Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3](COC2C=CC=C(F)C=2)=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C>[C:5]([OH:7])(=[O:6])[C:4]1[CH:10]=[CH:11][CH:12]=[CH:2][CH:3]=1
Reactant: CCOC(=O)c1cccc(F)c1COc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccccc1

Procedure:
To a solution of 13 g of ethyl 3-fluoro-2-[(3-fluorophenyloxy)methyl]benzoate in 100 ml of ethanol is added 50 ml of 5% aqueous solution of sodium hydroxide and the mixture is refluxed with heating for 1 hour. After the solvent is distilled off under reduced pressure, 300 ml of water is added and then 10% hydrochloric acid is added to make the mixture acidic. The precipitated crystals are collected by filtration and dried to give 11 g of 3-fluoro-2-[3-fluorophenyloxy)methyl]benzoic acid. Mass spectrum m/z: 264(M+).
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.Cl.[OH:15][CH:16]1[O:24][C@@H:23]([CH2:25][OH:26])[C@H:21]([OH:22])[C@@H:19]([OH:20])[C@@H:17]1[NH2:18]>CO.C([O-])(O)=O.[Na+]>[CH:3]1[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[C:6]2[C:10](=[N:9][O:8][N:7]=2)[C:2]=1[NH:18][C@@H:17]([C@H:19]([OH:20])[C@@H:21]([OH:22])[C@@H:23]([OH:24])[CH2:25][OH:26])[CH:16]=[O:15]
Reactant: N[C@@H]1C(O)O[C@@H](CO)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C[C@@H](Nc1ccc([N+](=O)[O-])c2nonc12)[C@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a brown flask, 4-chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) (483 mg) was placed and dissolved in methanol (14.0 ml). Under an argon atmosphere, a solution in which L-glucosamine hydrochloride (283 mg) was dissolved in 0.3 M NaHCO3 solution (5.57 ml) was added thereto, and the resulting mixture was stirred at room temperature. After 24 hours, methanol was removed by concentration under reduced pressure, and the resulting precipitates (unnecessary substances derived from NBD-Cl) were removed by filtration. The precipitates were washed with water, and the filtrate and the washing solution were combined, followed by purification by HPLC. A target fraction was collected and lyophilized, whereby a target product was obtained (yield: 102 mg, yield ratio: 23%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[S:16][C:15]([CH2:17][C:18]2([CH2:22][OH:23])[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:11][C:12]1[S:16][C:15]([CH2:17][C:18]2([CH:22]=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1
Reactant: OCC1(Cc2ccc(Cl)s2)CCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CC1(Cc2ccc(Cl)s2)CCC1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (12 mL, 24 mmol) was added to CH2Cl2 (250 mL) at −78° C. DMSO (3.75 g, 48 mmol) was added dropwise to the mixture and stirring was continued for 15 min. A solution of alcohol 20 (2.57 g, 12 mmol) in CH2Cl2 (20mL) was then added dropwise. After 1 hr at −78° C., Et3N (9.72 g, 96 mmol) was added and the mixture was warmed to 23° C. After 1 h, the mixture was poured into NaHCO3 (sat) and the organic layer was seperated. The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic layer was washed with brine, dried (Na2SO4), concentrated and purified by FCC (silica gel, 100% hexane; 2:1, hexane/CH2Cl2) to afford the above named aldehyde 21.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[C:22]([NH:26][NH2:27])[N:23]=[N:24][CH:25]=2)=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[N:24][N:23]3[C:1](=[O:2])[NH:27][N:26]=[C:22]3[C:21]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:18][CH:19]=1
Reactant: NNc1nncc(-c2ccc(Cl)cc2)c1-c1ccncc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a THF (100 mL) solution of carbonyldiimidazole (CDI) (7.25 g, 44.71 mmol) was added 1-(5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3-yl)hydrazine (3.8 g, 12.76 mmol) portionwise at RT under an atmosphere of argon. The reaction mixture was heated to reflux for 30 min. After this time, the reaction mixture was cooled to RT, and subsequently concentrated under reduced pressure to obtain a gum to which water (100 mL) was added. The resulting solid was collected by filtration, washed with water (2×50 mL) followed by 1:1 (v/v) of hexanes/ether (2×50 mL) to give the title compound, 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (3.75 g, 91%) as yellow solid. HPLC: 1.67 min; MS, M+H=324; 1H NMR (DMSO-d6) δ 12.90 (1H, s), 8.59 (2H, d, J=10.0 Hz), 8.41 (1H, s), 7.44 (2H, d, J=10.0 Hz), 7.32 (2H, d, J=5.0 Hz), 7.28 (2H, d, J=5.0 Hz).
Reaction SMILES: C([NH:4][C@@H:5]([C:17]([O:19]C)=[O:18])[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)(=O)C>Cl>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[CH2:6][C@H:5]([C:17]([OH:19])=[O:18])[NH2:4]
Reactant: COC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(C)=O
Agent: Cl
Product: N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A solution of 2.5 g of methyl N-acetyl-3-(2-naphthyl)-D-alaninate in 60 ml of 6 N HCl was heated at 120°-130° for 3 hours and cooled to room temperature. The white precipitate which formed was collected and recrystallized from 50 ml of H2O containing 1 ml of 12 N HCl by neutralization with NH4OH to pH 6, and dried in vacuo to yield 1.2 g of 3-(2-naphthyl)-D-alanine, m.p. 242°-244°, [α]D25 26.6° (c 0.5, CH3CO2H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][N:5]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]([CH2:23][N:24]2[CH2:29][CH2:28][N:27](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:26](=[O:49])[C:25]2=[O:50])=[CH:3]1.C(O)=O>ClCCl>[O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][N:5]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]([CH2:23][N:24]2[CH2:29][CH2:28][NH:27][C:26](=[O:49])[C:25]2=[O:50])=[CH:3]1
Reactant: O=C1C(=O)N(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1Cc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Solvent: ClCCl
Solvent: O=CO
Product: O=C1NCCN(Cc2cc(=O)c(OCc3ccccc3)cn2Cc2ccccc2)C1=O
Reaction time: 72 h
Yield: 94.9 %

