Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)N)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:18][CH2:19][O:20][C:21]([CH2:23][CH:24]1[C:29](=O)[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22]>>[CH2:2]([N:9]1[C:25]2[CH:24]([CH2:23][C:21]([O:20][CH2:19][CH3:18])=[O:22])[CH2:29][CH2:28][CH2:27][C:26]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NN(Cc1ccccc1)c1ccc(F)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccccc1)c1ccc(F)cc21

Procedure:
Following the procedure of Example 1, but using 1-(benzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:5][O:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:25][C:26]([F:49])([F:48])[CH2:27][CH2:28][C@@H:29](OS(C(F)(F)F)(=O)=O)[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:6]([C@H:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:29]([CH2:28][CH2:27][C:26]([F:25])([F:48])[F:49])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:5][O:4][N:3]=1
Reactant: Cc1nocc1CC(=O)OC(C)(C)C
Reactant: O=C(OCc1ccccc1)[C@@H](CCC(F)(F)F)OS(=O)(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nocc1[C@H](C(=O)OC(C)(C)C)[C@@H](CCC(F)(F)F)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
In a 250 mL round-bottomed flask a solution of tert-butyl 2-(3-methylisoxazol-4-yl)acetate (1.75 g, 8.87 mmol) in THF (56 mL) and toluene (27 mL) was cooled in −78° C. bath and treated with a solution of 1M KHMDS (11.09 mL, 11.09 mmol) in THF dropwise over 2 minutes via syringe. After stirring for 15 minutes at −78° C., the reaction mixture was placed in a room temperature water bath for 15 minutes and then again in −78° C. bath for another 15 minutes before a solution of Preparation 4D (R)-benzyl 5,5,5-trifluoro-2-(trifluoromethylsulfonyloxy)pentanoate (4.55 g, 11.53 mmol) in 6 mL THF and 3 mL toluene was added to the reaction over 2 minutes. The reaction mixture was stirred in −78° C. bath for 2 hours before being quenched with saturated aqueous NH4Cl and then warmed to room temperature. The mixture was diluted with brine and extracted with EtOAc. The organic layer was dried over MgSO4 filtered and concentrated. The residue was purified on silica gel column (330 g ISCO) eluting with a gradient of 0-30% EtOAc/CH2Cl2, and collected tubes containing product were concentrated to give (2R,3R)-1-benzyl 4-tert-butyl 3-(3-methylisoxazol-4-yl)-2-(3,3,3-trifluoropropyl)succinate (2.394 g, 61% yield) containing about 30% of the (2R,3S) isomer.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:4].[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[CH2:11]([O:13][P:14]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:4])([O:15][CH2:16][CH3:17])=[O:18])[CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: C=C(CBr)c1ccccc1
Product: C=C(CP(=O)(OCC)OCC)c1ccccc1
Temperature: 25 °C

Procedure:
α-(Bromomethyl)styrene was treated with an equimolar ratio of triethylphosphite at reflux for 1 h. After the mixture was cooled to room temperature, the by-product, ethyl bromide, was removed under reduced pressure, and the product α-(diethoxyphosphorylmethyl)styrene was obtained in quantitative yield as a yellowish syrup: 1H NMR (CDCl3) δ 1.20 (6H, t, 2×OCH2CH3, J 7.5 Hz), 3.05 (2H, d, CH2P(O), J 22.5 Hz), 4.00 (4H, m, 2×OCH2CH3), 5.35 (1H, d, olefinic proton, J 6.0 Hz), 5.50 (1H, d, olefinic proton, J 6 Hz), 7.25-7.55 (5H, m, aromatic protons).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:14].[Br:15][C:16]1[C:20]([CH3:22])([CH3:21])[O:19][C:18](=O)[CH:17]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>C1COCC1>[Br:15][C:16]1[C:20]([CH3:22])([CH3:21])[O:19]/[C:18](=[C:3]2/[C:2](=[O:14])[NH:1][C:9]3[C:4]/2=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=3)/[CH:17]=1
Reactant: CC1(C)OC(=O)C=C1Br
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)/C(=C1/C=C(Br)C(C)(C)O1)C(=O)N2
Temperature: 0 °C
Reaction time: 1.33 h

