Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[C:10]([F:16])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.OS(O)(=O)=O.[CH3:22]O>C(OCC)(=O)C>[CH3:22][O:15][C:13](=[O:14])[CH2:12][C:11]1[CH:2]=[C:3]2[C:8](=[CH:9][C:10]=1[F:16])[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: O=C(O)Cc1c(F)cc2ncccc2c1F
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc2cccnc2cc1F
Yield: 89.8 %

Procedure:
To a solution of (5,7-difluoro-quinolin-6-yl)-acetic acid (18.6 g, 83.4 mmol) in methanol (200 mL) was added conc. H2SO4 (4.7 mL, 87.0 mmol). The reaction mixture was concentrated to give a brown residue, which was diluted with 200 ml of ethyl acetate, washed with sat. aq. NaHCO3 and brine, then the organic layer was dried over anhydrous Na2SO4, and concentrated to give (7-fluoro-quinolin-6-yl)-acetic acid methyl ester as yellow solid (17.7 g, yield: 89.8%).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([O:14][C:15]1[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=1)=[CH:9]2)=[C:2]=[S:3].[CH3:29][O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:14][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([NH:1][C:2]([NH:35][C:34]1[CH:36]=[CH:37][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1)=[S:3])=[CH:13][CH:12]=[CH:11]2
Reactant: COc1cc2nccc(Oc3ccc4c(N=C=S)cccc4c3)c2cc1OC
Reactant: COc1ccc(N)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=S)Nc2cccc3cc(Oc4ccnc5cc(OC)c(OC)cc45)ccc23)cc1
Reaction time: 14 h

Procedure:
To a solution of 4-(5-isothiocyanatonaphthalen-2-yloxy)-6,7-dimethoxyquinoline (27 mg, 0.070 mmol) in DCM (348 μL) at RT was added 4-methoxyaniline (17.2 mg, 0.140 mmol) in one portion. After stirring for 14 h, the crude mixture was concentrated under reduced pressure and purified by silica gel chromatography. MS (ESI, pos. ion) m/z: 512.1. (M+1). Mass Calc'd for C18H15NO3: 511.60.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.B(OC)(OC)[O:25]C.C(O)(=O)C.OO>C1COCC1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([OH:25])[CH:18]=1
Reactant: COB(OC)OC
Reactant: Fc1ccc(Br)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Oc1cc(Br)ccc1F
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 85.3 %

Procedure:
To a solution of 2,2,6,6-tetramethyl piperidine (5.6 mL, 33.2 mmol) in THF at −20° C. was added n-BuLi (1.6 M in hexanes, 18.8 mL, 30 mmol). The mixture was stirred at −20° C. for 10 min before it was cooled to −78° C. 1-Bromo-4-fluorobenzene (2.95 mL, 27 mmol) was added over 10 min and the mixture was stirred at −78° C. for 2.0 h before trimethyl borate (6.0 mL, 54 mmol) was added. The mixture was stirred at −78° C. for 30 min and then at rt for 2.0 h. After it was cooled back to 0° C., glacial acetic acid (4.86 mL, 81 mmol) was added and stirred for 30 min, followed by addition of 30% H2O2 (4.86 mL, 81 mmol). The mixture was stirred at rt for 24 h, quenched by addition of MnO2 (40 mg). After stirring at rt for 30 min, the cloudy solution was filtered through a pad of wet Celite® and extracted with EtOAc. The EtOAc layer was washed with aqueous NaHSO3, brine and dried over Na2SO4. The crude residue was purified by flash column chromatography (EtOAc:hexanes=1:5) to give 4.4 g (85%) of 7A as a liquid. 1H NMR (400 MHz, CDCl3) δ ppm 5.39 (s, 1H) 6.90-6.98 (m, 2H) 7.14 (dd, J=8.13, 1.98 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@:11]2([C:16]([OH:18])=O)[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:19][C:20]1[CH:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=2[C:37]([F:40])([F:39])[F:38])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>>[NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:3]=1)[C:8]([NH:10][C@@:11]1([C:16](=[O:18])[NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[C:37]([F:38])([F:39])[F:40])=[CH:27][C:20]=2[F:19])[CH2:15][CH2:14][O:13][CH2:12]1)=[O:9]
Reactant: Nc1cncc(C(=O)N[C@@]2(C(=O)O)CCOC2)c1
Reactant: COc1ccc(Nc2ccc(CN)c(F)c2)c(C(F)(F)F)c1
Product: COc1ccc(Nc2ccc(CNC(=O)[C@]3(NC(=O)c4cncc(N)c4)CCOC3)c(F)c2)c(C(F)(F)F)c1
Yield: 27 %

