Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/P(OCC)(OCC)=O)=[CH:7]\[CH3:8])=[O:5].[K].C([O-])(C)(C)C.[Br:23][C:24]1[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][CH:25]=1.C(OCC)C>O1CCCC1>[CH2:2]([O:3][C:4](=[O:5])/[CH:6]=[CH:7]/[CH:8]=[CH:30]/[C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:23])[N:29]=1)[CH3:1]
Reactant: O=Cc1cccc(Br)n1
Reactant: C/C=C(\C(=O)OCC)P(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)/C=C/C=C/c1cccc(Br)n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A solution of 5.88 g of 4-phosphonocrotonic acid triethyl ester in 60 ml of tetrahydrofuran is mixed in portions with 2.5 g of potassium-tert-butanolate with stirring and under argon atmosphere at -20° C. After 30 minutes, a solution of 2.6 g of 6-bromopyridine-2-aldehyde is instilled at -20° C. and the mixture is stirred at this temperature for another hour. The reaction mixture is poured on ice, shaken out with diethyl ether, the organic phase is washed with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetate=95/5. 2.66 g of 5-(6-bromo-2-pyridyl)-(E,E)-2,4-pentadienoic acid ethyl ester is obtained as crude product.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([C:20]([CH3:26])([CH2:24][OH:25])[C:21](O)=[O:22])[CH:19]=2)[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:4]=2[CH:3]=1.C(O)C.O.C(=O)([O-])O.[Na+]>O1CCCC1>[F:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([C:20]([CH3:26])([CH2:21][OH:22])[CH2:24][OH:25])[CH:19]=2)[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:4]=2[CH:3]=1
Reactant: CC(CO)(C(=O)O)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(CO)(CO)n1cc(-c2cc(F)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Reaction time: 3 h
Yield: 67.6 %

Procedure:
To a solution of an optically active form (26.6 g) of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-methyl-propionic acid in tetrahydrofuran (40 ml) was added dropwise at room temperature a 1.09M solution (200 ml) of borane-tetrahydrofuran complex in tetrahydrofuran, and the mixture was stirred for 3 hr. To the reaction mixture was added dropwise ethanol (25 ml) at room temperature and the mixture was stirred at 80° C. for 1 hr. To this mixture were added water (200 ml) and saturated aqueous sodium hydrogen carbonate (100 ml) and the mixture was extracted twice with ethyl acetate (100 ml). The combined organic layer was successively washed twice with water (100 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 10/1) to give the title compound (17.4 g).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:23]=[C:22]([CH2:24][OH:25])[S:21][N:20]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:23]=[C:22]([CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])[S:21][N:20]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c(-c3nsc(CO)n3)cn(CC3CCCCC3)c12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c(-c3nsc(COS(C)(=O)=O)n3)cn(CC3CCCCC3)c12
Reaction time: 0.17 h
Yield: 104.7 %

Procedure:
To a cooled solution (ice/methanol bath) of [3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazol-5-yl]-methanol (2.3 g, 6.4 mmol) in dichloromethane (150 ml) was added methanesulfonyl chloride (0.595 ml, 7.68 mmol) and triethylamine (1.16 ml, 8.32 mmol) sequentially. The reaction was allowed to stir for 10 min and then poured into a separating funnel. The organics were washed with 5% aqueous sodium carbonate solution (2×100 ml), brine (100 ml), dried over magnesium sulfate and the solvent removed in vacuo to afford methanesulfonic acid 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazol-5-ylmethyl ester (2.9 g, 6.7 mmol) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[N:34]1([CH2:39][CH2:40][NH2:41])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH:41][CH2:40][CH2:39][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:15])=[CH:12][CH:11]=2)=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:31])([F:32])[F:33])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: O=C(O)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: NCCN1CCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCCN1CCCC1)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Yield: 71.3 %