Procedure:
To a 0° C. stirred solution of methyl oxindole-5-carboxylate (421 mg, 2.2 mmol) and 4-bromo-5,5-dimethylfuran-2(5H)-one (382 mg, 2.0 mmol) in THF (10 mL), was added 1M LiHMDS/THF solution (4.4 mL, 4.4 mmol) under nitrogen. The mixture was stirred at 0° C. for 80 min, quenched with 2.5M H2SO4 (3 mL), and poured into 100 mL of water. The precipitates were filtered, washed with water, and dried in vacuo to give methyl (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-2-oxoindoline-5-carboxylate as yellow solid. Yield: 408 mg, 56%.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:39]=[C:23]4[C:24]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[O:34][CH2:35][CH:36]([F:38])[F:37])=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[F:38][CH:36]([F:37])[CH2:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:24]1[C:23]2[N:22]([N:21]=[C:20]([NH:19][C:17]3[CH:16]=[CH:15][C:12]4[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=4[CH:18]=3)[N:39]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5ccccc5OCC(F)F)cccn4n3)cc2CC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)COc1ccccc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12

Procedure:
{8-[2-(2,2-Difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine was prepared from 7-{8-[2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.388 g, 0.725 mmol) and trifluoroacetic acid (1 mL) in a manner analogous to Example 312 to give product (0.264 g, 84%). MP=87-90° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.46 (s, 1H), 8.75 (d, 1H), 7.65 (m, 2H), 7.42 (m, 2H), 7.35 (s, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 6.22 (br m, 1H), 4.32 (m, 2H), 2.70 (br m, 9H). MS=436 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cc(F)ccc1F

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2,5-difluorophenyl-boronic acid (CAS RN 193353-34-3) and using preparative HPLC for the chromatographic purification. Off-white solid (36%). MS (ESI): m/z=461.2 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:12][O:13]CC1C=CC=CC=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([C@H:8]([CH2:12][OH:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H](COCc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@@H](CO)Cc1ccccc1
Yield: 103.6 %

Procedure:
420 mg of (2R)-2-benzyl-3-benzyloxypropionic acid was dissolved in 5.5 ml of ethanol, and hydrogenated at an ordinary temperature under an atmospheric pressure for two hours in the presence of palladium black. The insolubles were removed by filtration, and then the solvent was distilled off under reduced pressure to obtain 290 mg of (2R)-2-benzyl-3-hydroxypropionic acid as colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[Si](C)(C)[CH3:16].CCCCCCC>CO>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: C[Si](C)(C)Cl
Solvent: CO
Solvent: CCCCCCC
Product: COC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzoic acid 10-1 (5.22 g, 28.2 mmol) in methanol (30 mL) was added chlorotrimethylsilane 10-2 (6.00 g, 1.96 eq.). The reaction mixture was stirred under reflux during 16 h, then cooled down to room temperature, concentrated and the resulting precipitate was filtered off, washed with a small quantity of methanol, then heptane, to provide 4.36 g (78% yield) of 2-fluoro-5-nitro-benzoic acid methyl ester 10-3 as a white powder; m/z=200 (M+H)+.
Reaction SMILES: [CH:1]1([CH:4]2[CH2:9][N:8]3[N:10]=[C:11]([I:18])[C:12]([C:13]([O:15]CC)=[O:14])=[C:7]3[CH2:6][N:5]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O.C(Cl)Cl>[C:22]([O:21][C:19]([N:5]1[CH:4]([CH:1]2[CH2:2][CH2:3]2)[CH2:9][N:8]2[N:10]=[C:11]([I:18])[C:12]([C:13]([OH:15])=[O:14])=[C:7]2[CH2:6]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)c1c(I)nn2c1CN(C(=O)OC(C)(C)C)C(C1CC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2CC1C1CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 93.9 %