Procedure:
Analogously to Example 1e), (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (0.55 mmol) was reacted with 2-fluoro-4-(4-methoxy-2-trifluoromethyl-phenylamino)-benzylamine (0.55 mMol, from 1b). The product was obtained in a yield of 27% of theory.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[N:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1.CS(C)(=O)=O>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([NH:45][C:42]3[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=3)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: Nc1ccncc1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(Nc3ccncc3)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, pyridin-4-ylamine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give N*4*-((S)-1-methanesulfonyl-piperidin-3-yl)-N*2*-pyridin-4-yl-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidine-2,4-diamine. MS (ES+): 466.
Reaction SMILES: Cl.CS[C:4]1[NH:5][CH2:6][CH:7]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:8]=1.[CH2:17]([NH2:23])[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[ClH:15].[CH2:17]([NH:23][C:4]1[NH:5][CH2:6][CH:7]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:8]=1)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccco1
Reactant: CSC1=NC(c2c(Cl)cccc2Cl)CN1
Agent: Cl
Solvent: CCO
Product: Clc1cccc(Cl)c1C1CNC(NCc2ccco2)=N1
Temperature: 140 °C

Procedure:
A mixture consisting fo 6.0 gm (0.0202 mol) of 2-methylmercapto-4-(2',6'-dichloro-phenyl)-2-imidazoline hydrochloride and 2.8 gm (0.029 mol) of furfurylamine was heated for 30 minutes at 140° C. The resulting dark-brown mass was dissolved in ethanol and then crystallized by addition of acetone and ether; for further purification, the crystallizate was again dissolved in ethanol and acetone, reprecipitated by addition of ether, and recrystallized from water, yielding 2.5 gm (35.7% of theory) of the yellow crystalline compound of the formula ##STR12## which had a melting point of 191° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].C[C:10](=[N:13]O)CC>>[CH3:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[N-:13]=[C:10]=[O:5]
Reactant: CCC(C)=NO
Solvent: CCCCOCCO
Product: [N-]=C=O

Procedure:
To the reactant, butyl cellosolve (72.7 parts by mass) was added. Subsequently, the temperature of the reactant was set to 50° C. To the reactant, 5.8 parts by mass of 2-butanone oxime (manufactured by Ardrich) was added dropwise to obtain a butyl cellosolve solution of isocyanate compound E having an average number of functional groups: 3.5.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:29]([N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH2:27][CH3:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(CC)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 59 %

Procedure:
A solution of 4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.5 g), benzyl bromide (0.58 mL) and cesium carbonate (1.6 g) in N,N-dimethylacetamide (15 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.0 g, 59%) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Br.[Na+].[I-:11]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][I:11]
Reactant: [I-]
Reactant: Clc1ccccc1CBr
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1ccccc1CI
Yield: 95 %