Procedure:
To a solution of 1-[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinyl]-methyl]-4-(triphenylmethyl)-2,3-piperazinedione (8.77 g, 13.23 mmol) in 65 ml of dichloromethane was added dropwise at room temperature 65 ml of formic acid. After stirring for three days, the volatiles were distilled off in vacuo and the residue triturated twice with ether to give 5.24 g of 1-[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinyl]methyl]-2,3-piperazinedione, melting point 260°-265° C.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[O:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][O:19][C:16]2[CH:17]=[CH:18][C:13]([C:3]3[C:4]4[CH2:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[NH:1][N:2]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:25]1
Reactant: OCCN1CCOCC1
Reactant: Oc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: c1ccc2c(c1)Cc1c(-c3ccc(OCCN4CCOCC4)cc3)n[nH]c1-2
Temperature: 25 °C

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenol (0.76 g, Example 30) 4-(2-hydroxyethyl)morpholine (0.85 g), triphenylphosphine (1.77 g) and dichloromethane (20 ml) were stirred together with ice/water bath cooling and diethylazodicarboxylate (1.16 g) was added dropwise. The resultant mixture was allowed to warm to room temperature and stirred for about 24 hours. The solvent was evaporated off under reduced pressure and the residue purified by flash column chromatography on silica using ethyl acetate/ethanol (25%) to give a solid. The solid was triturated with diethyl ether (10 ml) and the solid filtered, washed with diether and dried at about 65° C. to give 3-[4-(2-morpholinoethoxy)phenyl]-1,4-dihydroindeno[1,2-c]pyrazole, m.p. 175-6° C.
Reaction SMILES: [CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[CH:21][CH:20]=2)[CH2:15][C@H:14]1[C:33]([O:35][CH3:36])=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CCCC(OCC)=O)CCOC1C=CC(CCC(O)C(F)(F)F)=CC=1)CCCCCCCCCCC>>[CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH:27]([OH:32])[C:28]([F:29])([F:31])[F:30])=[CH:23][CH:24]=2)[CH2:15][C@H:14]1[C:33]([O:35][CH3:36])=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(/C=C/C(O)C(F)(F)F)cc2)C[C@H]1C(=O)OC
Agent: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(O)C(F)(F)F)cc1
Product: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(CCC(O)C(F)(F)F)cc2)C[C@H]1C(=O)OC
Yield: 99 %

