Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[B:34]1[O:39]CCC[O:35]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:17]([N:25]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[B:34]([OH:35])[OH:39])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:18]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[B:34]([OH:39])[OH:35])[CH2:17][C:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1)[C:1]1[CH:14]=[CH:15][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCCCNCc1ccc2ccc3cccc4ccc1c2c34
Reactant: BrCc1ccccc1B1OCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OB(O)c1ccccc1CN(CCCCCCN(Cc1ccccc1B(O)O)Cc1ccc2ccc3cccc4ccc1c2c34)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
A solution of N-pyren-1-ylmethyl-hexane-1,6-diamine (291 mg, 0.69 mmol), 2-(2-bromomethyl-phenyl)-[1,3,2]dioxaborinane (422 mg, 1.66 mmol), and potassium carbonate (380 mg, 2.76 mmol) in dry acetonitril (10 ml) was heated at reflux for 20 hours under nitrogen atmosphere. The solvent was removed under vacuum, the residue was dissolved in chloroform and washed with water. The solvent was dried over magnesium sulphate and removed under vacuum. The residue was dissolved in THF (10 ml). Water (10 ml) was added to the THF solution, and the solution was stirred at room temperature for 3 hours. Organic phase was extracted with chloroform, washed with water, and dried over magnesium sulphate. The solvent was removed under vacuum. The residue was reprecipitated from chloroform with n-hexane to give a white yellow powder (172 mg, 35%). 1H NMR (CDCl3) δ/ppm 1.25-1.48 (8H, m, (CH2)4), 2.25 (2H, t, BnNCH2), 2.48 (2H, t, PyCNCH2), 3.45 (2H, s, PhB(OH)CH2NBn), 3.58 (2H, s, PhB(OH)CH2NCPy), 3.85 (2H, s, PhCH2), 4.21 (2H, s, PyCH2), 7.02-7.41 and 7.88-8.19 (22H m, Ar-H), 8.86 (4H, bs, BOH). 13C NMR (CDCl3) δ/ppm 51.69, 52.99, 54.42, 56.42, 57.11, 61.03, 61.86, 67.85, 122.90, 124.55, 124.99, 125.79, 127.31, 128.28, 128.57, 129.43, 130.00, 130.55, 136.32, 141.56; Found: C, 76.56; H, 6.69; N, 3.80, C44H46B2N2O4 requires C, 76.76; H, 6.73 N, 4.07%; m/z (FAB) 1230 ([M+H+4(3-HOCH2C6H4NO2)-4(H2O)]+, 100%); mp. 165-168° C.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][NH2:12])=[CH:6][C:5]=1[Br:13].[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH:31]=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>>[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1/[CH:31]=[N:12]/[O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:14])=[C:5]([Br:13])[CH:6]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(CON)cc1Br
Reactant: O=Cc1cc2ccccc2n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(CO/N=C/c2cc3ccccc3n2Cc2ccccc2)cc1Br
Temperature: 25 °C
Yield: 50.6 %

Procedure:
To a solution of 4-aminooxymethyl-2-bromo-benzoic acid methyl ester (0.21 g, 0.81 mmol) and 1-benzyl-1H-indole-2-carbaldehyde (0.19 g, 0.81 mmol) in 10/5/3 tetrahydrofuran/ethanol/water (18 mL) was added 2.5 M sodium hydroxide solution (3 mL). This mixture was heated to reflux for 3 hours and then allowed to cool back to room temperature. The mixture was concentrated to approximately 1/4 volume and partitioned between ethyl acetate and water. The aqueous layer was acidified to approximately pH 1 using 1 N hydrochloric acid. The layers were then separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (20/80 with 1% formic acid) to give 4-[({[(1E)-(1-benzyl-1H-indol-2-yl)methylidene]amino }oxy)methyl]-2-bromobenzoic acid (0.19 g, 51%) as an off-white powder. mp=148-149° C. 1H NMR (400 MHz, DMSO-d6); δ 13.35 (bs, 1H), 8.51 (s, 1H), 7.66 (m, 2H), 7.60 (d, 1H), 7.48 (d, 1H), 7.34 (d, 1H), 7.21-7.15 (m,4H), 7.06 (t, 1H), 6.93 (s, 1H), 6.90 (d, 2H), 5.70 (s, 2H), 5.14 (s, 2H). Mass spec; (ES+) m/z 462.9, (ES−) m/z 461.3. Elemental analysis; Calculated for C24H19BrN2O3: C, 62.22; H, 4.13; N, 6.05. Found: C, 62.07; H, 4.38; N, 5.88.
Reaction SMILES: C([Sn](CCCC)=O)CCC.[Cl:11][C:12]1[CH:13]=[C:14]2[C:20]([C:21]3[N:26]=[C:25]([NH:27][C@H:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([C:34]#[N:35])[CH2:29]4)[C:24]([F:36])=[CH:23][N:22]=3)=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1.[N:37]([Si](C)(C)C)=[N+:38]=[N-:39]>C1(C)C=CC=CC=1>[NH:37]1[C:34]([C@@H:30]2[CH2:31][CH2:32][CH2:33][C@H:28]([NH:27][C:25]3[C:24]([F:36])=[CH:23][N:22]=[C:21]([C:20]4[C:14]5[C:15](=[N:16][CH:17]=[C:12]([Cl:11])[CH:13]=5)[NH:18][CH:19]=4)[N:26]=3)[CH2:29]2)=[N:35][N:39]=[N:38]1
Reactant: N#C[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCC[C@@H](c2nnn[nH]2)C1
Temperature: 120 °C
Yield: 99.4 %