Procedure:
To a stirred solution of Intermediate 348E (0.85 g, 1.843 mmol) in ethanol (2 mL) and water (1 mL) was added NaOH (0.369 g, 9.21 mmol) and the resulting solution was stirred at RT for 10 h. The reaction mixture was diluted with DCM (10 mL) and washed successively with an aqueous solution of 1N HCl, water and brine. The organic layer was then dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford the Intermediate 348F as an off-white solid (0.75 g, 94%). MS(ES): m/z=434 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 12.6 (br. s., 1H), 5.11 (d, J=18.89 Hz, 1H), 4.45 (d, J=18.51 Hz, 1H), 4.16-4.25 (m, 2H), 3.82 (br. s., 1H), 1.43 (s, 9H), 0.82-0.96 (m, 1H), 0.47 (d, J=7.93 Hz, 2H), 0.35 (dd, J=6.80, 4.91 Hz, 2H).
Reaction SMILES: [C:1]([N:9]1[CH2:16][C@@H:15](OS(C2CCCCC2)(=O)=O)[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[C:1]([N:9]1[CH2:16][C@H:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@H](OS(=O)(=O)C2CCCCC2)CN1C(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)c1ccccc1

Procedure:
Following the procedure outlined in Example 2C, (cis)-1-benzoyl-4-[(cyclohexylsulfonyl)oxy]-L-proline was treated with aluminum chloride and benzene to afford a mixture consisting of:
Reaction SMILES: [O:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=O)CC.[CH:10](OCC)=O.[O-]CC.[Na+].[NH2:19][C:20]([NH2:22])=[O:21]>C1(C)C=CC=CC=1.CCO>[CH2:8]([O:7][C:5]1[C:4]([OH:1])=[N:19][C:20]([OH:21])=[N:22][CH:10]=1)[CH3:9]
Reactant: NC(N)=O
Reactant: CCOC=O
Reactant: CCOCC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1cnc(O)nc1O
Temperature: 110 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
A mixture of ethyl ethoxylacetate (20 g, 1.0 eq) and ethyl formate (11.21 ml, 1.0 eq) was added dropwise to a slurry of sodium ethoxide (10.3 g, 1.0 eq) in toluene (100 ml) in ice both. After dropping at room temperature and stirring overnight, the resulting solution was dried in vacuo. Then a mixture of residue, urea (9.09 g, 1.0 eq) and sodium ethoxide (10.3 g, 1.0 eq) in EtOH (100 ml) was refluxed at 110° C. for 6 hrs. After the solvent was dried in vacuo, water and conc. HCl solution (5<pH<4) were added. After formation of white precipitates, the mixture was filtered and dried solid in vacuo. A product was obtained as a white solid (7.76 g, 32%)
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([N:32]([C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:22][C:21]1[CH:20]=[N:19][CH:18]=[C:17]([Cl:23])[C:16]=1[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([N:32]([C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH:25]=2)[C:4]([OH:43])=[O:3])=[CH:8][CH:9]=1)=[O:15]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)c1ccc(OC)c(N(CC(C)C)C(=O)C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(Cc2ccc(NC(=O)c3c(Cl)cncc3Cl)cc2)C(=O)O)cc1N(CC(C)C)C(=O)C(C)(C)C