Procedure:
A mixture of 2-chlorophenylmethylbromide (4 g, 19.47 mmol) and NaI (14 g, 97.33 mmol) in acetone (40 ml) was stirred under reflux for 1 hour. The reaction mixture was cooled, filtered and concentrated in vacuo. The residue was triturated with hexane and filtered. The solution was concentrated in vacuo, and the resulting oil purified by flash chromatography (silica, hexane) to afford the title compound (4.67 g, 63%) as an oil: 1H NMR (CDCl3) δ 7.34 (4H, m), 4.54 (2H, s).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C@@H:7]([CH3:20])[C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH3:23][S:24]([CH2:27][C:28](O)=[O:29])(=[O:26])=[O:25].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:28](=[O:29])[CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])[C@@H:7]([CH3:20])[C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: C[C@@H]1Nc2ccc(Br)cc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2cc(Br)ccc2N1C(=O)CS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a 0° C. solution of tert-butyl(2S,3S)-7-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (130 mg, 351 μmol) and 2-(methylsulfonyl)acetic acid (53.4 mg, 386 μmol) in pyridine (3.51 ml) was added phosphoryl chloride (64.3 μl, 702 μmol). The reaction was stirred at 0° C. for 30 min, then quenched by the addition of H2O and extracted with EtOAc. The combined organic layers were washed with 1 N aq. citric acid, H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(2S,3S)-7-bromo-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (161 mg, 94%) as a white solid. MS m/z 512/514 (MNa)+.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[Br:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:11][CH2:10][CH2:9][Br:8])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: OCCBr
Reactant: C=CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCC(=O)OCCBr
Temperature: 0 °C
Reaction time: 19.5 h

Procedure:
4-Pentenoyl chloride (2.8 mL, 25.4 mmol) was dissolved in anhydrous methylene chloride (50 mL) and cooled to 0° C. under nitrogen. 2-Bromoethanol (2.0 mL, 28.2 mmol) and triethylamine (3.8 mL, 27.3 mmol) was added to the reaction solution resulting in a thick yellow slurry. The reaction solution was stirred for 19.5 h while slowly warming to 22° C. The reaction mixture was diluted to 100 mL with methylene chloride and extracted with 75 mL of each of the following: water, sat. ammonium chloride, and sat. sodium bicarbonate. The organic phase was dried (MgSO4), filtered and condensed in vacuo to yield a yellow oil (5.2 g cu. 100%) which was used as is for the next step. 1H NMR δ 5.90-5.65 (m, I H), 5.15-4.90 (m, 2H), 4.39 (t, 2H, J=6.0), 3.48 (t, 2H, J=6.0), 2.50-2.30 (m, 4H).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.[C:16]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:18])[CH3:17]>O1CCOCC1>[O:18]=[C:16]([CH3:19])[CH:17]=[CH:1][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: COC(=O)c1ccc2c(C=O)c[nH]c2c1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C=CC(C)=O)c[nH]c2c1
Yield: 17 %

Procedure:
To a stirred solution of methyl 3-formylindole-6-carboxylate (368 mg) in 1,4-dioxane (10 ml) was added acetylmethylene triphenylphosphorane (1.15 g), and the mixture was stirred under reflux for 12 hours. The resulting mixture was evaporated in vacuo, redissolved with ethyl acetate and washed with 1N hydrochloric acid and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of chloroform and ethyl acetate (1:2) to give methyl 3-(3-oxo-1-butenyl)indole-6-carboxylate (75 mg) as a solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)([C:17]([OH:19])=O)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)([C:17]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:19])[CH2:13][CH2:12]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)O)(C2CCCCC2)CC1
Reactant: CC(C)(C)N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)C1(C2CCCCC2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
4-Cyclohexyl-1,4-piperidinedicarboxylic acid 1-(phenylmethyl) ester (8-4) (2.50 g, 7.24 mmol) was dissolved in 36 mL of methylene chloride and cooled at 0° C. in an ice-water bath. Oxalyl chloride (2.0 M solution in CH2Cl2, 3.98 mL, 7.96 mmol) was then added dropwise followed by the addition of 1-2 drops of DMF. This mixture was stirred at 0° C. for 2 h and then concentrated with toluene. The residue was dissolved in 36 mL of methylene chloride and cooled at 0° C. in an ice-water bath. tert-Butylamine (2.28 mL, 21.7 mmol) was then added dropwise, and the reaction mixture was stirred at 0° C. for 2 h, warmed to room temperature, and stirred at room temperature overnight. The resulting mixture was diluted with methylene chloride, washed with brine, dried over MgSO4, filtered, and concentrated to give 2.92 g of title compound 8-5 as a solid. LCMS (ESI): m/z 401 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][C:38]([O:40]C(C)(C)C)=[O:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][N:25]5[CH2:37][C:38]([OH:40])=[O:39])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN1
Product: O=C(O)CN1CCC[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
[(2S)-2-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}pyrrolidin-1-yl]acetic acid was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2S)-pyrrolidin-2-ylmethyl]-1,3-thiazolidine-2,4-dione (Example 145) and tert-butyl bromoacetate using the same methods as described by Procedure I.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1/[CH:16]=[CH:17]/[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=1)[OH:19].[C:28]1([CH3:37])[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1/[CH:16]=[CH:17]/[CH:18]([OH:19])[C:20]1[CH:21]=[C:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:37])[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(O)c1cccc(Br)c1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(O)c1cccc(-c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.1 %

