Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([OH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=O)=[C:4]([F:19])[CH:3]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH:9]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16](=[O:17])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:19]
Reactant: O=C1C2=C(CCCC2)C(O)N1c1ccc(Cl)cc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1C2=C(CCCC2)C(Cl)N1c1ccc(Cl)cc1F
Yield: 87 %

Procedure:
In 30 ml of dichloromethane was suspended 21.0 g of 2-(4-chloro-2-fluorophenyl)-3-hydroxy-2,3,4,5,6,7-hexahydro-1H-isoindol-1-one, and 7.5 ml of thionyl chloride was added to the suspension with stirring over a 20-minute period. The reaction solution was warmed, stirred at 40° to 45° C. for 1 hour and concentrated to dryness under reduced pressure. The residue was dissolved in methylene chloride, and the insoluble matter resulting from the addition of hexane was filtered out. The filtrate was concentrated to dryness under reduced pressure, thereby producing 19.5 g (yield of 87%) of the subject compound as crystals. Recrystallization from cyclohexane yielded white crystals, m.p. 89°-90° C.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:8]([CH2:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][NH:23][C:22]=3[N:21]=2)[C:7]1=[O:30])C.[ClH:32]>>[ClH:32].[CH2:11]([C@H:10]1[N:6]([CH2:5][C:4]([OH:31])=[O:3])[C:7](=[O:30])[C@@H:8]([CH2:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][NH:23][C:22]=3[N:21]=2)[CH2:9]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CN1C(=O)[C@@H](CCc2ccc3c(n2)NCCC3)C[C@H]1Cc1ccccc1
Agent: Cl
Product: O=C(O)CN1C(=O)[C@@H](CCc2ccc3c(n2)NCCC3)C[C@H]1Cc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 12-7 (150 mg, 0.3559 mmol) and 6N HCl (10 mL) was heated at 60° C. for 1 h. Evaporative removal of the solvent gave 12-8 as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]([CH3:15])=[CH2:14])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[OH-].[Na+].[BH4-].[Na+]>O.C1COCC1.[Hg]>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][C:13]([CH3:15])([CH3:14])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)CN(CCO)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Hg]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CN(Cc2ccccc2)CCO1
Reaction time: 3 h
Yield: 54 %

Procedure:
Add 2-[benzyl-(2-methyl-allyl)-amino]-ethanol (13.0 g, 63.2 mmol) to a slurry of mercury (It) acetate (20.7 g, 65.0 mmol) in water (45 mL) and THF (45 mL). After 3 h, treat the mixture with NaOH (25 mL, 2.5 M aqueous, 125 mmol) followed by NaBH4 (2.72 g, 71.9 mmol). After 19 h, decant the mixture away from the metallic mercury and add to a separatory funnel with tert-butyl methyl ether (250 mL). Separate the organic solution, wash with water (250 mL), filter through a silica plug, and concentrate. Purify the residue by flash chromatography using a gradient from 5% to 10% tert-butyl methyl ether in CH2Cl2. Collect and concentrate the fractions containing product then dissolve the residue in hexanes (100 mL). Filter the solution through Celite® to remove metallic mercury and then concentrate the filtrate to give the title compound (7.01 g, 54%) as a colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.20-7.40 (5H, m), 3.60 (2H, m), 3.42 (2H, s), 2.29 (2H, m), 2.10 (2H, s), 1.14 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]2OCC[O:14]2)=[C:8]([CH3:18])[CH:7]=1>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:19])([CH3:20])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[C:8]([CH3:18])[CH:7]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C2OCCO2)c(C)c1
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-(4-[1,3]dioxolan-2-yl-3,5-dimethylphenyl)-2,2-dimethylpropionic acid methyl ester (1.7 g, 5.8 mmol) in acetone (20 mL) and water (0.3 mL) was added Amberlyst-15 (233 mg). The suspension was stirred at ambient temperature overnight and the suspension was filtered and washed with acetone. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (5:1) to give 3-(4-formyl-3,5-dimethylphenyl)-2,2-dimethylpropionic acid methyl ester as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39](=[O:49])[NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47]Br)=[CH:43][N:42]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:49])[NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][O:22][C:20]2[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=[C:16]([C:15](=[O:32])[NH:14][CH:11]3[CH2:12][CH2:13][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:33])[CH2:9][CH2:10]3)[CH:21]=2)=[CH:43][N:42]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Product: CC(C)(C)OC(=O)Nc1ccc(COc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cn1
Yield: 81.5 %

