Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:16][C:15]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)C.O.[OH-].[Na+]>CO>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:32])=[O:3])[CH2:7][CH2:8]2)=[N:13][CH:14]=[C:15]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:16]=1)=[O:27]
Reactant: CCOC(=O)CC1CCN(c2ncc(S(C)(=O)=O)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1cnc(N2CCC(CC(=O)O)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Yield: 82.8 %

Procedure:
To a suspension of 1.41 g (2.94 mmol) of [3′-(3-Chloro-benzoylamino)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester in a 1:1 mixture of water:methanol (30 mL) is added 4.0 mL (10 mmol) of sodium hydroxide as a 10% aqueous solution. After stirring at room temperature overnight the methanol is removed under reduced pressure and the pH of the resulting solution is adjusted to approximately pH 5 by the addition of a 2 N solution of hydrochloric acid. The mixture is extracted with ethyl acetate and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 1.10 g (82.9%) of [3′-(3-chloro-benzoylamino)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=2)[CH:5]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>ClCCCl>[CH:20]([C:16]1[CH:15]=[C:14]([N:13]2[CH2:12][CH2:11][N:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([O:2][CH3:1])=[O:23])[C:24]2=[O:25])[CH:19]=[CH:18][CH:17]=1)([CH3:21])[CH3:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1cccc(NCCNc2cccc(C(C)C)c2)c1
Solvent: ClCCCl
Product: COC(=O)c1cccc(N2CCN(c3cccc(C(C)C)c3)C2=O)c1
Temperature: 90 °C
Yield: 85.4 %

Procedure:
To the solution of 3-[2-(3-isopropylphenylamino)ethylamino]benzoic acid methyl ester (0.83 g, 2.7 mmol) prepared above in dry 1,2-dichloroethane (5.0 mL) was added, under nitrogen, 1,1′-carbonyldiimidazole (0.65 g, 4.0 mmol). The mixture was then heated at 90° C. for 24 h. After cooling to room temperature, the mixture was washed with water, diluted HCl, water and brine, then dried over anhydrous Na2SO4 and concentrated. The crude product was obtained after the removal of the solvent and further purified by column chromatography (silica gel, hexanes:ethyl acetate, 9:1) to give methyl 3-[3-(3-isopropylphenyl)-2-oxo-imidazolidin-1-yl]benzoate as colorless needles (0.78 g, 85.7%). MS (ES+) m/z: 339.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:41])[CH3:40])=[CH:34][CH:33]=2)[C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][C:11]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[C:17]([CH2:16][CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][N:23]=3)[CH:12]=2)[N:7]([C:32]2[CH:33]=[CH:34][C:35]([O:38][CH:39]([CH3:40])[CH3:41])=[CH:36][CH:37]=2)[C:6]=1[C:4]([OH:5])=[O:3])([OH:19])=[O:18]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)n(-c2ccc(OC(C)C)cc2)c2ccc(-c3ccc(C(F)(F)F)cn3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-n2c(C(=O)O)c(CCC(=O)O)c3cc(-c4ccc(C(F)(F)F)cn4)ccc32)cc1
Temperature: 90 °C

Procedure:
A mixture of 3-(2-ethoxycarbonylethyl)-1-(4-isopropoxyphenyl)-5-(5-trifluoromethylpyridin-2-yl)indole-2-carboxylic acid ethyl ester (150 mg, 0.26 mmol; see step (d) above), NaOH (aq, 1 M, 2.5 mL) and dioxane (4 mL) was heated at 90° C. for 1 h, cooled, acidified with HCl (aq, 1 M) to pH 2 and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to give the title compound. Yield 50 mg (38%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[O:12][CH2:13][C:14]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=2[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1>>[O:1]([CH2:8][CH2:9][NH:10][C:11]1[O:12][CH2:13][C:14]2[CH:20]=[C:19]([NH:21][S:25]([CH:22]3[CH2:24][CH2:23]3)(=[O:27])=[O:26])[CH:18]=[CH:17][C:15]=2[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Reactant: O=S(=O)(Cl)C1CC1
Product: O=S(=O)(Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2)C1CC1
Yield: 72.3 %

