Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCCC1.[OH:6][C:7]1C(C(NC)=O)=[CH:11][CH:10]=[C:9]([O:17][CH3:18])[C:8]=1[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([C:36]([NH2:38])=[O:37])[CH:34]=3)[CH:29]=[CH:28]2)[CH2:23][CH2:22]1.[C:39]([N:46]1[CH:50]=[CH:49]N=[CH:47]1)(N1C=CN=C1)=[O:40]>CN(C)C=O>[CH3:18][O:17][C:9]1[CH:10]=[CH:11][C:49]2[C:50](=[O:1])[N:46]([CH3:47])[C:39](=[O:40])[O:6][C:7]=2[C:8]=1[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([C:36]([NH2:38])=[O:37])[CH:34]=3)[CH:29]=[CH:28]2)[CH2:23][CH2:22]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNC(=O)c1ccc(OC)c(CCN2CCC(n3ccc4ccc(C(N)=O)cc43)CC2)c1O
Reactant: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)n(C)c(=O)oc2c1CCN1CCC(n2ccc3ccc(C(N)=O)cc32)CC1
Temperature: 25 °C

Procedure:
30 ml of anhydrous tetrahydrofuran was added to 408 mg of 1-(1-(2-(2-hydroxy-6-methoxy-3-((methylamino)carbonyl)phenyl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamide. Thereafter, 294 mg of 1,1′-carbonyldiimidazole was added thereto. The obtained mixture was then heated to reflux under nitrogen atmosphere for 5 minutes. Thereafter, 5 ml of N,N-dimethylformamide was added to the reaction solution, and the obtained mixture was then heated to reflux under nitrogen atmosphere for 45 minutes. The reaction solution was cooled to a room temperature, and the solvent was then removed under a reduced pressure. Thereafter, 294 mg of 1,1′-carbonyldiimidazole was added to the residue. The reaction mixture was heated to reflux under nitrogen atmosphere for 30 minutes. The reaction solution was cooled to a room temperature, and the solvent was then removed under a reduced pressure. Water was added to the residue, and the precipitate was collected by filtration. The precipitate was washed with diethyl ether. It was then suspended in ethanol, and the solvent was removed under a reduced pressure. Ethyl acetate was added to the residue, followed by filtration, so as to obtain 451 mg of the subject compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)[C:4](O)=[CH:3][CH:2]=1.CN(C)C1C=CC=CC=1.P(Br)(Br)(Br)(Br)[Br:26]>C(#N)C>[Br:26][C:4]1[C:5]2[C:10](=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: BrP(Br)(Br)(Br)Br
Reactant: Oc1ccnc2cc3ccccc3cc12
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: Brc1ccnc2cc3ccccc3cc12
Temperature: 0 °C
Yield: 56.2 %

Procedure:
Crude benzo[g]quinolin-4-ol (6) (5.07 mmol) was dissolved in 50 mL of acetonitrile (0.1 M) and cooled to 0° C. under a nitrogen atmosphere. N,N-dimethylaniline (3.2 mL, 5 equivalents) was added followed by 3.3 g of phosphorus pentabromide (1.5 equivalents). After removal of the bath, the mixture was heated to reflux and followed by TLC until complete. Upon cooling to rt, the mixture was slowly poured onto ice water and extracted with methylene chloride three times. The organic layers were combined, washed with brine, dried with magnesium sulfate, and concentrated in vacuo. Flash chromatography (gradient: 9:1 to 8:2 to 7:3 hexanes:EtOAc) afforded 736 mg of clean 4-bromobenzo[g]quinoline (7a) in 55% yield for the 2 steps.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:8]([O:10][CH2:11][CH:12]([NH2:15])[CH2:13][CH3:14])=[O:9])([CH3:7])[C:4]([O-:6])=[O:5].O1CCCC1.CO.[OH-].[Li+]>O>[CH3:1][CH2:2][C:3]([C:8]([O:10][CH2:11][CH:12]([NH2:15])[CH2:13][CH3:14])=[O:9])([CH3:7])[C:4]([OH:6])=[O:5]
Reactant: CCC(N)COC(=O)C(C)(CC)C(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCC(N)COC(=O)C(C)(CC)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 102.8 %

