
Product: Cc1ccccc1CC(=O)Cl

Procedure:
A solution of 2.0 g of o-tolylacetic acid in 27 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.1 g of the desired product as a light brown oil.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[CH:13][CH:12]=1.[Li+].[OH-].Cl>CO>[NH2:8][N:9]=[CH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[CH:15][CH:16]=1
Reactant: CCOC(=O)CC(NC(=O)NCCCCc1ccc(C=NN)cc1)c1cccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NN=Cc1ccc(CCCCNC(=O)NC(CC(=O)O)c2cccnc2)cc1
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
ethyl β-[[[[4-[4-(aminoiminomethyl)phenyl]butyl]amino]carbonyl]amino]-3-pyridinepropanoate TFA (100 mg; 2 mmol), methanol (5ml), and 2N LiOH (5ml) were stirred for 30 min. The solution was acidified to pH=3 with 3N HCl and reduced to dryness on a rotary evaporator. The residue was dissolved in acetonitrile/water and purified by HPLC on a C-18 HPLC column (30cm×5cm). A gradient of 10 to 40% acetonitrile/water/ 0.05% TFA in 30 min. was used and the acid eluted at an acetonitrile concentration of 15%. Fractions containing the desired peak were lyophilized to give 70 mg of white solid. FAB-MS: MH+ =384.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[F-:12].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:12]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Yield: 82 %

Procedure:
A suspension of 1,500 parts of 3,4-dichloronitrobenzene, 680 parts of potassium fluoride and 25 parts of 18-crown-6 in 1,420 parts of dimethylformamide is refluxed for 9 hours, the temperature being 165° C. The mixture is worked up by the method described in Example 1. 1,124 parts (82% of theory) of 3-chloro-4-fluoronitrobenzene of melting point 41°-42° C. are obtained.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]2N=[CH:11][CH:10]=[C:9]([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)[C:7]=2[CH:8]=1.C1C=CC=CC=1.[C:31]([O:34]CC)(=[O:33])[CH3:32]>>[C@@H:32]1([C:31]([OH:34])=[O:33])[C:8]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(C)=O
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: c1ccccc1
Product: O=C(O)[C@H]1CCCc2ccccc21

Procedure:
The quinine salt was suspended in 180 mL of ethyl acetate and the suspension was washed with 1N hydrochloric acid (2×92 mL). The mixture was then dried (NaSO4), filtered and concentrated. The residue was dissolved in hexane and crystallized to give (S)-1,2,3,4-tetrahydro-1-naphthoic acid (14.27 g 0.08 mol), m.p. 54°-56° C. [α]D -62.76° (c=1.0165, benzene).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[CH:9]([NH2:14])[CH2:10][CH2:11][CH2:12][S:13][C:7]=2[CH:6]=1)=[O:4].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[CH:9]([NH:14][C:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[CH2:10][CH2:11][CH2:12][S:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)SCCCC2N
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)c1ccc2c(c1)SCCCC2NC(=O)OCc1ccccc1
Yield: 90.2 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 4 using 5-amino-2,3,4,5-tetrahydro-1-benzothiepine-8-carboxylic acid methyl ester (2.50 g) and benzyloxycarbonyl chloride (2.69 g), the objective 5-(benzyloxycarbonylamino)-2,3,4,5-tetrahydro-1-benzothiepine-8-carboxylic acid methyl ester (3.53 g) was obtained as colorless crystals.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:13][O:14][CH2:15][CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:6]([O:5][C:3](=[O:4])[C:2]([C:21]1[CH:22]=[CH:23][C:18]([S:17][CH2:16][CH2:15][O:14][CH3:13])=[CH:19][CH:20]=1)=[O:8])[CH3:7]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COCCSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(SCCOC)cc1
Temperature: 0 °C