Procedure:
Prepared from the above described N2-(2-phenoxy-ethyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (155 mg, 0.50 mmol, HPLC 0.691 min) and cyclopropanesulfonyl chloride (77 mg, 0.55 mmol) according to the procedure described for Example 27. Obtained the title compound as an off-white foam (140 mg, 73%, HPLC 1.261 min), MS (ISP) m/e=388.3 [(M+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH2:7][N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15](O)=[O:16])[N:10]=[N:9]1)([O-:3])=[O:2].NOS(O)(=O)=O.[N+](C1C=C(C=CC=1)CN1C=C(C=CC(O)=O)N=N1)([O-])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH2:7][N:8]1[CH:12]=[C:11]([CH:13]=[CH:14][CH:15]=[O:16])[N:10]=[N:9]1)([O-:3])=[O:2]
Reactant: O=C(O)CCc1cn(Cc2cccc([N+](=O)[O-])c2)nn1
Agent: NOS(=O)(=O)O
Agent: O=C(O)C=Cc1cn(Cc2cccc([N+](=O)[O-])c2)nn1
Product: O=CC=Cc1cn(Cc2cccc([N+](=O)[O-])c2)nn1
Yield: 22 %

Procedure:
3-[1-(3-nitrobenzyl)-1,2,3-triazol-4-yl]-propionic acid (m.p. 147°-150° C.; prepared by reduction by means of hydroxylamine-O-sulphonic acid of 3-[1-(3-nitrobenzyl)-1,2,3-triazol-4-yl]-acrylic acid (m.p. 155°-158° C.), which is obtained by oxidation of the corresponding 3-[1-(3-nitrobenzyl)-1,2,3-triazol-4-yl]-acrolein (m.p. 136°-140° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[Cl:11][C:12]1[CH:35]=[CH:34][CH:33]=[CH:32][C:13]=1[CH:14]=[CH:15][CH2:16][C:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:23](=[O:25])[CH3:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21].[OH-].[Na+]>C(O)C.O>[Cl:11][C:12]1[CH:35]=[CH:34][CH:33]=[CH:32][C:13]=1[CH:14]=[CH:15][CH2:16][C:17]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:23](=[O:25])[CH:24]=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: COc1ccccc1C=O
Reactant: CC(=O)C(CC=Cc1ccccc1Cl)(CCC(=O)O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccccc1C=CC(=O)C(CC=Cc1ccccc1Cl)(CCC(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
o-Methoxybenzaldehyde (2.72 g., 0.02 mole) in ethanol (10 ml.) is added to a solution of 4-(o-chlorocinnamyl)-4-phenyl-5-oxohexanoic acid (3.57 g., 0.01 mole) and sodium hydroxide (0.56 g., 0.014 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (200 ml.), and extracted with ether to remove the excess o-methyoxybenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (10 ml.), and the yellow solid which precipitates is collected and air-dried. Several recrystallizations from ethanol yields a pale yellow material with m.p. 206.5°-209.5°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>ClCCl.O>[Si:17]([O:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: OCCOc1ccnc(Cl)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccnc(Cl)n1
Reaction time: 0.17 h