Procedure:
In a 50-mL flask, methyl-2-aminobutoxycarbonyl-2-methylpropanoate (327 mg, 1.50 mmol) was charged, and dissolved through addition of tetrahydrofuran (15 ml), and methanol (15 ml). Lithium hydroxide dissolved in purified water (15 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, neutralized with 2N-hydrochloric acid aqueous solution, and extracted with ethyl acetate (20 mL). The organic layer was dried with magnesium sulfate, and filtered. Through vacuum distillation, the solvent was removed so as to obtain methyl-2-aminobutoxycarbonyl-2-methylpropanoic acid compound (335 mg, 99%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[H][H]>CO.C(Cl)Cl.[Pd]>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)Nc1cc(C=Cc2cccc(C(F)(F)F)c2)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)Nc1cc(CCc2cccc(C(F)(F)F)c2)ccn1
Yield: 33.8 %

Procedure:
{4-[2-(3-Trifluoromethyl-phenyl)-vinyl]-pyridin-2-yl}-urea (210 mg, 0.68 mmol) is dissolved in methanol (3 mL) and DCM (3 mL). Then 5% palladium on carbon (145 mg, 0.068 mmol) is added. The reaction is stirred for 16 hours under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 71 mg of the titled product.
Reaction SMILES: [NH2:1][CH:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=2)=[CH:21][CH:20]=1
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(CCCc1ccccc1)NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (236 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (450 mg, 68%).
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].OO.CSC1[C:19]2[C:14](=[CH:15][C:16]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:17][CH:18]=2)[N:13]([C:28]2[N:33]=[CH:32][C:31]([C:34]3[S:38][CH:37]=[C:36]([C:39]#[N:40])[CH:35]=3)=[CH:30][N:29]=2)[CH:12]=1.[CH3:41][S:42]([CH3:44])=[O:43]>O>[CH3:41][S:42]([C:44]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:17][CH:18]=2)[N:13]([C:28]2[N:33]=[CH:32][C:31]([C:34]3[S:38][CH:37]=[C:36]([C:39]([NH2:40])=[O:2])[CH:35]=3)=[CH:30][N:29]=2)[CH:12]=1)=[O:43]
Reactant: O=C([O-])[O-]
Reactant: CS(C)=O
Reactant: CSc1cn(-c2ncc(-c3cc(C#N)cs3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Agent: OO
Agent: [K+]
Solvent: O
Product: CS(=O)c1cn(-c2ncc(-c3cc(C(N)=O)cs3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reaction time: 48 h

Procedure:
Potassium carbonate (90 mg, 0.650 mmol, 1.5 eq) and hydrogen peroxide (30%, 2.0 mL) were added at room temperature to a stirred solution of 5-(2-(3-(methylthio)-6-(morpholine-4-carbonyl)-1H-indol-1-yl)pyrimidin-5-yl)thiophene-3-carbonitrile (precursor of synthesis example 195, 200 mg, 0.433 mmol, 1.0 eq) in DMSO (2 mL). The reaction mixture was stirred at this temperature for 48 h and then diluted with water (10 mL). The precipitating solid was filtered off, washed with water, and dried under vacuum. The remnant was purified by column chromatography [silica gel 100-200 mesh, dichloromethane with 2% methanol].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[NH2:14][C@@H:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:14][C@@H:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17])[N:3]=1
Reactant: COC(=O)[C@H](C)N
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(N[C@@H](C)C(=O)OC)nc(Cl)n1
Temperature: 50 °C
Yield: 61.3 %

Procedure:
To a mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (5.175 g, 25.00 mmol) in acetonitrile (100 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (3.497 g, 25.05 mmol) and iPr2NEt (9.6 mL, 55.1 mmol). The mixture was heated at 50° C. overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 30-70% EtOAc in hexanes. The product fractions were evaporated in vacuo to yield (S)-methyl 2-chloro-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate as a thick yellow-orange oil (4.194 g, 15.33 mmol, 61% yield). LC/MS: m/z=274.2 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@@H:17]([OH:35])[CH2:18][C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Rh]>[C:1]([NH:8][C@H:9]([C@@H:17]([OH:35])[CH2:18][C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
A mixture of 100 mg of the resultant compound of Example 21 and 100 mg of 5% rhodium on carbon in 3 ml of methanol was shaken under 4 atmospheres of H2 for 1 day. The resulting mixture was filtered and concentrated in vacuo. Silica gel chromatography of the residue using 20% ethyl acetate in hexane provided 92 mg (90%) of the desired compound. 1H NMR (CDCl3) δ 0.75-1.90 (br envelope, 28 H), 1.44 (s, 18 H), 3.30 (br, 1 H), 3.63 (m, 2 H), 3.72 (m, 1 H), 4.41 (br, 1 H), 4.66 (br d, 1 H). Mass spectrum: (M+H)+ =497.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Mn]([O-])(=O)(=O)=[O:10].[K+].[OH2:15]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:15])=[N:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(F)cn1
Reactant: O
Agent: [K+]
Product: O=C(O)c1ccc(F)cn1
Yield: 28 %

