Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:12]([C:13](O)=[O:14])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].O1CCCC1>CCOCC>[OH:14][CH2:13][C@H:12]1[CH2:11][CH2:10][CH2:9][N:8]1[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CO

Procedure:
In accordance with Scheme I, N-α-t-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M borane-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][C:13]1=[O:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[C:13](=[O:18])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1=O
Reactant: O=Cc1ccc(Cl)nc1
Agent: Cl
Product: CN1CCN(Cc2ccc(Cl)nc2)CC1=O
Yield: 84.1 %

Procedure:
Following General Method B, 6-chloro-pyridine-3-carbaldehyde (500 mg, 3.532 mmol) and 1-methylpiperazine-2-one hydrochloride (559 mg, 3.709 mmol) gave 4-(6-chloro-pyridin-3-ylmethyl)-1-methyl-piperazin-2-one (712 mg, 84%) [following SiO2 chromatography, eluting with 0-10% MeOH/dichloromethane]. MS (ESI) m/z 240.1 (M+H)−
Reaction SMILES: [C:1]([N:5]([CH3:16])[S:6]([C:9]1[CH:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>>[C:1]([N:5]([CH3:16])[S:6]([C:9]1[CH:10]=[N:11][C:12]([NH:18][NH2:19])=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CN(C(C)(C)C)S(=O)(=O)c1ccc(Cl)nc1
Solvent: O
Product: CN(C(C)(C)C)S(=O)(=O)c1ccc(NN)nc1
Yield: 84 %

Procedure:
According to the process described in Example 4.2, starting with 0.66 g (2.53 mmol) of N-tert-butyl-6-chloro-N-methylpyridine-3-sulfonamide and 0.46 mL of hydrazine monohydrate, 0.55 g of N-tert-butyl-6-hydrazino-N-methylpyridine-3-sulfonamide is obtained in the form of a white solid, which is used without further purification in the following step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][N:19]1[C:25](=[O:26])[CH:24]([CH2:27][C:28]([F:31])([F:30])[F:29])[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[C:21]2[CH:36]=[CH:37][CH:38]=[CH:39][C:20]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][N:19]2[C:25](=[O:26])[CH:24]([CH2:27][C:28]([F:29])([F:30])[F:31])[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[C:21]3[CH:36]=[CH:37][CH:38]=[CH:39][C:20]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NN1C(=O)C(CC(F)(F)F)c2ccccc2-c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-7-(2′,2′,2′-trifluoroethyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-M), the title compound was prepared. The reaction was monitored by tlc (Rf=0.15, 5% MeOH/CHCl3) and product was purified by chromatography (silica, 5% MeOH/CHCl3).
Reaction SMILES: [N:1]1([C:15]([C@H:17]([NH:27][C:28](=[O:40])[C:29]([NH:32]C(OC(C)(C)C)=O)([CH3:31])[CH3:30])[CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:16])[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][CH2:7]2)[CH2:3][CH2:2]1.CN1CCOCC1.[CH2:48]([S:50](Cl)(=[O:52])=[O:51])[CH3:49]>ClCCl>[CH2:48]([S:50]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]2([CH2:5][CH2:6][N:1]([C:15]([C@H:17]([NH:27][C:28](=[O:40])[C:29]([NH2:32])([CH3:30])[CH3:31])[CH2:18][O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])[CH2:2][CH2:3]2)[CH2:7]1)(=[O:52])=[O:51])[CH3:49]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CNc1ccccc12
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCS(=O)(=O)N1CC2(CCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)N)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.158 g the intermediate from Step B in 5 mL of dichloromethane was added 0.053 mL of N-methylmorpholine, and 0.034 mL of ethanesulfonylchloride and stirred at 0° C. for 30 min and RT for 1 h. The reaction mixture was diluted with an additional 5 mL of dichloromethane and washed with 5 mL of saturated sodium bicarbonate solution, brine (5 mL), dried over MgSO4 and concentrated. Flash chromatography of the residue over 10 g of silica gel with CH2Cl2 -ether (3:1) as eluent gave 0.057 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14](S(C)(=O)=O)[N:9]3[CH:8]=[CH:7][C:6]=2[CH:19]=1.[CH3:20][O-:21].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14]([O:21][CH3:20])[N:9]3[CH:8]=[CH:7][C:6]=2[CH:19]=1
Reactant: CS(=O)(=O)c1nnc2n1C=Cc1cc(Cl)ccc1C2
Reactant: C[O-]
Agent: [Na+]
Product: COc1nnc2n1C=Cc1cc(Cl)ccc1C2