Procedure:
2-[(2-Chloropyrimidin-4-yl)oxy]ethanol (416 mg, 2.38 mmol) in dichloromethane (9.5 mL) at 0° C. was added to an oven-dried, nitrogen cooled vial containing imidazole (389 mg, 5.72 mmol). The solution was stirred for 10 minutes. TBS-Cl (424 mg, 2.81 mmol) was added and the reaction mixture was stirred at room temperature for 2 h then, diluted with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-2-chloropyrimidine as a clear, yellow oil. MS ESI calcd. for C12H22ClN2O2Si [M+H]+ 289. found 289. 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J=5.7, 1H), 6.67 (d, J=5.7, 1H), 4.62-4.30 (m, 2H), 4.02-3.87 (m, 2H), 0.87 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19]CC3C=CC(OC)=CC=3OC)=[N:15][CH:16]=2)[N:11]([CH3:31])[C:10]1=[O:32].FC(F)(F)C(O)=O>ClCCl>[NH2:19][C:14]1[N:13]=[C:12]2[N:11]([CH3:31])[C:10](=[O:32])[N:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:18][C:17]2=[CH:16][N:15]=1
Reactant: COc1ccc(CNc2ncc3c(n2)N(C)C(=O)N(c2c(Cl)cccc2Cl)C3)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
A solution of 200 mg (0.42 mmol) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-(2,4-dimethoxybenzylamino)-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one in 2 ml of dichloromethane was treated with 2 ml of trifluoroacetic acid and the mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The solvent was evaporated, the residue was triturated with saturated aqueous sodium bicarbonate solution and the product was collected by filtration and sucked dry. The dried product was purified further by suspension in dichloromethane and filtration through a polytetrafluoroethylene membrane. The filtrate was evaporated and the residue was dried to give 115 mg (84%) of 7-amino-3-(2,6-dichlorophenyl)-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 176-184° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[CH:6]=[CH:5]2.[Se](=O)=[O:16]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH:14]=[O:16])[CH:6]=[CH:5]2
Reactant: O=[Se]=O
Reactant: COc1cc2nc(C)ccc2cc1F
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2nc(C=O)ccc2cc1F
Yield: 73.4 %