Procedure:
Following General Procedure R, the title compound (345 mg, 71%) was prepared from 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (410 mg, 0.765 mmol), 2-(pyrrolidin-1-yl)ethanamine (0.15 ml, 1.15 mmol), EDC (293 mg, 1.53 mmol) and DMAP (cat.) in DMF (5 ml).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:9][C:8]=2[CH:18]=1)([O-])=O.S1C=CC=C1.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH2:9][C:8]=2[CH:18]=1
Reactant: CCOC(=O)C1CCc2cc([N+](=O)[O-])ccc2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: CCOC(=O)C1CCc2cc(N)ccc2O1
Yield: 90 %

Procedure:
A mixture of 59.8 parts of ethyl 3,4-dihydro-6-nitro-2H-1-benzopyran-2-carboxylate, 3 parts of a solution of thiophene in methanol 1% and 480 parts of methanol was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 48 parts (90%) of ethyl 6-amino-3,4-dihydro-2H-1-benzopyran-2-carboxylate as a residue (intermediate 24).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)#[N:13]>>[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(Cc1ccc(C#N)cc1)C(=O)OCC
Yield: 66.3 %

Procedure:
In the same manner as in Example 6 (1), a crude product was obtained using diethyl malonate (13.6 g) and 4-cyanobenzyl bromide (16.7 g). This was purified by silica gel column chromatography to give the title compound (15.5 g) as an oil.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]2[C:8]([C:11]3([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]3)=[N:9][N:10]=[C:6]2[C@@H:5]([NH:18]C(=O)OC(C)(C)C)[CH2:4][C@H:3]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-]>ClCCl>[CH3:1][C@H:2]1[N:7]2[C:8]([C:11]3([C:14]([F:15])([F:16])[F:17])[CH2:13][CH2:12]3)=[N:9][N:10]=[C:6]2[C@@H:5]([NH2:18])[CH2:4][C@H:3]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)OC(C)(C)C)c2nnc(C3(C(F)(F)F)CC3)n21
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)c2nnc(C3(C(F)(F)F)CC3)n21
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
To a solution of crude tert-butyl {(5R,6S,8S)-5-methyl-6-phenyl-3-[1-(trifluoromethyl)cyclopropyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-yl}carbamate (136 mg, 0.31 mmol) in dichloromethane (3.1 mL) was added trifluoroacetic acid (721 μL, 9.4 mmol) and the resulting mixture stirred 30 min. Saturated aqueous bicarbonate was added, and the resulting mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse chromatography (C-18, 95% water/acetonitrile 25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (38 mg). MS 337.2 (M+1).
Reaction SMILES: Cl.C(O[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C:8]1=O)=[O:6])C.FC(F)(F)C([O-])=O.[CH2:28]([N+:30]([CH2:34][CH3:35])=[C:31]([NH2:33])[NH2:32])[CH3:29].[O-]CC.[Na+]>CCO.O>[CH2:13]([N:10]1[CH2:11][CH2:12][C:7]2[C:5]([OH:6])=[N:33][C:31]([N:30]([CH2:34][CH3:35])[CH2:28][CH3:29])=[N:32][C:8]=2[CH2:9]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: CC[N+](CC)=C(N)N
Agent: CC[O-]
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Solvent: O
Product: CCN(CC)c1nc(O)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a solution of 1-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester hydrochloride (2.11 g, 7.1 mmol) in EtOH (35 mL) was added diethyl guanidinium trifluoroacetate (1.5 g, 7.1 mmol) and sodium ethoxide (21 wt % in EtOH, 6.7 mL). The reaction was heated at reflux for 16 h then cooled to room temperature (rt). The reaction mixture was diluted with H2O and extracted with CH2Cl2 (2×). The combined organic extracts were dried and concentrated. The resulting material was triturated with Et2O to give the title compound (1.54 g, 70%) as a light brown solid. MS (ESI): mass calcd. for C18H24N4O, 312.4; m/z found, 313.3 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(Cl)Cl>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]([N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]3)=[O:22])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)O)cc3[nH]c4ncc(C)cc4c23)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCS(=O)(=O)c1cccc(-c2cc(C(=O)N3CCN(C)CC3)cc3[nH]c4ncc(C)cc4c23)c1
Reaction time: 3 h
Yield: 67.1 %

