Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:29])=[O:28])(C)(C)C.Cl[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[C:22]1([C:7]2[S:6](=[O:29])(=[O:28])[N:5]([CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[C:9](=[O:10])[C:8]=2[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Reactant: ClCc1ccncc1
Product: O=C1C(NCCCCc2ccccc2)=C(c2ccccc2)S(=O)(=O)N1Cc1ccncc1

Procedure:
The title compound was prepared from 2-tert-butyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazol-3(2H)-one 1,1-dioxide (Example 1) and 4-(chloromethyl)pyridine in a similar manner as described for e.g. Example 2 and 3 1H NMR (500 MHz, CDCl3): δ 8.66-8.60 (m, 2H), 7.54-7.38 (m, 7H), 7.31-7.24 (m, 2H), 7.23-7.16 (m, 1H), 7.10-7.04 (m, 2H), 5.34-5.27 (m, 1H), 4.82 (s, 2H), 2.92-2.84 (m, 2H), 2.50-2.42 (m, 2H), 1.45-1.35 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 159.3, 150.3, 143.4, 141.5, 135.4, 131.7, 130.0, 128.8, 128.5, 128.4, 126.1, 124.7, 123.1, 107.2, 44.1, 42.3, 35.3, 31.5, 29.0, 28.2; Mass Spectrum: M−H+ 448.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:3]=2[C:4]#[N:5])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCC1
Reactant: N#Cc1c(F)cccc1-c1ccccc1
Product: N#Cc1c(NC2CCCCC2)cccc1-c1ccccc1
Temperature: 100 °C

Procedure:
The product of example la above, 2-fluoro-6-phenylbenzonitrile, (0.1 g, 0.51 mmol), and cyclohexylamine (1 mL) were combined in a sealed tube that had been flushed with argon. The tube was heated in an oil bath to 100° C. for 1.6 hours. The excess cyclohexylamine was evaporated, and the residue was flash chromatographed on silica gel eluted with 0-2% ethyl acetate in hexane, and then recrystallized from methylene chloride/hexane to give the title product as a white crystalline product. mp 125-126° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C=O)C.[Br:16][CH2:17][C:18](Br)=[O:19]>O1CCOCC1>[Br:16][CH2:17][C:18]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:19]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A solution of 4-nitroaniline (10.0 g, 72.4 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (14.60 g, 6.35 mL, 72.4 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 16.92 g (90%) of the title compound as a greenish yellow solid, mp 175°-178° C.: 1H NMR (DMSO-d6) δ10.98 (s, 1H), 8.24 (d, J=9.2, 2H), 7.83 (d, J=9.2, 2H), 4.10 (s, 2H); 13C NMR (DMSO-d6) δ165.77, 144.67, 142.62, 125.05, 119.01, 30.15; MS (EI, m/z) 285 (M+).
Reaction SMILES: S([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C@H:20]2[C@H:25]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@@H:24]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@H:23]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C@@H:22]([CH2:50][O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[O:21]2)=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+]>CCO.C1COCC1>[CH2:27]([O:26][C@@H:25]1[C@@H:24]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C@H:23]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:22]([CH2:50][O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[O:21][C@H:20]1[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][CH:12]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3ccccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: c1ccc(COC[C@H]2O[C@@H](c3c[nH]c4ccccc34)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
