Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:6]([C:18]([OH:20])=O)[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])([O:3][CH2:4][CH3:5])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:27][C:28]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:29]=1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>C(Cl)Cl.CN(C)C=O>[C:30]([C:29]1[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=1[NH:27][C:18](=[O:20])[CH:6]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Nc1cc(Cl)ccc1C(=O)c1ccccc1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)Nc1cc(Cl)ccc1C(=O)c1ccccc1

Procedure:
A suspension of 45.0 g. of 2-carbethoxy-N-(benzyloxycarbonyl)glycine in 120 ml. of dry methylene chloride, cooled to -20° C., is treated portionwise with 30 g. of phosphorus pentachloride and stirred for 30 minutes at -20° C. to -10° C. To the now clear solution, there is added at the same temperature a solution of 27.7 g. of 2-amino-4-chlorobenzophenone and 1 ml. of dimethylformamide in 120 ml. of dry methylene chloride. The mixture is concentrated under reduced pressure at 40°-45° C. The residue is partitioned between methylene chloride and 10% aqueous soda solution and the methylene chloride phase is dried over sodium sulfate and evaporated to dryness. There is obtained a reddish-colored resin of crude 2'-benzoyl-2-[(benzyloxycarbonyl)amino]-2-carbethoxy-5'-chloroacetanilide, which is then immediately reacted with 130 ml. of a 33% solution of hydrobromic acid in glacial acetic acid. After stirring at room temperature for 90 minutes, the obtained solution is concentrated at 45° C. and the oily residue partitioned between water and ether. The aqueous solution is made weakly alkaline with solid sodium bicarbonate while cooling with ice. The separated base is extracted with methylene chloride and the extracts are dried over sodium sulfate and evaporated to dryness. The resulting oil is dissolved in a mixture of 180 ml. of toluene and 180 ml. of glacial acetic acid and heated at 80° C. for 90 minutes. The solution is concentrated to an oil and is crystallized from ether so that there is obtained 8-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid ethyl ester, having a melting point of 214°-217° C. (decomposition). Recrystallization from acetonitrile does not increase the melting point.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:43]([CH3:44])=[N:42][C:41]2=[CH:45][C:38]3=[N:39][N:40]2[C:13]=1[N:14]1[CH2:48][CH2:47][C:17]([CH3:49])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([CH3:46])[O:24][C:25]2[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=4[CH:32]=[CH:33][C:34]=2[CH2:35][O:36][CH2:37]3)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:43]([CH3:44])=[N:42][C:41]2=[CH:45][C:38]3=[N:39][N:40]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:49])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([CH3:46])[O:24][C:25]2[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=4[CH:32]=[CH:33][C:34]=2[CH2:35][O:36][CH2:37]3)[CH2:47][CH2:48]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(ccc2ccccc12)COC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(ccc2ccccc12)COC3
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A mixture of ethyl (2S)-2-(tert-butoxy)-2-[(24S)-4,24,30-trimethyl-11,23,29-trioxa-1,5,7,8-tetraazahexacyclo[28.2.2.16,9.02,7.013,22.016,21]pentatriaconta-2,4,6(35),8,13(22),14,16(21),17,19-nonaen-3-yl]acetate (47 mg, 0.070 mmol) and NaOH (0.070 mL, 0.070 mmol) in EtOH (2 mL) was refluxed for 2 h. It was then cooled to rt and purified by preparative HPLC to obtain (2S)-2-(tert-butoxy)-2-[(24S)-4,24,30-trimethyl-11,23,29-trioxa-1,5,7,8-tetraazahexacyclo[28.2.2.16,9.02,7.013,22.016,21]pentatriaconta-2,4,6(35),8,13(22),14,16(21),17,19-nonaen-3-yl]acetic acid (31.3 mg, 0.046 mmol, 66.0% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.12 (d, J=8.4 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.53-7.43 (m, 3H), 6.58 (s, 1H), 5.82 (s, 1H), 4.83-4.75 (m, 2H), 4.75-4.67 (m, 1H), 4.58 (d, J=10.6 Hz, 1H), 4.49-4.35 (m, 2H), 3.74 (t, J=10.8 Hz, 1H), 3.37-3.53 (m, 2H), 3.06 (d, J=9.2 Hz, 1H), 2.64 (d, J=11.7 Hz, 1H), 2.50 (s, 3H), 1.95 (d, J=13.2 Hz, 2H), 1.88-1.45 (m, 8H), 1.20 (s, 3H), 1.16 (s, 9H), 1.07 (d, J=5.9 Hz, 3H). LCMS (M+1)=645.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([CH2:10][CH3:11])[CH:3]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1CN1C(=O)c2ccccc2C1=O
Temperature: 80 °C