Procedure:
The reaction of 8-chloro-3-methylsulfonyl-11H-s-triazolo[3,4-b][3]benzazepine with sodium methoxide yielded 8-chloro-3-methoxy-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from aqueous acetone), melting point: 177°-178° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:20]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([CH:8]1[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]1)[CH2:12][CH2:13]2
Reactant: c1ccc2c(c1)CCN2C1CCC2(CC1)OCCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)CCN2C1CCC2(CC1)OCCO2
Reaction time: 3.5 h
Yield: 90 %

Procedure:
A solution of compound 3 (3.45 g, 13.30 mmol) in dry DMF (30 mL) was treated with N-bromosuccinimide (2.36 g, 13.30 mmol) in DMF (20 mL) at 0° C. over a period of 30 min. The reaction was stirred at same temperature for 3.5 h. The reaction was diluted with water (200 mL) and product was extracted into ethyl acetate (3×25 mL). The combined ethyl acetate layer was washed with water (2×50 mL), brine (25 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by column chromatography on silica gel (ethyl acetate:hexanes, 1:4) to obtain compound 4 (4.05 g, 90%) as a syrup. 1H NMR (CDCl3) δ 7.12-7.10 (m, 2H), 6.25 (d, J=9.0 Hz, 1H), 3.95 (s, 4H), 3.38 (t, J=16.8 Hz, 3H), 2.91 (t, J=16.8 Hz, 2H), 1.86-1.57 (m, 8H). MS-ESI (m/z, %): 340 (98), 338 (M+, 100), 198 (18).
Reaction SMILES: [OH:1][C:2]1([C:23]2[C:32]([OH:33])=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]1=[O:22].Cl[CH2:35]I.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[F:19][C:18]([F:20])([F:21])[C:17]1[C:12]([CH2:11][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]3([C:23]4[CH:24]=[C:25]5[O:30][CH2:29][CH2:28][O:27][C:26]5=[CH:31][C:32]=4[O:33][CH2:35][O:1]3)[C:3]2=[O:22])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: ClCI
Reactant: O=C1N(Cc2ncccc2C(F)(F)F)c2ccccc2C1(O)c1cc2c(cc1O)OCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2ccccc2C12OCOc1cc3c(cc12)OCCO3
Temperature: 25 °C
Yield: 34 %