To a solution of compound 84 (740 mg, 0.93 mmol) in a mixture of EtOH (20 mL) and THF (10 ml) was added KOH (250 mg). The reaction mixture was stirred at 50° C. for 1 d. After reaction complete, the resulting solution was quenched with 1.0 M HCl and organic layer was extracted with EtOAc. After evaporating volatile material under reduced pressure, the residue was purified with normal phase column chromatography to afford titled compound 85 (370 mg, 62%) as off-white solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O.O1CCOCC1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)[C@H](C)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of D-threonine (5.0 g, 0.042 mol) in water (50 mL) and dioxane (50 mL) containing triethylamine (8.9 mL, 0.063 mol) at room temperature is added 4-methoxybenzenesulfonyl chloride (9.54 g, 0.046 mol). The reaction mixture is stirred overnight at room temperature. Most of the dioxane is evaporated off, and the pH is adjusted to pH=2 with 1N HCl. The mixture is then extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated in vacuo to provide N-[4-methoxybenzenesulfonyl]-(D)-threonine.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[Br:19][C:8]1[N:7]2[C:2]([Cl:1])=[N:3][C:4]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[CH:5][C:6]2=[N:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2cc3ncc(Br)n3c(Cl)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
200 mg (0.67 mmol) of 5-chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine (Example 6A) are suspended in chloroform (30 ml), 238 mg (1.34 mmol) of N-bromosuccinimide are added, and the reaction mixture is stirred at RT for 12 h. The reaction mixture is diluted with ethyl acetate (100 ml) and water (75 ml), and the organic phase is separated off, dried over magnesium sulphate and concentrated in a rotary evaporator. The residue is stirred with acetonitrile (20 ml) and then diethyl ether (20 ml), and the solid is filtered off with suction and dried. 103 mg (41% of theory) of the product are isolated.
Reaction SMILES: [CH2:1]([NH2:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=2[Cl:41])=[CH:26][C:19]=1[O:20][CH:21]([CH3:25])[C:22](Cl)=[O:23])([O-:17])=[O:16]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([NH:7][C:22](=[O:23])[CH:21]([O:20][C:19]1[CH:26]=[C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=2[Cl:41])[CH:28]=[CH:29][C:18]=1[N+:15]([O-:17])=[O:16])[CH3:25])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: NCC1CCCO1
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)NCC1CCCO1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Tetrahydrofurfurylamine (1.5 grams; 0.015 mole), methylene chloride (50 ml) and triethylamine (5 ml) were charged into a glass reaction vessel equipped with a stirrer, thermometer and addition funnel. The reaction mixture was cooled to -10° C. and 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride (4.3 grams) dissolved in methylene chloride (50 ml) was added dropwise with stirring. After the addition was completed stirring was continued for a period of about one hour. After this time the reaction mixture was transferred into a separatory funnel and was washed with water (300 ml) and with dilute aqueous sodium bicarbonate (100 ml). The washed solution was then dried by passing it through phase separation paper and was stripped of solvent in a rotary evaporator under aspirator pressure leaving a dark brown-orange oil as the residue. The residue was then dissolved in toluene (6 ml) and charged onto 150 cc of clay for chromatography. The product was then eluted using ethyl acetate-hexane mixtures with increasing concentrations of ethyl acetate. Twelve fractions were collected. Fractions 5 and 6 were combined and stripped of solvents to yield the desired product N-tetrahydrofurfuryl-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionamide as an orange solid melting at 102° to 104° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[CH:9][C:10]3[C:11]([CH:21]=2)=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:13][N:14]=3)[O:6][CH2:5][CH2:4][O:3]1.C(N(CC)CC)C>[Pd].O1CCCC1>[NH2:14][C:10]1[CH:9]=[CH:8][C:7]([C:2]2([CH3:1])[O:3][CH2:4][CH2:5][O:6]2)=[CH:21][C:11]=1[C:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:13]
Reactant: CC1(c2ccc3noc(-c4ccccc4)c3c2)OCCO1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(c2ccc(N)c(C(=O)c3ccccc3)c2)OCCO1
Yield: 89.4 %