Procedure:
(2S, 4S)-1-N-Dodecyl-4-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-en-1yl]phenoxy]pyrrolidine-2-carboxylic Acid, Methyl Ester (552 mg., 1.07 mmol) was hydrogenated as described in the preparation of 4-[N-dodecyl-N-2-[4-[3-hydroxy-4,4,4-trifluorobutyl]phenoxy] ethylamino]-butanoic acid, ethyl ester and afforded the title compound (546 mg, 99%) as a clear oil. [a]D=−89.0° (c 0.4, CHCl3)
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:9])[CH3:8])=[CH:3][CH:2]=1.C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[CH3:44][C:32]1[N:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:25][CH:26]=2)[C:39]2[C:34]([C:33]=1[CH3:43])=[CH:35][C:36]([C:40](=[O:41])[NH:9][C@H:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)[CH3:8])=[CH:37][CH:38]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: Cc1ccc([C@H](C)N)cc1
Product: Cc1ccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(p-tolyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 517 [M+H]+.
Reaction SMILES: CC(O)(C)C.C[Mg+].[Br-].[NH2:9][C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:12]([O:14][CH3:15])=[O:13].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[CH:29]=[C:30]([C:35](=O)[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][O:45][CH2:46][CH2:47][NH:48][C:49]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:31]([O:33][CH3:34])=[O:32]>C1COCC1.O.C(O)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[CH:29]1[C:30]([C:31]([O:33][CH3:34])=[O:32])=[C:35]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:44][O:45][CH2:46][CH2:47][NH:48][C:49]([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[NH:9][C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:11]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(=Cc1c(Cl)cccc1Cl)C(=O)CCc1ccccc1COCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C=C(N)CC(=O)OC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2COCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-methyl-2-propanol (1.25 g, 16.9 mmol) in anhydrous THF (50 ml) was added dropwise a 0.95 M solution of MeMgBr in THF (17.8 ml, 16.0 mmol) at room temperature under nitrogen atmosphere. The resulting solution was stirred at room temperature for 0.5 hour. Then to the mixture was added a solution of dimethyl 3-amino-2-pentenedioate (1.33 g, 7.66 mmol) in anhydrous THF (20 ml) dropwise at room temperature. The resulting pale yellow solution was stirred at the same temperature for 0.5 hour, then a solution of methyl 3-(2,6-dichlorophenyl)-2-[3-[2-[[2-(tritylamino)ethoxy]methyl]phenyl]propanoyl]-2-propenoate (6.38 mmol) in anhydrous THF (20 ml) was added at room temperature. The reaction mixture was stirred at room temperature for 8 h under nitrogen atmosphere, then acetic acid (3 ml) was added. The resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into water, and the whole was extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with 2N-HClaq. (50 ml) and sat.NaHCO3aq. (50 ml), dried over MgSO4 and concentrated to afford a crude mixture. Purification on silica gel column chromatography eluted with hexane/EtOAc (3/1) to afford the titled compound as a yellow amorphous. (3.80 g, 85%).
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:36][C:37]1[C:38]2[N:39]([C:43]([C@H:55]3[CH2:60][CH2:59][C@H:58]([C:61](O)=[O:62])[CH2:57][CH2:56]3)=[N:44][C:45]=2[C:46]2[NH:47][C:48]3[C:53]([CH:54]=2)=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:40]=[CH:41][N:42]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:36][C:37]1[C:38]2[N:39]([C:43]([C@H:55]3[CH2:60][CH2:59][C@H:58]([C:61]([NH:4][CH2:2][CH3:3])=[O:62])[CH2:57][CH2:56]3)=[N:44][C:45]=2[C:46]2[NH:47][C:48]3[C:53]([CH:54]=2)=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:40]=[CH:41][N:42]=1
Reactant: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)[C@H]1CC[C@H](c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn32)CC1