Procedure:
A 100 mL flask was charged under argon with 3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-{[3-(trifluoromethyl)pyridine-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (0.46 g, 1.0 mmol), chloroiodomethane (0.36 g, 2.0 mmol), cesium carbonate (1.3 g, 4.0 mmol) and anhydrous tetrahydrofuran (50 mL). The reaction mixture was heated at reflux for 3 h, allowed to cool to ambient temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography and eluted with a 0% to 50% gradient of ethyl acetate in dichloromethane to afford 1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-7,8-dihyrdospiro[1,4-dioxino[2,3-g][1,3]benzodioxine-4,3′-indol]-2′(1H)-one (0.16 g, 34%) as an off-white solid: mp>250° C. (methanol); 1H NMR (300 MHz, CDCl3) δ 8.65 (d, J=4.5 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.35-7.14 (m, 3H), 6.95-7.03 (m, 1H), 6.68 (s, 1H), 6.57 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 5.70 (ABq, 2H), 5.21 (ABq, 2H), 4.25-4.01 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 176.3, 152.3, 152.2, 147.8, 144.1, 143.3, 138.9, 134.3, 134.2, 134.2, 134.1, 130.7, 130.2, 129.2, 125.6, 125.2, 124.8, 124.4, 124.0, 123.5, 122.2, 122.0, 114.9, 114.2, 108.7, 105.3, 88.3, 77.2, 64.5, 64.0, 41.8, 41.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8]2.[OH-:16].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]2[C:9]=1[CH2:8][C@@H:7]([CH3:15])[C@H:6]([OH:16])[CH2:5]2
Reactant: COc1ccc(OC)c2c1CC=C(C)C2
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(OC)c2c1C[C@@H](C)[C@H](O)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4 (5.00 g, 24.5 mmol) in tetrahydrofuran (100 ml) was cooled to 0° C. and treated with 1 M borane-tetrahydrofuran complex (24.5 mL, 24.5 mmol) and the resulting solution was stirred at room temperature for 4 h. Then, 12 mL of 3 N NaOH solution was added slowly to the stirring reaction solution followed by the addition of 6 mL of 30% aqueous hydrogen peroxide. After stirring for 30 min, the resultant mixture was diluted with 500 mL of ethyl acetate and washed by brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated, and the residue was purified on silica gel (30% ethyl acetate\hexane) to give 5 as a white solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][N:6]1[CH2:11][CH2:10][C:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:12][CH:8]2[CH2:7]1.O1CCOCC1>O>[CH3:5][N:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([N:1]=[N+:2]=[N-:3])[CH:8]([OH:12])[CH2:7]1
Reactant: CN1CCC2(c3ccccc3)OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCC(N=[N+]=[N-])(c2ccccc2)C(O)C1

Procedure:
1.4 G. of sodium azide (NaN3) in 6 ml. of water was added to a solution of 3.6 g. of 1-methyl-4-phenyl-3,4-epoxypiperidine in 20 ml. of dioxane and the resulting combined solution refluxed for 2 hours. A further portion of 1.4 g. of NaN3 in 6 ml. of water was then added and the reaction mixture refluxed overnight. Upon cooling 3.2 g. of crystals of the desired 1-methyl-4-phenyl-4-azido-3-hydroxypiperidine were obtained, which had a melting point of 170°-71° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) (0.1 mmol, 32 mg) in 0.7 ml of DM in a 16×100 mm tube was treated with phenol (0.15 mmol, 15 mg), cesium carbonate (0.3 mmol, 95 mg). The mixture was stirred at room temperature overnight and the reactants were filtered and washed with DMF a several times. The solvent was evaporated under vacuum, and the residue was reconstituted in a mixture of ethanol (2 ml) and NaOH (1M, 1 ml), which was stirred at room temperature until temperature until reaction was completed by HPLC-MS. Upon completion, HCl (1M) was added pH=3) and the solvents were eliminated under vacuum. The residue was reconstituted in CH2Cl2/H2O and filtered through a hidrofobic syringer. The organic layer was separated, concentrated and purified by HPLC-MS to afford the title compound as a colorless oil. MS (ES) for C19H22O5 [M+NH4]+: 348.4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:8]=2[CH:14]=1)([O-])=O.[H][H]>CO.[Pd]>[CH:14]1[C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCOCC2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CCOCC2

Procedure:
2-Nitro-5,6,8,9-tetrahydro-7-oxa-benzocycloheptene (270 mg/1.3 mmol) was dissolved in anhydrous methanol (ca. 10 mL) and the solution added to a Parr flask. Palladium (10% on charcoal) was added carefully and the mixture shaken under 40 psi of hydrogen for 2 hours. The mixture was then filtered and the colorless filtrate concentrated onto celite. Chromatography on an amine-bonded column (eluting with 0→60% ethyl acetate/hexanes) afforded 5,6,8,9-tetrahydro-7-oxa-benzocyclohepten-2-ylamine as a colorless solid (200 mg/quantitative). 1H NMR (400 MHz, CDCl3) δ 6.89 (d, J=7.6 Hz, 1H), 6.42 (m, 2H), 3.78 (m, 4H), 3.55 (br s, 2H), 2.88 (m, 4H).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:30][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[N:15]=2
Reactant: CCCCCNc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCNc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of N2-pentyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (543 mg) in dry chloroform (4.6 mL) was cooled to 0° C. and NBS (334 mg) was added. The mixture was stirred at room temperature for 10 mins. The reaction was taken up in DCM (30 mL) and was washed with water (30 mL). The organics were separated, dried using a hydrophobic frit and concentrated in vacuo to give the title compound as a viscous brown residue (627 mg) which was used crude in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[CH2:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:27]1[CH:28]=[CH:29][C:24]([CH:22]=[CH:23][C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]3[CH2:14][CH2:13][N:12]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][C:7]=2[Cl:8])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Temperature: 25 °C
Yield: 35 %