Procedure:
Using 1.2 g (2.65 mmol) of {4-[3-(4-cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic acid tert-butyl ester and (5-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.76 g, 2.65 mmol) and following the procedure of Example 42(b) afforded 1.42 g of the required product. 1HNMR (DMSO-d6): δ 1.25 (4H, m), 1.4 (27H, s), 1.8 (4H, m), 3.20 (1H, m), 3.75 m), 5.25 (2H, s), 6.75 (1H, d), 7.05 (1H, s), 7.15 (2H, d), 7.2 (1H, s), 7.45 (2H, m), 7.85 (2H, d), 7.95 (1H, d), 8.25 (1H, d), 8.5 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[N:8]=1)[CH3:2].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][C@@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Oc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 26.9 %

Procedure:
(±) cis-2-Ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (2.2 g, 10.8 mmol), 4-benzyloxyphenol (2.17 g, 10.8 mmol), p-toluenesulfonic acid (40 mg) were dissolved in toluene (50 ml) and heated at 60° C. for 5 h, then 2 h at reflux under nitrogen. On cooling, the reaction mixture was diluted with diethyl ether (150 ml) and washed sequentially with 10% aq. sodium hydroxide, water and brine. After drying over sodium sulfate, solvents were removed in vacuo and the residue subjected to column chromatography on silica gel eluting with 20% diethyl ether in hexanes to afford the title compound (1.17 g) as a foam.
Reaction SMILES: C(OC([CH:8]1[NH:13][CH2:12][C:11]2[O:14][C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([S:25]([C:28]4[NH:29][C:30]5[C:35]([CH:36]=4)=[CH:34][C:33]([Cl:37])=[CH:32][CH:31]=5)(=[O:27])=[O:26])[CH2:21][CH:20]3[CH2:38][CH3:39])=[O:18])=[N:16][C:10]=2[CH2:9]1)=O)(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[Cl:37][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([S:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17]([C:15]3[O:14][C:11]4[CH2:12][NH:13][CH2:8][CH2:9][C:10]=4[N:16]=3)=[O:18])[CH:20]([CH2:38][CH3:39])[CH2:21]1)(=[O:27])=[O:26])=[CH:36]2
Reactant: CCC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1nc2c(o1)CNC(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1nc2c(o1)CNCC2
Reaction time: 0.17 h

Procedure:
To a solution of 1-[[6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-ethylpiperazine (320 mg) in methylene chloride (5.0 ml) was added trifluoroacetic acid (5.0 ml) at room temperature, followed by stirring for 10 minutes. The reaction mixture was concentrated under reduced pressure, whereby the title compound (423 mg) was obtained as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]2[NH:7][C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.C(N(CC)C(C)C)(C)C.[C:27](Cl)(=[O:29])[CH3:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:27]([N:10]1[CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]=2[NH:7][C:8](=[O:12])[CH2:9]1)(=[O:29])[CH3:28]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CNC2
Reactant: CC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(C(C)=O)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
To a slurry of 7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (100 mg, 0.42 mmol) in dichloromethane (10 mL) was syringed N,N-diisopropylethylamine (0.15 mL, 0.84 mmol). The mixture was cooled in an ice-water bath and acetyl chloride (0.04 mL, 0.55 mmol) was added via syringe. After 15 minutes LCMS indicated completion of the reaction. Dichloromethane (10 mL) and 10% aqueous citric acid (10 mL) were added and the mixture was stirred while being allowed to warm to room temperature. The mixture was filtered and the collected solid was washed with water and dried to constant weight to give 4-acetyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (70 mg, 60%) as a yellow solid. NMR analysis indicated a mixture of two conformational isomers, similar to that observed for the related trifluoroacetyl analog (see procedure 6c); NMR (400 MHz, DMSO-d6) δ 10.19/10.17 (2s, 1H), 7.69/7.66 (2s, 1H), 7.46/7.35 (2s, 1H), 4.78/4.67 (2s, 2H), 4.36/4.37 (2s, 2H), 3.90/3.92 (2s, 3H), 2.05 (s, 3H); MS (m/e) 278 (M−1); mp 266° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:32][CH2:31][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:18][C@@H:19]([C:21]4[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[CH3:20])[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:33]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:33][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:32][CH2:31][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:18][C@@H:19]([C:21]4[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[CH3:20])[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: C[C@@H](Nc1ncnc2c1CN(c1ccc(Br)cc1C#N)CC2)c1ccc(C(F)(F)F)nc1
Reactant: CB(O)O
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(N2CCc3ncnc(N[C@H](C)c4ccc(C(F)(F)F)nc4)c3C2)c(C#N)c1
Temperature: 100 °C
Yield: 68.9 %