Procedure:
Compound 139 (40 mg, 0.1 mmol) and HOBT (17 mg, 0.11 mmol) stirred in CH2Cl2 (2 mL) at r.t. EDC (29 mt, 0.15 mmol) and 1-methylpiperazine (45 mL, 0.4 mmol) were added, and the reaction stirred for 3 h. Organics were washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by prep-HPLC gave 32 mg (67%) of the title compound as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 8.22 (s, 1H), 8.12 (d, 1H, J=7.6 Hz), 8.03 (d, 1H, J=7.6 Hz), 7.87-7.95 (m, 2H), 7.80 (s, 1H), 7.40 (s, 1H), 3.39-3.62 (m, 4H), 3.31 (q, 2H, J=7.2 Hz), 3.16-3.30 (m, 4H), 2.95 (s, 3H), 2.38 (s, 3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C26H28N4O3S, 477; found 477.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O.C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:2]2[N:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=3[F:18])[CH:5]=[CH:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)n2)c(F)c1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CNc2nccc(Oc3ccc([N+](=O)[O-])cc3F)n2)cc1
Temperature: 100 °C
Yield: 30.4 %

Procedure:
A mixture of 2-chloro-4-(2-fluoro-4-nitrophenoxy)pyrimidine (0.66 g, 2.44 mmol), 4-methoxybenzylamine (0.34 g, 3.45 mmol), K2CO3 (0.37 g, 2.66 mmol), and DMF (15 mL) was heated at 100° C. for 1 h. The mixture was cooled, diluted with H2O (100 mL) and extracted with EtOAc (100 mL). The organic phase was washed twice each with saturated NaHCO3 solution and brine. The organics were dried (MgSO4) and concentrated to give the crude product. Flash chromatography on SiO2 using 1-3% MeOH in CH2Cl2 as the eluent gave the title compound (275 mg, 29%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 8.40-8.21 (m, 2H), 8.16 (dd, 1H, J=8.8, 1.7 Hz), 7.98 (br s, 0.5H), 7.73-7.55 (m, 1.5H), 7.16 (br s, 1H), 6.85-6.71 (m, 3H), 6.37 (s, 1H), 4.43 (br s, 1H), 3.95 (br s, 1H), 3.69 (s, 3H).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH2:34]([O:36][C:37](=[O:55])[C:38]1[CH:43]=[C:42]([C:44](=[O:46])[CH3:45])[CH:41]=[CH:40][C:39]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)C.O>O1CCCC1>[CH3:34][O:36][C:37](=[O:55])[C:38]1[CH:43]=[C:42]([C:44](=[O:46])[CH2:45][Br:1])[CH:41]=[CH:40][C:39]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: [Br-]
Reactant: CCOC(=O)c1cc(C(C)=O)ccc1OCc1ccccc1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Reaction time: 18 h
Yield: 72 %