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 66a (470 mg, 1.25 mmol) in acetonitrile (6.2 mL) was added 4-vinylpyridine (0.17 mL, 1.57 mmol), palladium acetate (26.0 mg, 0.11 mmol), tri-o-tolylphosphine (130 mg, 0.1 mmol) and triethylamine (2.6 mL). The reaction mixture was heated at reflux overnight, then cooled to room temperature. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with EtOAc:hexane 1:1 to 3:1 to afford the title compound (176 mg, 35% yield). MS (CI/NH3) m/z 402 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.27-2.43 (m, 2H), 3.86-3.95 (m, 2H), 4.27-4.24 (m, 1H), 4.36-4.67 (m, 1H), 4.50-4.60 (m, 1H), 7.07 (d, J=11, 1H), 7.41-7.47 (m, 4H), 7.57 (d, J=11, 1H), 7.58-7.65 (m, 1H), 8.09 (d, J=2, 1H), 8.61-8.68 (m, 2H).
Reaction SMILES: [CH2:1](O)[CH3:2].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[OH:15])[O:11][CH2:10][CH2:9][CH:8]2[C:16]([OH:18])=[O:17].S(=O)(=O)(O)O>C(OCC)(=O)C>[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[OH:15])[O:11][CH2:10][CH2:9][CH:8]2[C:16]([O:18][CH2:1][CH3:2])=[O:17]
Reactant: O=C(O)C1CCOc2cc(O)c(Cl)cc21
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(O)c(Cl)cc21
Temperature: 25 °C
Yield: 43 %

Procedure:
A 20-liter 4-neck round-bottom flask was charged with ethanol (8.6 L) and crude 6-chloro-7-hydroxychroman-4-carboxylic acid (1.70 kg, 7.44 mol) and the resulting mixture was stirred at ambient temperature. Concentrated sulfuric acid (397 mL) was added over 10 minutes. The resulting mixture was stirred and heated to reflux for 16 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (9.0 mL). The resulting mixture was washed with brine (2×12 L). The brine washes were combined and extracted with ethyl acetate (4 L). The ethyl acetate layer was washed with brine (2 L). The organic layers were combined and dried over sodium sulfate, then concentrated under reduced pressure at a temperature below 50° C. The residue was purified by chromatography on silica gel (18 kg), eluting with 85:15 hexanes:ethyl acetate (235 L), to afford ethyl 6-chloro-7-hydroxychroman-4-carboxylate as a white powder (822 g, 43% yield). MS (apci) m/z=255.1 (M−H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>C1CCN2C(=NCCC2)CC1.O1CCCC1>[N:1]1([CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C=CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)CCn1cnc2ccccc21
Yield: 91.5 %

Procedure:
A solution of 10.0 g (84 mmol) of benzimidazole, 22.7 ml (250 mmol) of methyl acrylate and 3 drops of DBU in 50 ml of tetrahydrofuran was heated at reflux for 2 days. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography using 3% methanol in chloroform to provide 15.7 g (92%) of the desired compound (Rf 0.58, 10% methanol in chloroform).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]1[CH:34]([CH2:35][CH2:36]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:33][N:32]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[C:31]1=[O:59].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:36][CH2:35][CH:34]2[CH2:33][N:32]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:51][CH:50]=3)[C:31](=[O:59])[N:30]2[CH3:29])=[CH:11][C:10]=1[CH2:16][N:17]1[C:18](=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN2C(=O)c3ccccc3C2=O)c1
Temperature: 60 °C
Yield: 72.1 %