Procedure:
A suspension of dibutyl(oxo)tin (0.016 g, 0.064 mmol) and (1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexane-carbonitrile (54c) (0.043 g, 0.107 mmol) in toluene (3 mL) was treated with azido(trimethyl)silane (0.200 mL, 1.507 mmol). The mixture was heated in a sealed tube at 120° C. overnight. The mixture was absorbed onto silica-gel and purified by silica gel chromatography (25-50% gradient of 20% MeOH:DCM containing 0.5% AcOH modifier). The combined fractions were concentrated to dryness to give a residue that was triturated with ether then dried under vacuum at 45° C. to afford 44 mg of a yellow solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[OH-].[Na+:21]>CC(O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]([P:16]([O-:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH3:7].[Na+:21]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Yield: 102.9 %

Procedure:
A slurry of amorphous ibandronic acid (5 g) in IPA (50 ml) was heated to reflux temperature. Sodium hydroxide (0.63 g, solid) was added, and the reaction mixture was heated at reflux temperature for an additional 4 hours to obtain a pH of 4.19. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was filtered, washed with IPA (2×25 ml), and dried in a vacuum oven at 50° C. for 24 hours to give 5.5 g of ibandronate sodium crystal form K. Form K can exhibit a weight loss of about 10% to about 14% in TGA.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:29][C:30]1([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:32][CH2:31]1.N12CCCN=C1CCCCC2.Cl>C1COCC1.O>[CH3:29][C:30]1([S:33]([NH:36][C:14]([C@@:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:11][C@H:10]2[CH:12]=[CH2:13])=[O:16])(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(S(N)(=O)=O)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(C)CC1
Temperature: 85 °C
Yield: 74.2 %

Procedure:
A round-bottom flask was charged with the carboxylic acid product of step 1 (2 g, 8.80 mmol) and 1,1′-carbonyldiimidazole (2.141 g, 13.20 mmol). Dry THF (44.0 ml) was added under anhydrous conditions and the mixture was heated (oil bath at 85° C.) for 2 hours with exclusion of moisture. The mixture was cooled to room temp and a solution of 1-methylcyclopropane-1-sulfonamide (2.379 g, 17.60 mmol) in dry THF (10 mL) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (2.63 ml, 17.60 mmol). The mixture was heated (oil bath at 75° C.) overnight. The reaction mixture was treated with aq 1M HCl (20 mL) and water (50 mL). The product was extracted into ethyl acetate (400 mL) Upon separation, the organic layer was washed with aq 1M HCl/water (1:2, 80 mL), and brine (80 mL), dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a gold cap RediSep® (120 g) silica gel column (gradient: 0 to 25% ethyl acetate in dichloromethane) to give the title compound (2.25 g, 6.53 mmol, 74.2% yield) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19]2[S:32][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)=[CH:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:47][CH2:48][CH2:49][CH2:50]Br>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:50][CH2:49][CH2:48][Br:47])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19]2[S:32][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)=[CH:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(-c2cc3c(s2)c(-c2cc4ccc(O)cc4n2C(=O)OC(C)(C)C)nn3C(=O)OC(C)(C)C)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cccc(-c2cc3c(s2)c(-c2cc4ccc(OCCCBr)cc4n2C(=O)OC(C)(C)C)nn3C(=O)OC(C)(C)C)c1
Temperature: 75 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
A mixture of 2-[1-tert-butoxycarbonyl-5-(3-methoxy-phenyl)-1H-thieno[3,2-c]pyrazol-3-yl]-6-hydroxy-indole-1-carboxylic acid tert-butyl ester [1.19 g, 2.12 mmol, Intermediate (57)], cesium carbonate (2.07 g, 6.35 mmol), and 1,3-dibromopropane (8.0 mL) was heated at 75° C. under nitrogen. After 6 hours, the mixture was cooled to ambient temperature and let stand overnight. The mixture was filtered, and the insolubles washed twice with dichloromethane (10 mL). The filtrate was concentrated in vacuo to yield a golden oil. The crude product was chromatographed on silica, eluting with a gradient of 30% ethyl acetate/heptane to 50% ethyl acetate/heptane to give 6-(3-bromo-propoxy)-2-[1-tert-butoxycarbonyl-5-(3-methoxy-phenyl)-1H-thieno[3,2-c]pyrazol-3-yl]-indole-1-carboxylic acid tert-butyl ester [1.11 g, 76%, Intermediate (58)] as a white foam. TLC Rf 0.46 (silica, 40% ethyl acetate/heptane); LC/MS: 682.2 (M+H), RT=3.23 minutes.
Reaction SMILES: COC1C=C(OC)C=CC=1C=[CH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22]C=C)=[CH:17][CH:16]=1)=[O:14].CC(C1C=CC(OCC=C)=CC=1)=O.COC1C=C(OC)C=CC=1C=O.Cl>C(O)C>[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:14]
Reactant: C=CCOc1ccc(C(=O)C=Cc2ccc(OC)cc2OC)cc1
Agent: C=CCOc1ccc(C(C)=O)cc1
Agent: COc1ccc(C=O)c(OC)c1
Agent: Cl
Solvent: CCO
Product: COc1ccc(C(C)=O)cc1
Reaction time: 0.5 h
Yield: 122.7 %