Procedure:
Ethyl chloroglyoxylate (8.76 mL) was added dropwise to a suspension of aluminum chloride (13.2 g, crushed) in methylene chloride (127 mL) under stirring and cooling with ice, and (2-methoxyethyl)phenylsulfide (12.0 g) was added dropwise thereto. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (200 mL), and the mixture was stirred for 10 minutes. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution (40 mL×3), and washed with saturated brine (60 mL). The washed organic layer was dried over anhydrous sodium sulfate, filtrated, and evaporated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane:ethyl acetate=4:1) to give 2-[4-(2-methoxyethylthio)phenyl]-2-oxoacetic acid ethyl ester (1.98 g).
Reaction SMILES: Cl.CC1(C)[O:7][C@H:6]([C@@H:8]([CH2:23][S:24][CH3:25])[CH2:9][N:10]([CH2:12][C:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:22])[C:16]=3[NH:15][CH:14]=2)[CH3:11])[CH2:5][O:4]1>CO>[NH2:22][C:21]1[C:16]2[NH:15][CH:14]=[C:13]([CH2:12][N:10]([CH3:11])[CH2:9][C@H:8]([CH2:23][S:24][CH3:25])[C@@H:6]([OH:7])[CH2:5][OH:4])[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: CSC[C@@H](CN(C)Cc1c[nH]c2c(N)ncnc12)[C@@H]1COC(C)(C)O1
Agent: Cl
Solvent: CO
Product: CSC[C@@H](CN(C)Cc1c[nH]c2c(N)ncnc12)[C@@H](O)CO
Yield: 60.4 %

Procedure:
Concentrated hydrochloric acid (0.5 ml, 178 μmol) was added to a solution of 7-((((S)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-(methylthio)propyl)(methyl)amino)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (65 mg, 178 μmol) in methanol (5 ml) and the resulting reaction concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel eluting with 15% 7N NH3 in MeOH/DCM=>20% 7N NH3 in MeOH/DCM to afford (2R,3S)-4-(((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)(methyl)amino)-3-(methylthiomethyl)butane-1,2-diol (35 mg, 61% yield) as a syrup. 1H NMR (CD3OD) δ 8.16 (s, 1H), 7.49 (s, 1H), 3.84 (d, J=13.5. Hz, 1H), 3.68 (m, 2H), 3.54 (d, J=4.8 Hz, 2H), 2.70 (m, 2H), 2.53 (dd, J=12.8, 3.8 Hz, 1H), 2.39 (dd, J=13.1, 8.1 Hz, 1H), 2.28 (s, 3H), 2.14 (m, 1H), 2.08 (s, 3H). 13C NMR (CD3OD) 152.5, 151.4, 147.6, 130.6, 115.6, 112.9, 75.4, 65.7, 59.7, 52.0, 42.7, 41.0, 36.0, 16.6.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:23][N:7]2[C:8](=[O:22])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH2:10][C@@H:6]2[CH2:5]1.[CH2:24]([CH:27]1[CH2:29][O:28]1)[CH2:25][CH3:26].O>C1COCC1>[OH:28][CH:27]([CH2:24][CH2:25][CH3:26])[CH2:29][O:3][C@H:4]1[CH2:23][N:7]2[C:8](=[O:22])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=3)[CH2:10][C@@H:6]2[CH2:5]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](O)CN12
Reactant: CCCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(O)CO[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
NaH (25 mg, 70% in oil, 0.7 mmol) was added to a solution of (6R,7aS)-6-Hydroxy-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 1, step e) (300 mg, 1 mmol) in anhydrous THF (10 mL), the mixture was stirred at room temperature for 0.5 hour, then 2-propyloxirane (300 mg, 3.5 mmol) was added to the solution, the mixture was stirred at 75° C. overnight in a sealed tube. The mixture was cooled and poured into water (50 mL), extracted with ethyl acetate (3×30 mL), the organic layers was combined and washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate=4:1) to yield 100 mg (26%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.62 (d, 2H, J=8.7 Hz), 7.19 (d, 2H, J=8.7 Hz), 4.20 (t, 1H, J=5.7 Hz), 4.09-4.00 (m, 3H), 3.82-3.74 (m, 2H), 3.52-3.43 (m, 1H), 3.37-3.18 (m, 2H), 2.26-2.10 (m, 2H), 1.60-1.38 (m, 5H), 0.96 (t, 3H, J=6.9 Hz); LC-MS: 389.1 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[CH:5][C:4]=1[O:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:18](Br)[CH:17]=1)#[N:2].[CH3:30][N:31](C)C=O>>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[CH:5][C:4]=1[O:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:18]([C:30]#[N:31])[CH:17]=1)#[N:2]
Reactant: CCCCCOc1ccc(C(=O)Oc2ccc(CCCCC)cc2C#N)cc1Br
Reactant: CN(C)C=O
Product: CCCCCOc1ccc(C(=O)Oc2ccc(CCCCC)cc2C#N)cc1C#N