Procedure:
To 4-bromo-1-bromomethyl-2-ethyl-benzene (4.0 g, 14.2 mmol) in dimethylformamide (100 mL) at room temperature was added potassium phthalimide (2.9 g, 15.6 mmol), and the solution was heated at 80° C. for 5 h. The solution was cooled to room temperature and poured into water. The aqueous solution was extracted with ethyl acetate. The pooled organics were washed with saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to a yellow solid (4.0 g, 82%). 1H NMR (300 MHz, CDCl3): δ ppm 1.27 (t, J=7.54 Hz, 3 H) 2.85 (q, J=7.60 Hz, 2 H) 4.84 (s, 2 H) 7.14-7.18 (m, 1 H) 7.24-7.27 (m, 1 H) 7.34 (d, J=2.07 Hz, 1 H) 7.73 (dd, J=5.46, 3.01 Hz, 2 H) 7.86 (dd, J=5.56, 3.11 Hz, 2 H).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:29][C:30]1[CH:53]=[CH:52][C:33]([CH2:34][N:35]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[N:37]=[C:36]2[C:44]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[O:45])=[CH:32][CH:31]=1>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[CH2:13][CH2:14][N:49]1[CH2:50][CH2:51][CH:46]([C:44]([C:36]2[N:35]([CH2:34][C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:53][CH:52]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[N:37]=2)=[O:45])[CH2:47][CH2:48]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(C(CCS(C)(=O)=O)CN(C)C(=O)c2ccccc2)cc1OC
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Product: COc1ccc(C(CCN2CCC(C(=O)c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)CN(C)C(=O)c2ccccc2)cc1OC

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(3,4-dimethoxyphenyl)-4-methanesulfonylbutyl)benzamide and 4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O)(=O)C.[CH:8]([C:10]1[CH:11]=[CH:12][C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([CH:24]=1)[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:16])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.ClCCl>[CH3:1][N:2]([CH2:8][C:10]1[CH:11]=[CH:12][C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([CH:24]=1)[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:16])[CH3:3]
Reactant: CNC
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Dimethylamine (60 uL, 0.33 mmol) and acetic acid (19 uL, 0.33 mmol) were added to a solution of 5-formyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 66; 100 mg, 0.33 mmol) in DCE (5 ml). The solution was stirred for 3 hours at 50° C. then sodium triacetoxyborohydride (105 mg, 0.50 mmol) was added. The mixture was stirred overnight. Saturated NaHCO3 solution (5 ml) was then added and the mixture was stirred for 5 minutes. The organic layer was diluted with dichloromethane (5 ml), separated and dried (MgSO4). The solvent was removed in vacuo and the residue purified by MDAP to yield the title compound as an opaque solid. 17 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])C=CC=1.[CH3:18][C:19](=O)[CH3:20].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][N:8]1[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[NH:13][C:19]1([CH3:20])[CH3:18]
Reactant: NC(=O)c1ccccc1Nc1cccc(Cl)c1
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC1(C)NC(=O)c2ccccc2N1CCCCl

Procedure:
A mixture of 10 parts of 2-[(3-chlorophenyl)amino]benzamide, 16 parts of 2-propanone, 1 part of 4-methylbenzenesulfonic acid and 40 parts of ethanol is stirred and refluxed overnight. The reaction mixture is evaporated and the oily residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 10 parts of 1-(3-chloropropyl)-2,3-dihydro-2,2-dimethyl-4(1H)-quinazolinone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[O:24]C)=[C:4]([CH3:26])[N:3]=1.[CH3:27]O.Cl>C(Cl)Cl.B(Br)(Br)Br.O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:27])=[O:22])=[CH:16][C:15]=2[OH:24])=[C:4]([CH3:26])[N:3]=1
Reactant: CO
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1O
Reaction time: 5 h

Procedure:
To the product from example 72 step (i) (550 mg) in DCM (20 mL), BBr3 (0.29 ml) was added dropwise and the reaction mixture stirred for 5 h. MeOH (4 mL) was added followed by 4M HCl in dioxane (0.5 mL) and stirred for 16 h and the solvents evaporated. The residue was purified by RPHPLC to give the title compound as a white solid, 8 mg.
Reaction SMILES: ClCCl.[C:4]([C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1)#[N:5].Br[C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:4]([C:6]1[CH:7]=[C:8]([C:18]2[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=[CH:16][C:17]=2[O:25][CH3:26])[CH:9]=[CH:10][CH:11]=1)#[N:5]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc([N+](=O)[O-])cc1-c1cccc(C#N)c1
Temperature: 90 °C
Yield: 99.9 %