Procedure:
To a solution of 7-{(R)-2-[(E)-3-(3-bromo-phenyl)-3-hydroxy-propenyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid methyl ester, (0.2 g, 0.46 mmol) in 10 mL of DME stirred at room temperature was added Pd(Ph3P)4 (0.03 g, 0.05 eq). After stirring for 5 minutes, o-tolylboronic acid (0.12 g, 2 eq) an 2M Na2CO3 (0.6 mL, 2.5eq) were added and the mixture was refluxed overnight under N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with 25% NH4Oac (10 mL), stirred for 5 minutes and then was extracted with ethyl acetate, the organic layer was dried over MgSO4 (anhydrous), concentrated under the reduced pressure and purified to yield 87 mg of 7-{(R)-2-[(E)-3-hydroxy-3-(2′-methyl-biphenyl-3-yl)-propenyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid methyl ester.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH2:2][CH3:3].Cl[C:12]1[N:13]=[N+:14]([O-:25])[C:15]2[C:24]3[CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=[CH:18][C:16]=2[N:17]=1>COCCOC>[O-:25][N+:14]1[C:15]2[C:24]3[CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=[CH:18][C:16]=2[N:17]=[C:12]([NH:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][CH3:10])[CH2:1][CH2:2][CH3:3])[N:13]=1
Reactant: CCCN(CCC)CCN
Reactant: [O-][n+]1nc(Cl)nc2ccc3c(c21)CCC3
Solvent: COCCOC
Product: CCCN(CCC)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCC3
Yield: 91.9 %

Procedure:
N,N-Dipropyl-1,2-ethanediamine (297) (0.53 g, 3.7 mmol) was added to a stirred solution of chloride 5 (325 mg, 1.5 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 10 (454 mg, 94%) as a pale yellow solid: mp (MeOH) 148-151° C.; 1H NMR δ 7.54 (d, J=8.4 Hz, 1H, H-6), 7.40 (d, J=8.4 Hz, 1H, H-5), 5.77 (br s, 1H, NH), 3.63-3.68 (m, 2H, H-9), 3.48-3.52 (m, 2H, CH2N), 2.95-3.00 (m, 2H, H-7), 2.68 (dd, J=6.0, 5.8 Hz, 2H, CH2N), 2.40-2.45 (m, 4H, 2×CH2N), 2.16-2.23 (m, 2H, H-8), 1.43-1.52 (m, 4H, 2×CH2), 0.90 (t, J=7.3 Hz, 6H, 2×CH3); 13C NMR δ 158.5, 149.0, 142.0, 137.3, 132.2, 129.2, 124.7, 55.9 (2), 52.6, 38.9, 35.3, 32.9, 24.8, 20.3 (2), 11.9 (2). Anal. calcd for C18H27N5O: C, 65.6; H, 8.3; N, 21.3. Found: C, 65.7; H, 8.6; N, 21.5%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8](=[O:10])[CH3:9])[CH:4]=1.[C:11](=O)([O-])[O-].[Cs+].[Cs+].CI>C1COCC1>[CH3:11][O:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8](=[O:10])[CH3:9])[CH:4]=1
Reactant: CC(=O)c1cc(CO)on1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Product: COCc1cc(C(C)=O)no1
Temperature: 60 °C