Procedure:
Ethylamine hydrochloride (30 mg, 0.37 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (35 mg, 0.11 mmol), and N,N-diisopropylethylamine (80 μL, 0.53 mmol) were added to a solution of trans-4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylic acid (25 mg, 0.07 mmol) in anhydrous DMF (2 mL). Upon completion of reaction (as monitored by LCMS), the mixture was added to a saturated aqueous sodium bicarbonate solution (10 mL). The resulting precipitate was collected by filtration and washed with cold acetonitrile (3×10 mL) to afford 13 mg of the desired product. 1H NMR (d6-DMSO, 400 MHz): δ 11.41 (br s, 1H), 7.75 (dd, J=4.0, 4.0 Hz, 1H), 7.69 (d, J=4.0 Hz, 1H), 7.58 (d, J=8.0, 4.0 Hz, 1H), 7.45 (d, J=4.0, 4.0 Hz, 1H), 7.12 (dd, J=8.0, 8.0 Hz, 1H), 7.08-7.00 (m, 2H), 6.63 (m, 1H), 6.43 (br s, 2H), 3.16 (m, 1H), 3.07 (m, 2H), 2.18 (m, 1H), 2.02 (m, 2H), 1.84 (m, 2H), 1.66 (m, 4H) and 1.02 (t, J=4.0 Hz, 3H). MS (ES+): m/z 403.09 [MH+].
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:6]=2[CH:5]=[C:4]([F:19])[CH:3]=1.BrC1C=C(F)C=CC=1O.FC1C=C(C=CC=1)C=CC=O.[Cl:40][S:41](O)(=[O:43])=[O:42].N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl.O>[Br:1][C:2]1[C:10]2[O:9][C:8]([S:41]([Cl:40])(=[O:43])=[O:42])=[C:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:6]=2[CH:5]=[C:4]([F:19])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1cccc(Cc2coc3c(Br)cc(F)cc23)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=CC=Cc1cccc(F)c1
Agent: Oc1ccc(F)cc1Br
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Cl)c1oc2c(Br)cc(F)cc2c1Cc1cccc(F)c1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
7-Bromo-5-fluoro-3-(3-fluoro-benzyl)-benzofuran (0.97 gm, 3.0 mmol, prepared from 2-bromo-4-fluoro-phenol and 3-fluoro-cinnamaldehyde following the procedure of steps 1 and 2 of Example 8) was dissolved in dichloromethane (30 ml) and chilled to −15° C. Chlorosulfonic acid (0.26 ml, 3.9 mmol) in dichloromethane (2 ml) was added in portions, and the reaction mixture was stirred for 10 minutes then warmed to room temperature and stirred for 16 hours. To the resulting slurry was added pyridine (0.33 ml, 4.08 mmol) and phosphorus pentachloride (0.812 gm, 3.9 mmol) and the reaction mixture was stirred for 24 hours. Water was added and the reaction mixture was stirred for 30 minutes. The organic layer was separated, dried over magnesium sulfate, dried onto silica gel, and layered over a pad of silica gel in a fritted funnel. The silica gel was eluted with ethyl acetate/hexanes (1/9) to give 7-bromo-5-fluoro-3-(3-fluoro-benzyl)-benzofuran-2-sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]3)=[CH:16][CH:15]=2)[CH:13]=1.[Br:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][C:11]3[N:12]([C:14]4[CH:19]=[CH:18][C:17]([N:20]5[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]5)=[CH:16][CH:15]=4)[CH:13]=[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:10]=3)=[CH:30][CH:31]=2)=[CH:39][CH:38]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(I)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{-4-[4-(2,4-Dichloro-phenyl)-2-(4-iodo-benzyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (3.2 g, 5 mmol) was treated as described in general procedure G using 4-bromophenylboronic acid (2.0 g, 10 mmol) to give 5-{-4-[2-(4′-bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:11]=[N:10][C:9]([CH3:12])=[C:8]2[N:13]=[CH:14][NH:15][C:7]=12.S(=O)(=O)(O)[OH:17]>O.C(O)(=O)C>[CH3:12][C:9]1[C:8]2[N:13]=[CH:14][NH:15][C:7]=2[C:6](=[O:17])[NH:11][N:10]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1nnc(N)c2[nH]cnc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1n[nH]c(=O)c2[nH]cnc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 4.00 g sodium nitrite in 15 ml of water is added dropwise at 50° C. to 2.20 g of 4-amino-7-methyl-3H-imidazo[4,5-d]pyridazine in a mixture of 30 ml acetic acid, 5 ml of water and 0.5 ml concentrated sulphuric acid. The reaction mixture is stirred for a further two hours at 50° C. and then heated to 90° C. for one hour. After cooling to ambient temperature the reaction mixture is diluted with 30 ml of water. The precipitate formed is suction filtered, washed with water, ethanol and diethyl ether and dried.
Reaction SMILES: [CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:28])=[CH2:27])=[CH:22][N:21]=1.O>CN1C(=O)CCC1>[CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[N:6]([CH2:27][CH:26]([C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=3)[CH3:28])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(C)C3
Reactant: C=C(C)c1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(C)c2ccc(C)nc2)CC(C)N(C)C1
Temperature: 140 °C