Procedure:
To a mixture of (R)-5-bromo-2-(4-(1-(6-(trifluoromethyl)pyridin-3-yl)ethylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (240 mg, 0.48 mmol), methylboronic acid (37.0 mg, 0.619 mmol), potassium phosphate (354 mg, 1.67 mmol), tricyclohexylphosphine (25 mg, 0.089 mmol), toluene (10 mL), and water (0.6 mL) under argon was added palladium acetate (10 mg, 0.04 mmol). The mixture was heated at 100° C. for 3 h and then cooled to rt. The mixture was filtered and concentrated. The residue was purified by semi-preparative HPLC to yield a light yellow solid (145 mg, 69%).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([O:28]C)[C:5]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[C:14]3[C:9](=[N:10][C:11]([OH:27])=[N:12][C:13]=3[O:25]C)[O:8][C:6]=2[N:7]=1.C(O)(=O)C.C(OC(=O)C)(=O)C>S(=O)(=O)(O)O.O>[OH:1][C:2]1[N:3]=[C:4]([OH:28])[C:5]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[C:14]3[C:9](=[N:10][C:11]([OH:27])=[N:12][C:13]=3[OH:25])[O:8][C:6]=2[N:7]=1
Reactant: COc1nc(O)nc2c1C(c1ccc([N+](=O)[O-])cc1)c1c(OC)nc(O)nc1O2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(C2c3c(O)nc(O)nc3Oc3nc(O)nc(O)c32)cc1
Reaction time: 9 h
Yield: 25 %

Procedure:
To a mixture of 3.4 mmol of 2,8-dihydroxy4,6-dimethoxy-5-(p-nitrophenyl)-5H-pyrano[2,3-d:6,5-d′]dipyrimidine, 10 ml of acetic acid, and 10 ml of acetic anhydride there are added 8-12 drops of concentrated sulfuric acid. The mixture is stirred while being boiled for 8-10 hours, and then poured into 150 ml of cold water and left over night. Separation and purification of the resulting substances is as described above. Yield 25-30%
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[CH:12]1([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH2:14][CH2:13]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:24]1[C:15]([CH:12]2[CH2:14][CH2:13]2)=[CH:16][C:17]([O:25][CH2:26][CH3:27])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Reactant: CCOc1cc(C2CC2)ccc1C(=O)OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(C2CC2)c(Br)cc1C(=O)OC
Temperature: 90 °C
Reaction time: 1 h
Yield: 154 %

Procedure:
Dibromoisocyanuric acid (2.54 g) was added at room temperature to a DMF (60 mL) solution of methyl 4-cyclopropyl-2-ethoxybenzoate (3.25 g), and the mixture was stirred at 90° C. for 1 hour in a nitrogen atmosphere. Dibromoisocyanuric acid (423 mg) was added to the reaction mixture, and the mixture was stirred at 90° C. for 30 minutes in a nitrogen atmosphere. An aqueous sodium thiosulfate solution was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.08 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:5]2.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15]>C(N(CC)CC)C.C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][Si:16]([C:14]#[C:15][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:5]2)([CH3:19])[CH3:18]
Reactant: OCCn1ccc2cc(I)ccc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc2c(ccn2CCO)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
398 mg (2.1 mmol) CuI and 1.47 g (2.1 mmol) Pd(PPh3)2Cl2 are added to a solution, cooled to 0° C., of 30 g (104 mmol) 2-(5-iodo-indol-1-yl)-ethanol and 18 mL (125 mmol) ethynyl-trimethyl-silane in 480 mL triethylamine and 120 mL THF and stirred for 30 min at 0° C. and 2 h at RT. The mixture is evaporated down i. vac., the residue is taken up in 300 mL EtOAc, the organic phase is washed with 150 mL water and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient: cyc/EtOAc 4:1 to 2:1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1)(=[O:16])=[O:15]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:23]([C:20]2[CH:21]=[CH:22][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:18][C:19]=2[N+:27]([O-:29])=[O:28])(=[O:24])=[O:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1ccc(Cl)c2cccnc12
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)c3cccnc23)c([N+](=O)[O-])c1
Yield: 70.7 %