Procedure:
To 6-fluoro-7-methoxy-2-methylquinoline (1.4 g, 7.3 mmol) in dioxane/water (10 ml/l mL) at ambient temperature was added selenium dioxide (0.97 g, 8.8 mmol) and the reaction was heated to reflux for 2-3 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 6-fluoro-7-methoxyquinoline-2-carbaldehyde (1.1 g, 73% yield) as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].CO.Cl>O1CCCC1>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1cc(Br)c(N)c(C(=O)O)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Br)c(N)c(CO)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
The 2-amino-3-bromo-5-methylbenzoic acid (20.0 g, 86.0 mmol) was dissolved in tetrahydrofuran (200 ml) and cooled to 0° C. A solution of borane dimethylsulfide complex (15.6 mL, 156.0 mmol) was dissolved in tetrahydrofuran (40 mL) and added dropwise. The solution was kept at 0° C. for an additional 30 minutes, warmed to room temperature for 2 h and finally refluxed for 16 h. The solution was cooled to room temperature and methanol (10 mL) added slowly to control the gas evolution. The solution was stirred for 30 minutes at room temperature and 1 N hydrochloric acid added. The solution was stirred for 3 h and solvent removed to a volume of about 100 mL. Water (200 mL) was added and the solution extracted with diethylether (200 mL). The aqueous layer was collected, adjusted to pH=12 with 1N sodium hydroxide which formed a solid in the solution. The solid was collected, dissolved in ethyl acetate (100 mL), dried over sodium sulfate and solvent removed at reduced pressure. The (2-amino-3-bromo-5-methylphenyl)methanol (9.5 g, 43.9 mmol) was obtained as a off white solid. (51% yield): HRMS m/z 216.0047; calcd for M+H 216.0024.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([CH:14]([OH:21])[CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:8]2=[N:9][CH:10]=1)=[O:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.ClCCl>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](=[O:21])[CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11]([S:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)(=[O:23])=[O:24])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(c1)cc(C(O)CC1CCCC1)n2S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)cc(C(=O)CC1CCCC1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a 25 mL round bottomed flask charged with 1-benzenesulfonyl-2-(2-cyclopentyl-1-hydroxy-ethyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (730 mg, 1.7 mmol) was added a solution of Dess-Martin periodinane in dichloromethane (0.3M, 12 mL, 3.6 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (3×20 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to give 1-benzenesulfonyl-2-(2-cyclopentyl-acetyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (670 mg, 93%) as a light yellow solid which was used without further purification: 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (m, 2H), 1.52-1.74 (m, 4H), 1.97 (m, 2H), 2.45 (m, 1H), 3.04 (d, J=7.2 Hz, 2H), 3.98 (s, 3H), 6.99 (s, 1H), 7.57 (m, 2H), 7.65 (m, 1H), 8.43 (m, 2H), 8.55 (d, J=2.0 Hz, 1H), 9.21 (d, J=2.0 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[S:8][C:7]([OH:9])=[N:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][O:25][C:21]=2[CH:20]=1.C(N(C(C)C)CC)(C)C>CO>[OH:9][C:7]1[S:8][C:4]([CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:23]3[C:22]4[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=4[O:25][CH:24]=3)[CH2:27][CH2:28]2)=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]=1
Reactant: Fc1ccc2c(C3CCNCC3)coc2c1
Reactant: Oc1nc(-c2ccc(F)cc2)c(CCCl)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Oc1nc(-c2ccc(F)cc2)c(CCN2CCC(c3coc4cc(F)ccc34)CC2)s1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A mixture of 0.134 g of 5-(2-chloroethyl)-2-hydroxy-4-(4-fluorophenyl)thiazole, 0.11 g of 4-(6-fluorobenzofuran-3-yl)piperidine hydrochloride, 0.28 ml of diisopropylethylamine and 0.5 ml of methanol was stirred with heating under reflux for 15 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by a flush chromatography (silica gel: Merckkieselgel 60 230- to 400-mesh, eluent: hexane-ethyl acetate=2:1). The purified product was recrystallized from ethyl acetate-hexane to obtain 0.066 g of 2-hydroxy-4-(4-fluorophenyl)-5-[2-[4-(6-fluorobenzofuran-3-yl)piperidin-1-yl]ethyl]thiazole.
Reaction SMILES: Br.NC1C=C(C=C(S(=O)(=O)N)C=1CC1C=CC=CC=1)CBr.C(N)CCC.Br.[NH2:28][C:29]1[C:30]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:31]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:32]=[C:33]([CH:36]=1)[CH2:34]Br.[CH3:49][NH:50][CH3:51]>>[NH2:28][C:29]1[C:30]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:31]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:32]=[C:33]([CH:36]=1)[CH2:34][N:50]([CH3:51])[CH3:49]
Reactant: CCCCOc1cc(CBr)cc(N)c1Cc1ccccc1
Reactant: CNC
Agent: Br
Agent: Nc1cc(CBr)cc(S(N)(=O)=O)c1Cc1ccccc1
Solvent: CCCCN
Product: CCCCOc1cc(CN(C)C)cc(N)c1Cc1ccccc1

Procedure:
By replacing in Example 110 3-amino-4-benzyl-5-sulfamylbenzylbromide hydrobromide and n-butylamine with 5-amino-4-benzyl-3-n-butoxybenzyl bromide hydrobromide and dimethylamine (40% in water) respectively, and following the procedure described, (5-amino-4-benzyl-3-n-butoxybenzyl)dimethylamine is obtained as a semi-solid material.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:30][C:31]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1cc(OC(F)(F)F)ccc1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(OC(F)(F)F)ccc1Cl
Yield: 1 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted 2-chloro-5-(trifluoromethoxy)phenylboronic acid (available from Frontier Scientific, Inc.; 120 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-5′-trifluoromethoxy-biphenyl-2-carboxylic acid (1.3 mg, 1%). LCMS analysis indicated that the material was ˜100% pure, as measured by UV at 214 nm.
Reaction SMILES: O=[O+][O-].[C:4]1([CH:10]([O:17][C:18](=[O:50])/[C:19](/[N:23]2[CH:26]([S:27][S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:24]2=[O:49])=[C:20](\O)/[CH3:21])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:51](Cl)Cl>>[C:4]1([CH:10]([O:17][C:18](=[O:50])[CH:19]([N:23]2[CH:26]([S:27][S:28]([C:31]3[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)(=[O:30])=[O:29])[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:24]2=[O:49])[C:20](=[CH2:51])[CH3:21])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: ClCCl
Reactant: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: O=[O+][O-]
Product: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1