Procedure:
9.3 g (0.020 mol) of the (2'-cyano-4'-n-pentylphenyl)-3-bromo-4-n-pentyloxybenzoate prepared in Step VI was reacted with cuprous cyanide and N,N-dimethylformamide to yield 3.0 g of purified (2'-cyano-4'-n-pentylphenyl)-3-cyano-4-n-pentyloxybenzoate. The yield was calculated to be 36.7%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]([NH2:14])=[S:13]>CO>[C:5]1([C:3]2[N:11]=[C:12]([NH2:14])[S:13][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(N)=S
Solvent: CO
Product: Nc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
2-Bromo-1-phenyl-ethanone (19.9 g, 0.100 mol) and thiourea (7.9 g, 0.10 mol) were mixed in a 150 mL of methanol. The reaction mixture was warmed to dissolve the reagents and then allowed to stir overnight at room temperature. The methanol was evaporated to dryness and the crude product was dissolved in a minimum of ethyl acetate. The crude product was then extracted twice with 1M sodium hydroxide and once with a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness to yield the pure product (16.8 g, 0.0953 mol, 95.3%) of product. ESI-MS m/z calc. 176.0. found 177.2 (M+1)+ Retention time 1.41 minutes. 1H NMR (400 MHz, CD3CN) δ 5.73 (s, 2H), 6.87 (s, 1H), 7.28-7.34 (m, 1H), 7.36-7.43 (m, 2H), 7.79-7.85 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[CH:10]3)[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]([N:30]1[CH2:35][CH2:34][CH:33]([SH:36])[CH2:32][CH2:31]1)([CH3:29])[CH3:28].CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:24][O:25][C:26](=[O:37])[C:27]([N:30]1[CH2:31][CH2:32][CH:33]([S:36][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)=[CH:10]4)[C:6]=3[CH:23]=2)[CH2:34][CH2:35]1)([CH3:29])[CH3:28]
Reactant: COC(=O)C(C)(C)N1CCC(S)CC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Temperature: 120 °C
Yield: 138 %

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (326 mg, 0.871 mmol), 2-(4-mercaptopiperidin-1-yl)-2-methylpropionic acid methyl ester (284 mg, 1.307 mmol), Pd2(dba)3 (40 mg, 5 mol %), XantPhos (50 mg, 10 mol %) and DIPEA (0.60 mL, 3.48 mmol) in dioxane (8 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. After cooling to RT, the reaction mixture was diluted with DCM (200 mL) and purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM) affording 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester as an orange oil (614 mg, quantitative yield). LCMS: RT 2.23/2.28 min [M+H]+ 511.3.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][S:14]([CH2:17][CH2:18][NH2:19])(=[O:16])=[O:15].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH2:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:6]
Reactant: CS(=O)(=O)CCN
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCNC(=O)c1cccc(Br)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a 100-mL round-bottomed flask was added 2-amino-3-bromobenzoic acid (0.8 g, 3.70 mmol) and 2-(methylsulfonyl)ethanamine hydrochloride (0.709 g, 4.44 mmol, ChemBridge Inc.) in EtOAc (15 mL) followed by DIEA (1.61 mL, 9.26 mmol) and T3P (2.59 mL, 4.07 mmol, Sigma Aldrich). The mixture was stirred at RT for 2 h, then quenched with sat. NaHCO3. EtOAc (100 mL) was added and the layers were separated. The organic layer was washed with sat. NaHCO3 (20 mL), brine (15 mL), then dried (MgSO4), filtered and concentrated to give the crude product 485 mg. MS (ESI, pos. ion) m/z: 321 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH3:12])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([OH:7])[CH3:12])=[C:10]([CH2:8][OH:9])[CH:11]=1
Reactant: CC1OC(=O)c2cc(F)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(O)c1ccc(F)cc1CO

Procedure:
This compound was prepared in an analogous manner to Example X1 from 8.0 (48 mM) of 6-fluoro-3-methylphthalide and lithium aluminium hydride to yield the title compound as a yellow oil.