Procedure:
To water (100 ml) were added 5-fluoro-2-methylpyridine (J. Med. Chem., 32, 1970(1989): 2.2 g, 20 mmol) and potassium permanganate (19.1 g, 120 mmol), and heated under reflux for 4 hours. The reaction mixture was filtrated and the filtrate was concentrated, acidified with KHSO4, extracted with ethyl acetate and the extract was dried over Na2SO4. The solvent was evaporated to give the title compound (0.80 g; 28%).
Reaction SMILES: C(OS([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=CC=1)(=O)=O)CC#C.[NH:16]1C[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:17]([N:16]1[CH2:15][CH2:12][CH2:13][CH2:14][CH2:9]1)[CH2:18][C:19]#[CH:20]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C#CCCN1CCCCC1
Temperature: 80 °C

Procedure:
A solution of toluene-4-sulfonic acid but-3-ynyl ester (45.0 g) and piperidine (40 mL) in ethanol (70 mL) was treated with a solution of potassium carbonate (27.8 g) in water (70 mL). The mixture was heated to 80° C. for 2 h, cooled to RT, and extracted with DCM (3×100 mL). The combined organic phases were dried (magnesium sulfate), and evaporated. Distillation of the residue (110° C., 30 mm Hg) gave the title compound as a colorless oil (17.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][CH2:7][C:6]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)(=[O:21])[CH3:20]>CS(C)=O>[C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][CH2:7][C:6]=2[CH:12]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OCCCCBr
Reactant: O=C1Nc2ccc(O)cc2CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)OCCCCOc1ccc2c(c1)COC(=O)N2
Temperature: 50 °C
Reaction time: 6 h

Procedure:
One hundred two grams (0.62 mol) of 6-hydroxy-4H-3,1-benzoxazin-2-one are dissolved in 1 liter of dimethylsulfoxide and mixed with 227 gm (1.64 mol) of potassium carbonate and 166 gm (0.73 mol) of 4-acetoxy-butylbromide. The reaction mixture is stirred for six hours at 50° C., and then ice water is added. The precipitate is subjected to suction filtration, washed with water, and dried.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:9][N:10]([CH3:31])[C:11](=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[C:22]([F:28])[C:21]=1[F:29]>ClCCCl>[CH3:31][N:10]([CH3:9])[C:11](=[O:30])[CH2:12][C:13]1[CH:18]=[C:17]([C:1](=[O:3])[CH3:2])[CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[C:21]([F:29])=[C:22]([F:28])[CH:23]=[C:24]([F:27])[C:25]=1[F:26]
Reactant: CN(C)C(=O)Cc1ccccc1Nc1c(F)c(F)cc(F)c1F
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc(Nc2c(F)c(F)cc(F)c2F)c(CC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an inert atmosphere, acetyl chloride (29.1 ml, 0.385 mol) is slowly added to a suspension of aluminum chloride (51.2 g, 0.385 mol) stirred in 1,2-dichloroethane (750 ml). After stirring at room temperature for 1 hour a yellow solution is obtained. The solution is cooled in an ice bath and N,N-dimethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamide (40 g, 0.123 mol) is added. The reaction is allowed to warm to room temperature and then warmed to 80° for 0.5 hours. The reaction is poured over ice and extracted with EtOAc (2×750 ml). The organic extract is washed with water (750 ml), saturated NaHCO3 solution (500 ml) and brine (500 ml). Evaporation on a rotovap and trituration with Et2O gives N,N-dimethyl-5-acetyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamide as a white solid, m.p. 112-114°.
Reaction SMILES: N[C@H](C([O:8][CH2:9][CH2:10][C@@H:11]([CH2:24][O:25][C:26](=[O:32])[C@H:27]([CH:29]([CH3:31])[CH3:30])[NH2:28])[CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2)=O)C(C)C.[OH-].[Na+].FC(F)(F)C(O)=O>>[OH:8][CH2:9][CH2:10][C@@H:11]([CH2:24][O:25][C:26](=[O:32])[C@H:27]([CH:29]([CH3:30])[CH3:31])[NH2:28])[CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2
Reactant: CC(C)[C@H](N)C(=O)OCC[C@@H](COC(=O)[C@@H](N)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)OC[C@H](CCO)Cn1cnc2c(=O)[nH]c(N)nc21
Reaction time: 4 h
Yield: 13.6 %