Procedure:
To a solution of 1-[5-(hydroxymethyl)-1,2-oxazol-3-yl]ethanone (1.00 g, 7.09 mmol) in dry THF (20 mL) under an atmosphere of nitrogen was introduced cesium carbonate (2.31 g, 7.09 mmol) and methyl iodide (5.03 g, 35.43 mmol). The reaction mixture was warmed to 60° C. for 16 hr, cooled to RT and the solids removed by filtration. The filtrate was re-treated with additional cesium carbonate (4.31 g, 13.23 mmol) and methyl iodide (9.59 g, 67.58 mmol) and warmed to 60° C. for 34 hr. After cooling to RT, the reaction mixture was filtered, concentrated in vacuo and the residue re-dissolved in EtOAc (50 mL). The EtOAc solution was washed with water (25 mL), brine (25 mL), dried (Na2SO4) and filtered. After concentrating the filtrate in vacuo, the residual oil was purified by silica gel flash column chromatography (95:5-50:50 gradient of heptane/EtOAc) to furnish the title compound as a colorless oil: 1H NMR (500 MHz, CDCl3) delta 2.66 (3H, s), 3.44 (3H, s), 4.59 (2H, s), 6.64 (1H, s).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:6]([O:15][CH3:16])=[CH:7][C:8]([OH:14])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].[Br:17]Br.O>C(Cl)Cl>[Br:17][C:7]1[C:8]([OH:14])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[O:15][CH3:16]
Reactant: BrBr
Reactant: COc1cc(O)c(C(C)=O)cc1C(C)(C)C
Solvent: O
Solvent: ClCCl
Product: COc1c(C(C)(C)C)cc(C(C)=O)c(O)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution of 10.7 g (48.1 mmol) of 1-[5-(1,1-dimethylethyl)-2-hydroxy-4-methoxyphenyl]ethanone in 250 ml of methylene chloride was added 8.11 g (50.7 mmol) of bromine. The reaction mixture was stirred at ambient temperature for 2 hours. Water (500 ml) was added. The organic phase was separated, washed with saturated aqueous sodium bicarbonate, dried and evaporated. The residue was filtered through 150 g of silica gel using 10:90 (v/v) ether:hexane as eluent. There was obtained 8.70 g (28.8 mmol, 60%) of 1-[3-bromo-5-(1,1-dimethylethyl)-2-hydroxy-4-methoxyphenyl]ethanone as white crystals after crystallization from hexane; mp 69°-71° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:15]([O:17][CH3:18])=[O:16])([CH3:14])[CH2:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>C(Cl)Cl>[F:26][C:27]([F:37])([F:38])[C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35]([N:11]2[CH2:12][C:13]([C:15]([O:17][CH3:18])=[O:16])([CH3:14])[C:9]([C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=3)=[N:10]2)=[O:36])=[CH:32][CH:33]=1
Reactant: COC(=O)C1(C)CNN=C1c1ccc(Cl)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Yield: 95 %

Procedure:
3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole hydrochloride (Example P) (10 mmole), triethylamine (20 mmole), methylene chloride (30 ml) were added together and stirred for 10 minutes, whereon 10 mmole of 4-trifluoromethylphenyl isocyanate was added and after 30 minutes the resulting mixture was washed twice with water, dried with magnesium sulfate and concentrated giving a 95% yield of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide. NMR data was consistent with the structure.