Procedure:
A flask was charged with 2,3,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (117 mg, 0.5 mmol) and KOH (392 mg, 7 mmol) in NMP (2 mL) and heated at 140° C. for 10 min. The mixture was cooled to 0° C. and to it was added 2-methyl-5-(prop-1-en-2-yl)pyridine (199 mg, 1.5 mmol) dropwise. The mixture was heated at 140° C. for 2 h. The progress of the reaction was monitored by LCMS (5% conversion). The mixture was cooled to RT, water was added and the mixture filtered and evaporated. The solid obtained was purified by HPLC. 1HNMR (CD3OD, TFA salt) d (ppm): 8.10 (m, 2H), 7.60 (m, 1H), 7.22 (s, 1H), 7.10 (d, 1H), 6.96 (d, 1H), 4.62 (m, 1H), 4.38 (m, 2H), 4.22 (m, 2H), 3.50 (m, 2H), 3.0 (s, 3H), 2.80 (s, 3H), 2.40 (s, 3H), 1.60-1.30 (m, 7H).
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24](Cl)=[O:25])[CH:19]=[C:20]([F:22])[CH:21]=1>>[C:1]([C:5]1[C:6]([NH:14][C:24](=[O:25])[CH2:23][C:18]2[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cc1cc(F)cc(F)c1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)c1c(NC(=O)Cc2cc(F)cc(F)c2)nn2cccnc12

Procedure:
The product from Example 105B and 3,5-difluorophenylacetyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H), 3.70 (s, 2H), 6.98-7.16 (m, 4H), 8.49 (dd, J=4.1, 1.7 Hz, 1H), 8.92 (dd, J=6.8, 1.7 Hz, 1H), 10.01 (s, 1H); MS (DCI) m/z 345 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([NH:13][NH2:14])=[CH:12][C:6]=2[N:5]=1.[C:15]1([S:21]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[C:25]2[C:33]([C:35](=[CH:38]N(C)C)[C:36]#[N:37])=[O:34])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[NH2:37][C:36]1[N:13]([C:11]2[CH:10]=[CH:9][C:7]3[NH:8][C:4]([CH3:3])=[N:5][C:6]=3[CH:12]=2)[N:14]=[CH:38][C:35]=1[C:33]([C:25]1[N:24]([S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[C:32]2[C:27]([CH:26]=1)=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:34]
Reactant: Cc1nc2cc(NN)ccc2[nH]1
Reactant: CN(C)C=C(C#N)C(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: Cc1nc2cc(-n3ncc(C(=O)c4cc5ccccc5n4S(=O)(=O)c4ccccc4)c3N)ccc2[nH]1
Temperature: 25 °C
Yield: 91 %

Procedure:
(2-Methyl-1H-benzimidazol-5-yl)-hydrazine dihydrochloride (830 mg) was added to an ethanol solution (15 ml) of crude 2-(1-benzenesulfonyl-1H-indole-2-carbonyl)-3-dimethylamino acrylonitrile (1.17 g). The reaction mixture was heated with stirring under reflux for four hours. After cooling to room temperature, the mixture was allowed to stand at room temperature. The precipitated solid was collected by filtration, and washed with ethanol to give [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-(1-benzenesulfonyl-1H-indol-2-yl)-methanone was obtained as a yellow solid (1.5 g, with a two-step yield of 91%).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12](O)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:27][C:2]1([CH3:1])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(N2CCOCC2)cc1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1ccc(N2CCOCC2)cc1
Temperature: 65 °C
Yield: 40.3 %

Procedure:
A mixture of 3,3-dimethyl-2-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (70 mg, 0.19 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (55 mg, 0.29 mmol), 4-dimethylaminopyridine (35 mg, 0.29 mmol), methane sulfonamide (54 mg, 0.57 mmol) in dichloromethane (10 mL) was heated for at 65° C. for 12 hours. Removal of the solvent to afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[3,3-dimethyl-2-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (34 mg, 40%) as a light yellow solid: LC/MS m/e calcd for C23H29N3O4S (M+H)+: 444.6, observed: 444.2.