Procedure:
Phenyltrimethyl ammonium tribromide (10.60 g, 28.20 mmol) was added in 7 portions to a stirring solution of acetophenone 44 (8.00 g, 28.10 mmol) in anhydrous tetrahydrofuran (50 mL). After 18 h, the reaction mixture was poured into water (250 mL) and stirred for 1 h. The formed precipitate was collected by vacuum filtration. Re-crystallization of the collected solid from ethanol gave the α-bromide 45 (7.35 g, 72%) as a white, needle solid: 1H NMR (500 MHz, DMSO-d6) δ 3.85 (s, 3H), 4.89 (s, 1H), 5.38 (s, 2H), 7.22 (d, 1H), 7.31-7.51 (m, 6H), 8.17-8.31 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:34]=[CH:33][C:13]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:17]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:16]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:34]=[CH:33][C:13]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:17]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:16]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3C)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ncccc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
A mixture of ethyl 3-[1-[4-(2-methy-3-pyridylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (568 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 4 hours, and 1N hydrochloric acid (3 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-(2-methyl-3-pyridylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (465 mg, yield: 87%). This was recrystallized from ethyl acetate-hexane. Melting point: 158–159° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:19]S(C2C=CC=CC=2)(=O)=O)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:6]=1)#[N:4].CC1CCCO1.[F:39][C:40]([F:56])([F:55])[C:41]1[CH:46]=[C:45]([NH:47][C:48]2[CH2:53][CH2:52][CH2:51][C:50](=[O:54])[CH:49]=2)[CH:44]=[CH:43][N:42]=1>O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:19][C:49]2[C:50](=[O:54])[CH2:51][CH2:52][CH2:53][C:48]=2[NH:47][C:45]2[CH:44]=[CH:43][N:42]=[C:41]([C:40]([F:39])([F:55])[F:56])[CH:46]=2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([S:29]([CH3:32])(=[O:30])=[O:31])[CH:6]=1)#[N:4]
Reactant: O=C1C=C(Nc2ccnc(C(F)(F)F)c2)CCC1
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2ccnc(C(F)(F)F)c2)CCCC1=O)c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 153 mg, 3.84 mmol) is added in portions to a mixture of tert-butyl (4-cyano-2-(methylsulfonyl)phenyl)(phenylsulfonyl)methylcarbamate (step 1, 1.60 g, 3.20 mmol based on 90% purity) and 2-methyltetrahydrofuran (15 mL), and the mixture is stirred at room temperature for 20 min. 3-(2-(Trifluoromethyl)pyridin-4-yl-amino)cyclohex-2-enone (intermediate 55, 940 mg, 3.70 mmol) is added, and the mixture is stirred for 2 h. Water is added, and the phases are separated. The organic layer is washed with water and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient dichloromethane/methanol 99:1 to 97/3). Yield: 2.10 g; ESI mass spectrum [M+H]+=565; Retention time HPLC: 0.67 min (X012_S02).
Reaction SMILES: C(O)C.[F:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([N+:17]([O-])=O)=[C:15]([C:20]#[C:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:14]([F:26])=[CH:13][C:12]=2[C:27](=[O:29])[CH3:28])[CH:8]=[CH:9][CH:10]=1>CO>[NH2:17][C:16]1[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=2)=[C:12]([C:27](=[O:29])[CH3:28])[CH:13]=[C:14]([F:26])[C:15]=1[C:20]#[C:21][Si:22]([CH3:24])([CH3:23])[CH3:25]
Reactant: CC(=O)c1cc(F)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1-c1cccc(F)c1
Solvent: CO
Solvent: CCO
Product: CC(=O)c1cc(F)c(C#C[Si](C)(C)C)c(N)c1-c1cccc(F)c1
Yield: 90 %

Procedure:
The desired compound was prepared according to the procedure of Example 16, step F, using ethanol (instead of methanol) and 1-{3′,4-difluoro-6-nitro-5-[(trimethylsilyl)ethynyl]biphenyl-2-yl}ethanone as the starting material in 90% yield. LCMS for C19H20F2NOSi (M+H)+: m/z=344.1; Found: 343.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)(=[O:13])=[O:12].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)(=[O:12])=[O:13]
Reactant: COC(=O)c1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(N)cc1