Procedure:
Thus obtained 3-[4-(3,5-dichloropyridine-4-carbonylamino)phenyl]-2-{3-[(2,2-dimethylpropionyl) isobutylamino]-4-methoxyphenyl}propionic acid ethyl ester (400 mg, 0.64 mmol) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), and added with a 2 mol/L aqueous sodium hydroxide solution (5 mL, 10 mmol). The solvent was evaporated under reduced pressure, the resultant residue was added with water to be dissolved, and the solution was washed with diethyl ether. The separated aqueous phase was added with a 1 mol/L hydrochloric acid so as to adjust pH of the solution to 5 to 7. The solution was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure so as to remove the solvent to thereby obtain 3-[4-(3,5-dichloro pyridine-4-carbonylamino)phenyl]-2-{3-[(2,2-dimethyl propionyl)isobutylamino]-4-methoxyphenyl}propionic acid (yield: 353 mg, yield ratio: 92%) as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:18]=[C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])[CH:16]=2)[CH:10]=1)(=O)=O.[CH:35]([NH2:38])([CH3:37])[CH3:36].[CH:39]([OH:41])=[O:40].ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:39]([OH:41])=[O:40].[Cl:26][C:22]1[CH:21]=[C:20]([N:19]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][NH:38][CH:35]([CH3:37])[CH3:36])[CH:10]=3)=[CH:16][C:17]([C:27]([N:29]3[CH2:33][C:32](=[O:34])[NH:31][CH2:30]3)=[O:28])=[N:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)N
Reactant: CS(=O)(=O)OCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Agent: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: CC(C)NCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 121A and isopropylamine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 29 mg (28% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Na+].[F:3][CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:8]2[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:7]=2[NH:6][C:5]1=[O:23].[CH3:24]I>O1CCCC1>[F:3][CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:8]2[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:7]=2[N:6]([CH3:24])[C:5]1=[O:23]
Reactant: O=C1Nc2ccc(Br)cc2C(c2ccccc2F)=NC1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)C(F)N=C(c2ccccc2F)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A slurry of 0.17 g (0.007 mole) of sodium hydride in 10 ml of tetrahydrofuran was added to a solution of 1.8 g (0.005 mole) of 3-fluoro-7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 10 ml methyl iodide in 100 ml tetrahydrofuran. The reaction mixture was stirred for 3 hr at 25° and then poured into 300 ml ice water. The aqueous mixture was extracted with methylene chloride, and the extracts were dried (MgSO4) and then evaporated to dryness under reduced pressure. The residue was recrystallized from heptane to give 0.91 g (50%) of cream-colored crystals: mp 127°-130° (with previous softening); 1H nmr (CDCl3) δ 3.49 ppm (s, 3H), 5.62 ppm (d, J = 57 Hz, 1H) and 6.9-7.9 ppm (m, 7H); 19F nmr (CDCl3) δ -111.9 ppm (m, 1F) and -162.4 ppm (d, J = 57 Hz, 1F).
Reaction SMILES: [CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:5][CH2:6][C:7]1[S:8][CH:9]=[CH:10][C:11]=1[CH3:12])([CH3:3])[CH3:2].C([Li])CCC.C(O[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1)(C)C.[Cl-].[NH4+]>O1CCCC1>[CH:16]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:13]([CH3:15])[CH3:14])[O:5][CH2:6][C:7]1[S:8][C:9]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)=[CH:10][C:11]=1[CH3:12])([CH3:18])[CH3:17]
Reactant: Cc1ccsc1CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)sc1CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A mixture of triisopropyl[(3-methylthien-2-yl)methoxy]silane (intermediate 115, 1.42 g) in tetrahydrofuran (20 ml), stirred at −78° C. under nitrogen, was treated with 1.6M butyllithium in hexanes (3.9 ml). The reaction temperature was slowly allowed to rise to 0° C. over 2 hours and then re-cooled to −78° C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.28 ml) was added and the reaction stirred at this temperature for 4 hours and then warmed to 0° C. The reaction was added to a mixture of saturated ammonium chloride and ice. The aqueous mixture was extracted with diethyl ether and the organic solution dried with brine and over sodium sulfate. Evaporation of the solvent afforded the title compound as a white solid
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:10][CH3:11])=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[N+:12]([CH2:15][CH2:16][CH3:17])([O-])=[O:13].C1(N=C=O)C=CC(N=C=O)=CC=1.O>C(N(CC)CC)C.C1C=CC=CC=1>[CH2:16]([C:15]1[CH:9]=[C:8]([C:6]2[CH:5]=[N:4][C:3]([S:10][CH3:11])=[C:2]([Cl:1])[CH:7]=2)[O:13][N:12]=1)[CH3:17]
Reactant: C#Cc1cnc(SC)c(Cl)c1
Reactant: CCC[N+](=O)[O-]
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: CCc1cc(-c2cnc(SC)c(Cl)c2)on1
Reaction time: 8 h
Yield: 479.8 %