Procedure:
(R)-9-(4-(L-valyloxy)-2-(L-valyloxymethyl)butyl)guanine from Example 23 step b) (100 mg, 0,126 mmole) was dissolved in 0.1 N NaOH aqueous solution (6.3 ml, 0.63 mmole) at room temperature. At intervals, an aliquot was taken and neutralized with 0.5 N trifluoroacetic acid. The aliquots were evaporated and analyzed by HPLC to monitor the progress of the reaction. After 4 hours, 0.5 N trifluoroacetic acid solution (1.26 ml, 0.63 mmole) was added to the solution and the reaction mixture was evaporated. The desired product was purified by HPLC, (YMC, 50×4.6 mm, gradient 0.1% TFA+0–50% 0.1% TFA in acetonitrile, in 20 minutes, UV detection at 254 nm. Yield: 13.6%
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([S:27]([C:30]1[CH:35]=[CH:34][C:33](CO)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:26]>O1CCCC1>[CH2:25]([S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH2:20][Cl:24])=[CH:32][CH:31]=1)(=[O:28])=[O:29])[CH3:26]
Reactant: CCS(=O)(=O)c1ccc(CO)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
Triphenylphosphine (12.77 g, 481 mmol), carbon tetrachloride (19.0 mL, 197 mmol) and tetrahydrofuran (40 mL) were combined and stirred at room temperature for 15 minutes. A solution of (4-ethanesulfonyl-phenyl)-methanol (4.87 g, 24.4 mmol) in 45 mL tetrahydrofuran was added, then the reaction mixture was heated at 75° C. for 3 hours. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was dried over MgSO4, filtered, and concentrated to give the crude product as an oily solid. A solution of this crude product and dichloromethane was evaporated over silica gel, and the resulting silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (15%-35% ethyl acetate in hexanes) afforded 5.16 g (97%) of 4-(ethanesulfonyl)benzyl chloride as a white, crystalline solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.88 (d, J=8.2 Hz, 2 H), 7.70 (d, J=8.2 Hz, 2 H), 4.86 (s, 2 H), 3.29 (q, J=7.4 Hz, 2 H), 1.07 (t, J=7.4 Hz, 3 H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]1([C:52]2[S:53][CH:54]=[C:55]([C:57](O)=[O:58])[N:56]=2)[CH2:51][CH2:50][CH2:49][CH2:48]1.C(N(CC)CC)C>CN(C=O)C>[CH:47]1([C:52]2[S:53][CH:54]=[C:55]([C:57]([N:28]3[CH2:29][C:30]4([CH2:35][CH2:34][N:33]([CH2:36][C:37]5[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=5)[CH2:32][CH2:31]4)[O:25][CH2:26][CH2:27]3)=[O:58])[N:56]=2)[CH2:48][CH2:49][CH2:50][CH2:51]1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Reactant: O=C(O)c1csc(C2CCCC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1csc(C2CCCC2)n1)N1CCOC2(CCN(Cc3cc(F)cc(CCO)c3)CC2)C1
Reaction time: 0.5 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.33 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.21 g), 2-cyclopentylthiazole-4-carboxylic acid (example 59, step d) (0.13 g) and triethylamine (0.38 mL) in DMF (7 mL) and the resulting yellow solution was stirred for 30 min. The mixture was partitioned between ethyl acetate and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.19 g.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.C1(C2C3C=CC=CC=3N([CH2:57][C:58](C3CCCC3)=[O:59])C(=O)N(CC(O)=O)N=2)CCCCC1.C(OC(C1SC=C(C2C=CC=C(N)C=2)N=1)=O)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:58]([O:59][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:57]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)c1nc(-c2cccc(N)c2)cs1
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 22, step a) and 4-(3-amino-phenyl)-thiazole-2-carboxylic acid ethyl ester were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.51 (1H, s), 8.05 (1H, s), 7.88 (1H, s), 7.63 (1H, d), 7.49 (3H, m), 7.40-7.27 (2H, m), 7.07 (1H, d), 4.70 (1H, d), 4.45 (1H, d), 4.27 (2H, m), 2.95 (1H, m), 2.81 (1H, m), 2.06-1.56 (14H, m), 1.28 (4H, m). The compound was further characterised the N-methyl-D-glucamine salt. Found: C, 57.65; H, 6.41; N, 9.83%; C33H35N5O5S.C7H17NO5.1.5H2O requires: C, 57.51; H, 6.63; N, 10.06%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)=[C:9]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)=[C:9]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
To a solution of ethyl(1RS)-1-(4-fluorophenyl)-1-hydroxy-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (45 mg, 0.11 mmol) in CH2Cl2 (3 ml) at 0° C. was added triethylsilane (38 μl, 0.24 mmol), followed by boron trifluoride etherate (121 μl, 0.98 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 15 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (40 mg, 90%) as a mixture of Δ1 and Δ2 double bond isomers.