Procedure:
[1,1′Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane(1:1) (1.43 g) was added to a stirred mixture of 3-cyanophenylboronic acid (10.0 g, 61.8 mmol) and 2-bromo-4-nitroanisole (14.35 g, 62 mmol) in 2.0 N cesium carbonate (92.7 mL, 185.4 mmol) and ethylene glycol dimethylether (200 mL). The flask was purged with nitrogen and heated at 90° C. (oil bath) for 4 hours. The mixture was allowed to cool to room temperature overnight, during which time the product precipitated from solution. The solid was collected on a Buchner funnel, washed with water and dried under reduced pressure to give 2-(3-cyanophenyl)-4-nitroanisole (15.7 g).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH:1]1([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2c(c1)CCC2N1CCCCC1
Reaction time: 48 h

Procedure:
A mixture of 100 g. of 1-indanone (0.758 mole) and 125 ml. of piperidine in 750 ml. of toluene is treated with 0.5 g. of p-toluenesulfonic acid and heated under reflux with a water take-off trap attached. Heating is continued for 48 hours. Solvent and excess piperidine are removed in vacuo and the residue is dissolved in 1500 ml. of absolute methanol. The resulting solution is stirred and treated portionwise with 50 g. of sodium borohydride below 30° C. After stirring several hours longer, the mixture is treated with a small amount of acetic acid then made strongly basic by the addition of sodium hydroxide solution. After 400 ml. of water is added, most of the methanol is removed in vacuo. Product is extracted into ether, dried over potassium hydroxide and distilled. 119.7 g. of 1-(1-indanyl)piperidine is collected at 101°-102° (0.2 mm.).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[I:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[O:17][CH2:18][CH2:19][C:12]=12>>[I:10][C:11]1[C:16]([N+:1]([O-:4])=[O:2])=[CH:15][N:14]=[C:13]2[O:17][CH2:18][CH2:19][C:12]=12
Reactant: Ic1ccnc2c1CCO2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnc2c(c1I)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
A solution of fuming nitric acid (15.0 mL, 358 mmol) in concentrated sulfuric acid (15.0 mL, 281 mmol) was added slowly over a period of 15 min. to a stirred solution of 4-iodo-2,3-dihydrofuro[2,3-b]pyridine (2.237 g, 9.055 mmol) in sulfuric acid (10.0 mL, 188 mmol) at −10° C. The reaction mixture was allowed to warm to room temperature, and stirred for a further 16 h. The reaction mixture was quenched by pouring onto crushed ice and was then extracted with EtOAc (6×100 mL). The organic extracts were combined and washed with saturated aq. NaHCO3 (2×300 mL) and brine (300 mL), then dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a pale yellow solid (2.43 g, 92%). LCMS calc. for C2H61N2O3 (M+H)+: m/z=292.9. found 293.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][CH3:20])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[N:27]([CH3:35])[C:26]=1[CH3:36])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:21][NH:22][C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][CH3:20])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:31][CH:32]=2)[N:27]([CH3:35])[C:26]=1[CH3:36])=[O:24]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: CNCC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNCC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NC)c(C)n(C)c5c4)c3s2)C1
Yield: 54.6 %

Procedure:
This material was prepared by the reaction of N-({1-[(7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl]pyrrolidin-3-yl}methyl)-N-methylamine 46a (0.115 g, 0.41 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.090 g, 0.41 mmole) and Cs2CO3 (0.147 g, 0.41 mmole) in a manner as previously described for example 1 to give an off-white solid (0.110 g, 54%). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (1H, s), 8.01 (1H, s), 7.83 (1H, m), 7.54 (2H, m), 7.02 (1H, s), 6.64 (1H, d, J=5.46 Hz), 3.93 (2H, m), 3.68 (3H, s), 3.54 (2H, m), 3.16 (2H, m), 2.99 (1H, m), 2.80 (3H, s), 2.79 (3H, s), 1.98 (2H, m), 1.65 (1H, m); HRMS (MH+): Calcd: 492.2064. Found: 492.2048.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]([CH:12]=[C:13]([C:15]3[NH:23][C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH:14]=2)[NH2:11])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[Na+].[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.O>C(Cl)Cl.CO>[Cl:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]([CH:12]=[C:13]([C:15]3[NH:23][C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH:14]=2)[NH:11][CH2:29][C:30]2[CH:37]=[CH:36][C:33]([CH3:34])=[CH:32][CH:31]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Nc1cc(-c2nc3cccnc3[nH]2)cc(-c2ncccc2Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(CNc2cc(-c3nc4cccnc4[nH]3)cc(-c3ncccc3Cl)c2)cc1
Reaction time: 8 h
Yield: 47 %