Procedure:
In the similar fashion using route 14 general procedure 27, 5-chloro-quinolin-8-ylamine (Intermediate 27) (200 mg, 1.12 mmol), 4-methanesulfonyl-2-nitro-benzenesulfonyl chloride (Intermediate 439) (456 mg, 1.46 mmol), DMAP (cat.) and pyridine (5 ml) gave the title compound (350 mg, 60%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][CH:11]=2)[CH:3]=1.[CH3:18][C:19]([O-:21])=[O:20].[Na+].O.C(OCC)(=O)C>CN(C=O)C>[C:19]([O:21][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[Cl:8])=[CH:11][CH:12]=1)(=[O:20])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: Clc1ccc(Br)cc1Cc1ccc(CBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-2-(4-(bromomethyl)benzyl)-1-chlorobenzene (intermediate AI) (15.5 g) in DMF (70 mL), NaOAc (16.27 g) was added. The solution was heated to 70° C. After 3 h, H2O (100 mL) and ethyl acetate (200 mL) were added. The organic layer was separated, washed with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography to obtain pure intermediate AJ (8.86 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[NH:14][C:13]([CH3:22])=[C:12]2[C:23]([O:25][CH3:26])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C)C=O.[C:32]1([CH2:38][CH2:39][CH2:40]Br)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:12]([C:23]([O:25][CH3:26])=[O:24])=[C:13]([CH3:22])[N:14]([CH2:40][CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:15]([CH3:21])=[C:16]2[C:17]([O:19][CH3:20])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccc(OC)c(OC)c1
Reactant: BrCCCc1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(CCCc2ccccc2)C(C)=C(C(=O)OC)C1c1ccc(OC)c(OC)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
60% Sodium hydride (0.26 g) was washed with several milliliters of anhydrous n-hexane in an argon gas atmosphere, and 10 ml dimethylformamide was added. To the resulting mixture, was added dropwise 20 ml of a dimethylformamide solution containing 2 g (5.5 mmol) dimethyl 1,4-dihydro-4-(3,4-dimethoxyphenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate with stirring. The mixture was heated at 90° C. for one hour, 20 ml of a dimethylformamide solution of 3-phenylpropyl bromide was then added, and heating at 90° C. was continued for one hour. After cooling the mixture to room temperature, 20 ml diethyl ether was added, the resulting mixture was washed with water, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by column chromatography (SiO2 /n-hexane-ethyl acetate 2:1), affording 0.8 g (30%) of the pure product. M.P.: 97°-98° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2(/[CH:15]=[CH:16]/[C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:39]=[CH:38][C:25]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([O:33]C(C)(C)C)=[O:32])[CH2:28]5)=[CH:24][CH:23]=4)[N:18]=3)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2(/[CH:15]=[CH:16]/[C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]5)=[CH:38][CH:39]=4)[N:18]=3)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(/C=C/C4(c5ccc(F)c(F)c5)CCCCC4)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccc(-c3noc(/C=C/C4(c5ccc(F)c(F)c5)CCCCC4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(E)-tert-butyl 1-(4-(5-(2-(1-(3,4-difluorophenyl)cyclohexyl)vinyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (59 mg, 0.110 mmol) was dissolved in TFA (2 mL, 26.0 mmol), and the mixture was stirred for 30 mins at room temp. The acid was evaporated off, and the residue was dissolved in 2 mL of DMF and was purified by preparative LC/MS with the following conditions: Column: Waters SunFire C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing product were combined and dried via centrifugal evaporation. (E)-1-(4-(5-(2-(1-(3,4-difluorophenyl)cyclohexyl)vinyl)-1,2,4-oxadiazol-3-yl)benzyl) azetidine-3-carboxylic acid was obtained as a waxy solid (28.7 mg, 54.3% yield). LC/MS: m/e 479.7 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (2H, d, J=8.28 Hz), 7.55 (1H, ddd, J=12.99, 7.97, 2.38 Hz), 7.39-7.48 (3H, m), 7.31 (1H, ddd, J=6.46, 4.33, 2.01 Hz), 7.15 (1H, d, J=16.31 Hz), 6.50 (1H, d, J=16.56 Hz), 3.65 (2H, s), 3.44 (2H, br. s.), 3.25 (3H, m), 2.08 (4H, m), 1.47 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=Cc1cccs1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NCc4cccs4)nc23)CC1

Procedure:
Beginning with 0.25 gm (1.09 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.20 mL (2.17 mMol) thiophene-2-carboxaldehyde, the title compound was prepared essentially as described in Example 2.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][CH2:28][CH2:29][C:30]1[N:31]=[C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[S:33][CH:34]=1.[CH3:43][C:44]([CH3:46])=[O:45]>C1COCC1>[OH:45][C:44]([C:34]1[S:33][C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[N:31][C:30]=1[CH2:29][CH2:28][O:27][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1)([CH3:46])[CH3:43]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1nc(CCOC2CCCCO2)cs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)Nc1nc(CCOC2CCCCO2)c(C(C)(C)O)s1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a solution of diisopropylamine (9.5 mL, 67.2 mmol) in THF (100 ml) was added butyllithium (42 mL, 1.6M in hexanes, 67.2 mmol) drop wise at −78° C. and stirred for 30 min. Thus obtained LDA solution was immediately added by cannulation to a solution of Example 89C (7.36 g, 22.4 mmol) in THF (100 ml) at −78° C. and stirred for 30 min at the same temperature. Then, dry acetone (8.2 ml, 112 mmol, Acros) was added slowly and the reaction mixture was removed from cold bath and allowed to reach room temperature for overnight while stirring. The reaction mixture was quenched with saturated aqueous NH4Cl solution (100 mL) and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-100% ethyl acetate in hexanes) to afford 4.6 g (53%) of the title compound. MS (ESI+) m/z 387 (M+H)+