Procedure:
5-(2-Methyl-1,3-dioxolan-2yl)-3-phenyl-2,1-benzisoxazole (1.50 g, 5.3 m mol), triethyl amine (0.3 ml) and 5% palladium on carbon (0.15 g) were combined in dry tetrahydrofuran (13 ml). The apparatus wa flushed with nitrogen and then hydrogen. A static hydrogen atmosphere was maintained (1 atm.) and the progress of the reaction followed by gas chromatography. The starting material and product have retention times of 11.15 and 11.33 min. respectively. When conversion was complete, the mixture was filtered through a pad of Celite to yield a clear yellow solution. Evaporation of the solution yielded a yellow solid (1.35 g) of mp. 108°-111° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:21])[NH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:32]([O:36][C:37](=[O:40])[CH2:38]Br)([CH3:35])([CH3:34])[CH3:33]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:21])[N:14]([CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:40])[C:15]([CH:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)c1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
3-(Benzyloxycarbonyl)amino-6-isopropyl-2 (1H)-pyridinone (1.10 g, 3.84 mmol), as prepared in the preceding step, was dissolved in anhydrous tetrahydrofuran (30 mL) and cooled to 0° C. under nitrogen. A 1.0 M solution of lithium bis(trimethylsilyl)amide in hexanes (4.2 mL, 4.2 mmol) was added via syringe and the reaction stirred for one hour. tert-Butylbromoacetate (0.70 mL, 4.3 mmol) was then added-via syringe and the reaction stirred at ambient temperature for 16 hours. After concentration in vacuo, the crude product was purified by flash column chromatography (1:1 hexane:ethyl acetate) giving the title compound as a pale yellow oil (1.38 g, 90%). 1H NMR (300 MHz, CDCl3) δ 8.00 (br d, 1H, J=7.8 Hz), 7.78 (s, 1H), 7.36 (m, 5H), 6.15 (d, 1H, J=7.9 Hz), 5.19 (s, 2H), 4.79 (s, 2H), 2.72 (m, 1H), 1.46 (s, 9H), 1.26 (s, 3H), 1.23 (s, 3H). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for C22N28N2O5: 423.2 (M+Na). Found: 423.6.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[CH2:21][C:20]([CH3:23])=[CH:19]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:30](I)([CH3:32])[CH3:31]>CN(C=O)C>[CH:30]([N:11]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH2:17][C:18]2[C:22]=1[CH:21]=[C:20]([CH3:23])[CH:19]=2)[S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])([CH3:32])[CH3:31]
Reactant: CC1=Cc2cccc(CCNS(=O)(=O)c3ccc(C)cc3)c2C1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1=CC2=C(CCN(C(C)C)S(=O)(=O)c3ccc(C)cc3)C=CCC2=C1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
At room temperature, to a solution of 11.4 g (34.8 mmol) of 4-methyl-N-[2-(2-methyl-1H-inden-7-yl)ethyl]-benzenesulfonamide in 75 mL of dry DMF, 17.0 g (52.3 mmol) of Cs2CO3 was added, and then 11.9 g (69.8 mmol) of iPrI was added dropwise over a period of 10 minutes. This mixture was then stirred for 3 days at 50° C., and then evaporated via vacuum. To the residue, 200 mL of water and 200 mL of dichloromethane were added. The organic layer was separated, and the aqueous layer was washed with 200 mL of dichloromethane. The combined organic extract was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent—dichloromethane). Yield, 10.9 g (85%) of white solid. This product was further used without additional purification. 1H NMR (CDCl3): δ 7.20 (m, 1H, 5-H in indenyl), 7.15 (m, 1H, 6-H in indenyl), 6.95 (m, 1H, 4-H in indenyl), 6.52 (m, 1H, 3-H in indenyl), 4.06 (set, J=6.8 Hz, 1H, CHMe2), 3.13-3.27 (m, 4H, 1,1′-H in indenyl and CH2CH2N), 2.96-3.07 (m, 2H, CH2CH2N), 2.34 (s, 3H, 2-Me in indenyl), 0.99 (d, J=6.8 Hz, 6H, CHMe2). Anal. Calc. for C22H27NO2S: C, 71.51; H, 7.36; N, 3.79%. Found: C, 72.01; H, 7.49; N, 3.33%.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]([F:21])([F:20])[CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]#[N:19])[CH:13]=1>C(O)C>[F:21][C:10]([F:9])([F:20])[CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH2:19])=[O:2])[CH:13]=1
Reactant: O=C([O-])O
Reactant: N#Cc1cc(CC(F)(F)F)ccn1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(CC(F)(F)F)ccn1
Reaction time: 4 h
Yield: 91.2 %