Procedure:
A solution of the title A compound, 2-(4-nitro-benzenesulfonylamino)-benzoic acid methyl ester (1 g, 2.98 mmol) in 40 mL of ethanol containing 0.32 g of 10% palladium on carbon is shaken under 40 psi of hydrogen pressure at RT for 2.5 h. The mixture is filtered and concentrated under vacuum to give 2-(4-amino-benzenesulfonyl-amino)-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([O:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:26](=[O:35])[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(N(C(C)C)CC)(C)C.[NH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[O:35]=[C:26]1[C:25]([CH:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C@H:12]([CH2:11][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)[C:13](=[O:14])[N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)=[O:18])[CH2:24][CH2:23]2)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn[nH]c12
Reactant: C1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCCCC2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and piperidine (21 μL, 2.0 equiv) in dimethylformamide (0.5 mL) and dichloromethane (0.5 mL) at 0° C. was added PyBOP® (57.6 mg, 0.11 mmol). The reaction was stirred at 0° C. for 4 h. The reaction was concentrated and purified by column chromatography (95:5:1 to 90:10:1 dichloromethane/methanol/triethylamine). The resulting residue was dissolved in 5% methanol/dichloromethane and passed through a basic alumina column to give 55 mg (93%) as a white powder. 1H-NMR (CD3OD, 500 MHz) δ 0.75-1.70 (m, 9H), 1.70-1.95 (m, 4H), 2.51 (s, 3H), 2.72-3.04 (m, 3H), 3.11 (m, 4H), 3.19-3.58 (m, 4H), 3.98-4.49 (m, 2H), 5.47 (dd, J=7.3, 7.3, 1H), 7.07 (s, 1H), 7.17 (m, 1H), 7.27 (m, 1H), 7.43 (m, 2.5H), 7.58 (d, J=7.3, 1H), 7.65 (bs, 0.5H), 7.96 (s, 1H). Mass spec.: 542.29 (MH)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](F)=[C:7]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[NH:18]C(=O)C(C)(C)C)[CH:8]=[CH:9][CH:10]=1)=[O:4].[Cl-].[NH+]1C=CC=CC=1>>[F:17][C:15]1[CH:16]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:18][C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][CH:9]=[CH:8][C:7]2=1
Reactant: COC(=O)c1cccc(-c2cc(F)ccc2NC(=O)C(C)(C)C)c1F
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Product: O=C(O)c1cccc2c1[nH]c1ccc(F)cc12
Temperature: 200 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
A mixture of 2′-(2,2-dimethyl-propionamido)-2,5′-difluoro-biphenyl-3-carboxylic acid methyl ester (92 mg) and pyridinium chloride (3.0 g) was stirred for 3 hours at 200° C., and then poured into ice-water. The suspension was stirred for 10 minutes. The precipitate was collected by filtration, washed with water and dried to give 6-fluoro-9H-carbazole-1-carboxylic acid (46 mg, 76.7%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=1)#N.CO.[Na]>C(O)(=O)C>[CH2:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[N:12][CH:13]=1)[CH3:18]
Reactant: Nc1ccccc1N
Reactant: CCc1ccc(C#N)nc1
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(-c2nc3ccccc3[nH]2)nc1

Procedure:
1.1 g. of o-phenylenediamine and 1.3 g. of 2-cyano-5-ethylpyridine were dissolved in 5 ml. of methanol. To the solution was added 0.05 g. of sodium in 1 ml. of methanol. The mixture was refluxed for 2 hours, then acidified with acetic acid and refluxed again for additional 4 hours. The reaction mixture was evaporated.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:20](OCC)=[O:21].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:20]([C:3]2[C:2](=[O:1])[C:11]3[C:6]4=[C:7]([CH:4]=[C:3]([C@H:2]([OH:1])[CH3:11])[N:5]4[CH:4]=2)[CH:8]=[C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:10]=3)=[O:21])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Product: C[C@@H](O)c1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 190 °C

Procedure:
To a flask containing ethyl 4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxylate of Preparation 25 (3.11 g) is added 4-chlorobenzylamine (8.0 mL). The mixture is degassed under reduced pressure. The mixture is placed under an argon atmosphere and is heated at 190° C. for 3 h. The reaction is cooled to room temperature. The excess benzylamine is removed by high vacuum distillation. The residue is crystallized from acetonitrile:methanol (1:1, 800 mL) to yield 3.08 g of the title compound as a white solid:.