Procedure:
A mixture of 3-chloro-5-ethynyl-2-methylthiopyridine (0.5 g, 2.72 mmol), 1-nitropropane (0.24 g, 0.27 mmol), 1,4-phenylenediisocyanate (1.3 g, 7.93 mmol) and triethylamine (5 drops) in benzene (20 mL) was heated under reflux with stirring for 8 hours, and allowed to stir at room temperature overnight. Water (1 mL) was added and the mixture stirred at room temperature for 2 hours. It was filtered through Celite, dried over anhydrous sodium sulphate and evaporated under reduced pressure. Recrystallisation of the residue from hexane gave the desired product (0.33 g, 48%) as a cream solid, melting point. 78-80° C.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[N:15]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19][CH:18]([C:21](OC)=O)[CH2:17][CH2:16]1.O>C1(C)C=CC=CC=1.CO>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]=[C:21]2[CH:18]2[CH2:19][CH2:20][N:15]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:16][CH2:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCNc1ccccc1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Al](C)C
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C2=NCCN2c2ccccc2)CC1
Temperature: -10 °C
Reaction time: 5 h

Procedure:
To a stirred solution of phenyl ethylene diamine (3 g) taken in dry toluene (50 ml), cooled to −10° C., trimethylaluminium (36 ml, 2M solution in hexane) was added drop wise for 30 minutes. The reaction mixture was brought to room temperature and was heated to 50° C. 1-tert-Butyl 4-methyl piperidine-1,4-dicarboxylate (8 g) taken in dry toluene (50 ml) added to the above mixture in a drop wise fashion. The combined mixture was stirred at 110° C. for 5 hours, then allowed stir over night at room temperature. To the reaction mixture water (50 ml) was added followed by methanol (50 ml) and allowed to stir for 15 minutes at 0° C. The whole mixture was then filtered through celite bed and washed with chloroform. The combined filtrate was concentrated under reduced pressure. The resulting crude was purified by column chromatography using methanol/chloroform (2:8) as eluent to afford tert-butyl 4-(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)piperidine-1-carboxylate as solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:14]([N:17]([CH2:33][C:34]([OH:36])=[O:35])[C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH2:31][CH3:32])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:16])=[O:15])[CH:5]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:14]([N:17]([CH2:33][C:34]([OH:36])=[O:35])[C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH2:31][CH3:32])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:16])=[O:15])[CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1
Reactant: CCn1c2ccccc2c2cc(N(CC(=O)O)S(=O)(=O)c3cc(Cl)cc(C#C[Si](C)(C)C)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1cc(Cl)cc(S(=O)(=O)N(CC(=O)O)c2ccc3c(c2)c2ccccc2n3CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
134 mg [(3-chloro-5-trimethylsilylethynyl-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino]-acetic acid are dissolved in 2 ml of methanol, combined with 50 mg potassium carbonate and stirred for 2 hours at ambient temperature. Then the mixture is diluted with dichloromethane and washed with 4 M hydrochloric acid. The organic phase is dried on magnesium sulphate and the solvent is then eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 100:0 to 95:5).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([N:18]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCC(O)C2)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 36.2 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70.0 mg, 0.29 mmol), 3-pyrrolidinol (Aldrich Chemical Company) (0.12 mL, 1.44 mmol) and K2CO3 (0.40 g, 2.87 mmol) in H2O (2 mL). The crude material was purified by flash chromatography on silica gel with 10:1 CHCl3:MeOH as eluant to give 30.9 mg (37%) of the title compound as an off-white solid. An analytical sample was obtained by recrystallization from EtOH. Mp: 234-235° C. 1H NMR (DMSO-d6; 500 MHz): δ 1.96-2.05 (m, 2), 2.39 (s, 3), 3.77-3.93 (m, 4), 4.43 (s, 1), 5.03 (s, 1), 6.71 (s, 1), 7.38-7.50 (m, 3), 7.88 (d, 2, J=7.6), 10.64 (br s, 1). MS m/z: 295 (M+1), 293 (M−1). HRMS: Calcd for M+H: 295.1923. Found: 295.1910.