Procedure:
To 3 ml of ethanol were added 0.2 g of sodium bicarbonate and 0.17 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.3 g of 4-(2,2,2-trifluoroethyl)pyridine-2-carbonitrile was added at 0° C., and the mixture was stirred for 4 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.3 g of 4-(2,2,2-trifluoroethyl)pyridine-2-carboxamide=oxime.
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[I:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.Cl.[NH2:61][CH2:62][CH2:63][S:64]([NH2:67])(=[O:66])=[O:65]>>[I:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:50])=[C:33]2[S:53]([NH:61][CH2:62][CH2:63][S:64]([NH2:67])(=[O:66])=[O:65])(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: NCCS(N)(=O)=O
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(I)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: NC(=O)c1[nH]c2ccc(I)cc2c1S(=O)(=O)NCCS(N)(=O)=O

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole -2-carboxylate with ethyl 5-iodo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with 2-aminoethanesulfonamide hydrochloride, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 473.0 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]([F:42])([F:41])[C:26]1[CH:27]=[C:28]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]([F:41])([F:42])[C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][C:31]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)=[O:32])[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 70.3 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 3,5-bis(trifluoromethyl)cinnamic acid (3.5 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (3.4 g, 70%) as an oily product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:20])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1>C(O)(=O)C.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccc(O)cc1)C=Cc1ccc(O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(CCc1ccc(O)cc1)CCc1ccc(O)cc1
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A mixture of 20 g (0.075 mol) of 1,5-bis(4-hydroxyphenyl)penta 1,4-diene-3-one of Example 16 in 200 ml of glacial acetic acid and 1.5 g of 5% Pd/C was placed on a Parr hydrogenator for 2 hours under hydrogen. This reaction was repeated and the two solutions were filtered and evaporated to give a viscous oil (18 g). This was chromotographed on a silica gel column (Woelm) and eluted with CHCl3 :MeOH (95:5). The product (7.0 g) was recovered first and then 9.0 g of the corresponding alcohol.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14]>>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1]
Reactant: COC(=O)C(OC)OC
Reactant: NCc1ccccc1Br
Product: COC(OC)C(=O)NCc1ccccc1Br
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Into a sealed tube were added methyl dimethoxyacetate (1.0 g, 7.5 mmol) and 2-bromobenzylamine (1.1 g, 5.8 mmol), this mixture was stirred at 50° C. for 16 h. The completed reaction was transferred to a flask and re-crystallized from heptane yielding the desired product as an off-white solid. MS (ES+): m/z=288.04/289.69 [MH+]. HPLC: tR=2.93 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([F:18])[C:6]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[OH-].[Na+].Cl.[CH3:24][C:25]([CH3:27])=[O:26]>O.C(Cl)Cl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([F:18])[C:6]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[CH:24][C:25](=[O:26])[CH3:27])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)C=Cc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a slurry of 28.5 g (0.10 mol) of 4-(5-(trifluoromethyl)-3-fluoro-2-pyridyloxy)benzaldehyde in 250 mL of acetone and 250 mL of water was added 7.5 mL of 1N sodium hydroxide. The slurry was stirred at ambient temperature for 19 hours and then diluted with 300 mL of methylene chloride and 200 mL of water and made acidic to a pH of 2 with concentrated HCl. The organic layer was separated in a separatory funnel and washed with 500 mL of water and dried over sodium sulfate. The solvent was removed in vacuo leaving 32.5 g (100 percent of theoretical) of the above named compound, as the crude product. The above named product (melting at 71°-72.5° C.) was recovered in a yield of 27.9 g (85.8 percent of theoretical) after recrystallization of the crude product from hexane; Rf -0.19 (silica gel, 15:85 EtOAc:hexane), 1H NMR (CDCl3): δ 2.35 (s, 3H, --CH3), 6.65 (d, 1H, J=15 Hz, vinyl), 7.15-8.3 (m, 6H, ArH and vinyl).
Reaction SMILES: [SH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:46]([O:48][C:49](=[O:56])/[CH:50]=[C:51](\[CH3:55])/[CH2:52][CH2:53]O)[CH3:47]>C(OCC)(=O)C.C1COCC1>[CH2:46]([O:48][C:49](=[O:56])/[CH:50]=[C:51](\[CH3:55])/[CH2:52][CH2:53][S:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1)[CH3:47]
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCOC(=O)/C=C(\C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)CCSc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
This reaction was performed with reference to the literature (Mitsunobu, O., Synthesis, 1981, 1-28.). 5-Mercapto-1-phenyltetrazole (16.30 g, 91.20 mmol), triphenylphosphine (27.30 g, 104 mmol) and diisopropyl azodicarboxylate (95%, 21.10 g, 104 mmol) were added to a THF (410 ml) solution of ethyl-(2E)-5-hydroxy-3-methylpent-2-enoate (13.80 g, 86.90 mmol) while ice cooling. The reaction solution was warmed to room temperature and stirred for four hours. After the reaction solution was diluted with ethyl acetate, it was washed with distilled water and brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:ethyl acetate=5:1) to obtain the title compound (27.16 g) as a white solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10](Br)[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[CH2:15]([N:17]1[CH2:22][CH:21]=[C:20]([CH2:23]O)[CH2:19][CH2:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH2:22][CH2:21][C:20]2([C:10]3[C:9](=[CH:8][C:7]4[CH2:6][CH2:5][NH:4][C:12]=4[CH:11]=3)[O:14][CH2:23]2)[CH2:19][CH2:18]1)[CH3:16]
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Reactant: CCN1CC=C(CO)CC1
Product: CCN1CCC2(CC1)COc1cc3c(cc12)NCC3
Yield: 45 %

Procedure:
This was prepared from 1-acetyl-6-bromo-2,3-dihydro-1H-indol-5-ol (Tetrahedron, 1973, 29 (8), 1115) and 1-ethyl-1,2,3,6-tetrahydropyridine-4-methanol (D108), following the procedure of Description 8 (alternative preparation), steps a), b), and c). This gave the title compound (overall yield: 45%) as a fine grey powder.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6](B(O)O)[C:5]=2[CH:4]=[CH:3][N:2]=1.Cl[C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.[IH:22]>>[I:22][C:15]1[CH:20]=[C:19]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[N:18]=[CH:17][N:16]=1
Reactant: OB(O)c1cccc2cnccc12
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Product: Ic1cc(-c2cccc3cnccc23)ncn1

Procedure:
The compound was prepared according to Example 1 using isoquinolin-5-boronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.