Procedure:
To a solution of 3-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-hydroxy-phenyl]-propionic acid tert-butyl ester (57 mg, 0.15 mmol) and Toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (75 mg, 0.16 mmol) in DMF (1 ml) is added Cs2CO3 (64 mg, 0.19 mmol), and the mixture heated at 60° C. for 14 hours. The mixture is cooled, diluted with water (25 ml) and extracted with ethyl acetate (2×25 ml). The combined organic extracts were washed with brine (30 ml), dried (Na2SO4), and concentrated to an oil. Purification by flash chromatography on a Biotage silica cartridge (gradient elution, 5:1 to 1:1 hexanes:acetone) produced an oil (72 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[C:11]1(C)[CH:16]=[CH:15][C:14](S(O)(=O)=O)=[CH:13][CH:12]=1.O>C1(C)C=CC=CC=1>[CH3:14][C:13]1[N:1]([C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=2)[C:16]([CH3:15])=[CH:11][CH:12]=1
Reactant: Cc1cc(N)nc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(-n2c(C)ccc2C)nc(C)c1Br

Procedure:
To a stirred solution containing 2.76 g (13.75 mmol) of 2-amino-5-bromo-4,6-dimethylpyridine (13) in 25 mL of toluene were added 2.02 mL (17.18 mmol) of 2,5-hexadienone followed by 130 mg (0.68 mmol) of p-toluene sulfonic acid. The reaction mixture was stirred at reflux overnight under argon atmosphere. The reaction mixture was poured into 150 mL of water and then extracted with a portion of 200 mL of ethyl acetate. The organic solution was washed with a portion of 150 mL of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 5:1 gave the expected product as an orange oil: yield 2.37 g (62%). 1H-NMR (CDCl3) δ 6.93 (s, 1H), 5.88 (s, 2H), 2.70 (s, 3H), 2.47 (s, 3H), 2.12 (s, 6H); 13C-NMR (CDCl3) δ 157.35, 149.32, 128.42, 122.49, 121.22, 25.58, 23.41, 13.10.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.Cl[CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:28][C:22]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=1[N:18]1[CH2:17][CH2:16][N:15]([C:13]([C:5]2[CH:4]=[CH:3][C:2]([N:1]3[CH2:30][CH2:31][CH2:32][S:33]3(=[O:35])=[O:34])=[CH:7][C:6]=2[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:14])[CH2:20][CH2:19]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3NS(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3NS(C)(=O)=O)CC2)c(C)c1

Procedure:
Using N-{5-amino-2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}methanesulfonamide (588 mg) described in Preparation Example 153 and 3-chloropropane-1-sulfonyl chloride (0.23 mL) and by the reaction and treatment in the same manner as in Example 78, the title compound (94 mg) was obtained.
Reaction SMILES: O.[OH-].[Li+].[N:4]([CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([Cl:18])[CH:9]=1)=[N+:5]=[N-:6]>O.O1CCCC1>[N:4]([CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([Cl:18])[CH:9]=1)=[N+:5]=[N-:6]
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A solution of lithium hydroxide monohydrate (7.00 g, 166.8 mmol) in water (100 mL) was added to a solution of 4-(azidomethyl)-2-chlorobenzoic acid, methyl ester (12.17 g, 53.9 mmol) in tetrahydrofuran (100 mL) and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated to remove some of the tetrahydrofuran. The solution was extracted with ethyl acetate (200 mL) and the extract was discarded. Then 1 M HCl (100 mL) was added and the mixture was extracted with ethyl acetate (2×200 mL). The combined organic layers were dried (MgSO4), filtered, and evaporated to give 4-(azidomethyl)-2-chlorobenzoic acid (6.82 g, 60%) as a white solid, mp 87-88° C.