Procedure:
Analogously to Example 1(d), 10.8 g (16.2 mM) of 2[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester in 1 l of methylene chloride and 1.1 equivalents of ozone give 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester; melting point 142°-143° C. (from ether/pentane).
Reaction SMILES: [NH2:1][NH2:2].[O:3]=[C:4]1[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][C:6](=O)[O:5]1>C(O)(=O)C>[OH:5][C:6]1[CH:7]=[C:8]([CH2:9][C:10]([OH:12])=[O:11])[C:4](=[O:3])[NH:1][N:2]=1
Reactant: NN
Reactant: O=C(O)CC1=CC(=O)OC1=O
Solvent: CC(=O)O
Product: O=C(O)Cc1cc(O)n[nH]c1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of hydrazine (103 mg, 3.21 mmol) in acetic acid (16 mL) was added to (2,5-dioxo-2,5-dihydro-furan-3-yl)acetic acid (500 mg, 3.04 mmol) under cooling with ice, and the mixture was heated with stirring at an external temperature of 76 to 84° C. for one hour. The reaction mixture was concentrated under reduced pressure. The resulting solid was sequentially washed with water, ethanol and ether to give the title compound (414 mg, 80%).
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]1([CH3:22])[C:10]([CH3:12])([CH3:11])[O:9][B:8]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[O:7]1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28].C1C=C2N=NN(O)C2=CC=1.O>O.CN(C=O)C>[CH3:23][O:24][CH2:25][CH2:26][N:27]([CH3:28])[C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([B:8]2[O:9][C:10]([CH3:11])([CH3:12])[C:6]([CH3:5])([CH3:22])[O:7]2)=[CH:21][CH:20]=1
Reactant: CNCCOC
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COCCN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 72 h
Yield: 18 %

Procedure:
EDC (310 mg, 1.6 mmol) was added to DMF (4 mL) solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (200 mg, 0.81 mmol), 2-methoxy-N-methylethanamine (144 mg, 1.6 mmol), TEA (0.23 mL, 1.6 mmol) and HOBT hydrate (247 mg, 1.60 mmol). After 3 days at room temperature, the reaction mixture was diluted in water (15 mL), extracted with DCM (3×10 mL), the combined organic portions dried over Na2SO4, filtered, concentrated under reduced pressure and purified by reverse phase HPLC (Phenomemenx Luna AXIA 5 micron C18, 21.2×100, UV at 220 nm, 10 to 70% B over 30 minutes with 10 minute hold time, solvent A: 90% water/ACNl/0.1% TFA, solvent B:90% ACN/water/0.1% TFA, Flow rate 20 mL/min; detector at 254) to isolate Compound B172a (47 mg, 18% yield) as a clear oil. HPLC: RT=0.96 min (LCMS Method M). MS (ES): m/z=319.7 [M+H]+. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.45-8.71 (m, 1H), 7.85 (d, J=7.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 3.89-3.64 (m, 2H), 3.42 (d, J=12.1 Hz, 3H), 3.34-3.12 (m, 3H), 3.04 (s, 2H), 1.36 (s, 12H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)([CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1CCN(Cc2ccccc2)CC1c1cccc(Cl)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(c2cccc(Cl)c2)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-benzyl-3-(3-chlorophenyl)-4-piperidone (75 mmol) in anhydrous THF (250 mL) is cooled to −30° C., then treated with a solution of freshly prepared lithium diisopropylamide (2.0 M in THF/heptane, 45 mL). After stirring for 15 minutes, a solution of methyl iodide (80 mmol) in THF (40 mL) is rapidly added. The mixture is stirred for 1 hour at −30° C., warmed quickly to room temperature, and quenched with a saturated aqueous solution of ammonium chloride. The organic layer is collected, washed with water, brine, and dried (MgSO4). After filtering, the filtrate is concentrated in vacuo to afford the desired intermediate.