Procedure:
NaCNBH4 (15.5 mg, 0.25 mmol) was added to a solution of Example 183 (32.1 mg, 0.1 mmol) in CH2Cl2-MeOH (2 mL) containing sodium acetate (12.3 mg, 0.15 mmol) and p-methyl benzaldehyde (14.4 mg, 0.12 mmol) at 0° C. The resulting suspension was stirred overnight and water (50 mL) was slowly added and the mixture extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting material was purified by LCMS (acetonitrile-water gradient) to give the title compound (20 mg, 45%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 2.27 (s, 3H) 4.3 (s, 2H) 7.01 (t, J=5.21 Hz, 1 H) 7.08 (d, J=5.11 Hz, 2 H) 7.13 (dd, J=7.21, 4.42, Hz, 1 H) 7.25 (dd, J=5.27, 3.48 Hz, 1 H) 7.39 (t, J=5.11 Hz, 1 H) 7.46 (t, J=5.11 Hz, 1 H) 7.58 (d, J=5.11 Hz, 2 H) 7.68 (dd, J=9.21, 5.42, Hz, 1 H) 8.76 (d, J=5.91 Hz, 1 H) 8.82 (d, J=5.91 Hz, 1 H). MS (ES) [M+H] calculated for C25H21ClN5, 426.14; found 426.09.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([OH:26])=O)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[S:34]([NH2:38])([NH2:37])(=[O:36])=[O:35]>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:27])[N:19]([CH2:23][C:24]([NH:37][S:34](=[O:36])(=[O:35])[NH2:38])=[O:26])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:30]([F:33])([F:31])[F:32])[CH:3]=1
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: NS(N)(=O)=O
Product: NS(=O)(=O)NC(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-sulfamoylacetamide was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid (Example 4) and sulfamide following General Procedure L.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[CH3:52][N:53]([CH3:58])[CH2:54][CH2:55][CH2:56][NH2:57].OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](=[O:46])[NH:57][CH2:56][CH2:55][CH2:54][N:53]([CH3:58])[CH3:52])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CN(C)CCCN
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)NCCCN(C)C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and N,N-dimethyl-1,3-propanediamine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)-piperazine, respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=4[CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: Cc1cccc(B(O)O)c1C
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C)c4C)c3O2)cc1
Yield: 62.8 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,3-dimethylphenyl)boronic acid (0.294 g, 1.96 mmol) generally according to the procedure described for Intermediate 184 provided 0.335 g (62%) of (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4).
Reaction SMILES: [OH-].[K+].FC(F)(F)C([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:20][O:21][CH3:22])=[C:13]([CH2:17][O:18][CH3:19])[CH:14]=2)[CH2:9]1)=O>O.CO>[NH2:7][CH:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH2:17][O:18][CH3:19])=[C:12]([CH2:20][O:21][CH3:22])[CH:11]=2)[CH2:16]1
Reactant: COCc1cc2c(cc1COC)CC(NC(=O)C(F)(F)F)C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCc1cc2c(cc1COC)CC(N)C2

Procedure:
A solution of potassium hydroxide (150 mg, 2.60 mmol) in water (0.5 ml) is added to a solution of 2-(trifluoroacetylamino)-5,6-bis(methoxymethyl)indane (240 mg, 0.75 mmol) in methanol (3 mL) and the mixture is heated at reflux for 2.5 hours. The solvent was removed in vacuo and the residue is partitioned between aqueous sodium hydroxide (10 mL) and ethyl acetate (20 mL). The organic extract is dried (MgSO4) and the solvent is removed in vacuo to leave the product as a dark oil.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[F:40][C:41]([F:56])([F:55])[C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:51]1[CH2:50][CH2:49][CH:48]([C:45]2[CH:44]=[CH:43][C:42]([C:41]([F:40])([F:55])[F:56])=[CH:47][CH:46]=2)[CH2:53][CH2:52]1
Reactant: O=C1CCC(c2ccc(C(F)(F)F)cc2)CC1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C2CCC(=CCC3OCCCO3)CC2)cc1
Reaction time: 1 h

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (12.2 g, 27 mmols), followed by adding tetrahydrofuran (100 ml), suspending, and stirring under ice cooling till the liquid temperature reached 10° C. The resulting reaction mixture was added potassium t-butoxide (3.0 g, 27 mmols), followed by elevating the temperature up to room temperature under ice cooling, stirring for one hour, dropwise adding a tetrahydrofuran (50 ml) solution of 4-(4-trifluoromethylphenyl)cyclohexanone (6.0 g, 25 mmols) over 30 minutes from the dropping funnel, further stirring the reaction mixture for 5 hours after completion of the dropwise addition, adding ether (100 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)-ethylidene)-4-(4-trifluoromethylphenyl)cyclohexane.