Procedure:
Preparation of 2,4dimethoxy4'-prop-2-enyloxychalcone ##STR30## 0.88 g of 4-allyloxyacetophenone and 0.42 g of 2,4-dimethoxybenzaldehyde were dissolved in 3.5 ml of ethanol, and to the solution was added ethanol saturated with 3.5 ml of hydrogen chloride. The mixture was left at room temperature for 30 min during which time it turned heavily red. The solution was concentrated in vacuo and the residue chromatographed (column chromatography over silica gel 60 (Merck 0.0630-0.200 mm, 100 g), eluent toluene and toluene to which increasing amounts of ethyl acetate were added) to give 500 mg of 4-methoxyacetophenone and 471 mg of 2,4-dimethoxy-4'-prop-2-enyloxychone. The chalcone was recrystallized from petroleum ether-ethyl acetate to give 370 mg of slightly yellow crystals. For data, see Example 2.24.
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][CH:17]=[O:18])[C:3]([NH:5][C:6]1[S:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=1)=[O:4].Cl>O>[F:14][C:11]([F:12])([F:13])[C:8]1[S:7][C:6]([N:5]2[CH:17]([OH:18])[CH2:16][CH2:15][N:2]([CH3:1])[C:3]2=[O:4])=[N:10][N:9]=1
Reactant: CN(CCC=O)C(=O)Nc1nnc(C(F)(F)F)s1
Agent: Cl
Solvent: O
Product: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O

Procedure:
The dimethyl acetal of 3-[1-methyl-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled resulting in the formation of a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O.O>[CH3:17][NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[CH2:5][O:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1OCc1ccccc1N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1ccccc1COc1ccccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 5 g (23 mmol) of 2-(2'-methylphenoxymethyl)-aniline (Example 1b), 5 g (36 mmol) of K2CO3 and 3.4 g (24 mmol) of methyl iodide in 50 ml of dimethylformamide is stirred overnight at room temperature. The reaction mixture is diluted with water and the aqueous phase is extracted three times with methyl tert-butyl ether. The combined organic phases are extracted with water, dried over MgSO4 and evaporated down. The residue is purified chromatographically using mixtures of hexane and methylene chloride. There is obtained 3.0 g (70% purity, about 40% yield) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:39])([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])=[CH:29][CH:28]=1)[O:3][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]([F:23])([F:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:12][CH:11]=2)=[C:6]([CH3:26])[CH:5]=1.[C:40](Cl)(=[O:44])[C:41]([CH3:43])=[CH2:42]>>[C:40]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([C:2]([O:3][C:4]2[CH:25]=[CH:24][C:7]([O:8][C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:2](=[O:3])[C:27]([CH3:32])=[CH2:28])=[CH:14][CH:15]=3)([F:22])[F:23])=[C:6]([CH3:26])[CH:5]=2)([F:39])[F:1])=[CH:28][CH:29]=1)(=[O:44])[C:41]([CH3:43])=[CH2:42]
Reactant: Cc1cc(OC(F)(F)c2ccc(CCCCCO)cc2)ccc1OC(F)(F)c1ccc(CCCCCO)cc1
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)OCCCCCc1ccc(C(F)(F)Oc2ccc(OC(F)(F)c3ccc(CCCCCOC(=O)C(=C)C)cc3)c(C)c2)cc1

Procedure:
An analogous synthesis to that described under 1.3. starting from 5-{4-[(4-{difluoro-[4-(5-hydroxypentyl)phenyl]methoxy}-2-methylphenoxy)difluoromethyl]phenyl}pentan-1-ol and methacryloyl chloride gives 5-{4-[(4-{[4-(5-methacryloyloxypentyl)phenyl]difluoromethoxy}-3-methylphenoxy)difluoromethyl]phenyl}pentyl methacrylate as a colourless solid of m.p. 26° C.
Reaction SMILES: CC(C)([O-])C.[K+].CCO[CH:10]([O:19]CC)[C:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1.[Br-].[C:23]1([N:29]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:30]2[CH:49]=[CH:48][C:33]([CH2:34][P+](CCCC)(CCCC)CCCC)=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C1COCC1>[C:50]1([N:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:30]2[CH:49]=[CH:48][C:33]([CH:34]=[CH:17][C:14]3[CH:13]=[CH:12][C:11]([CH:10]=[O:19])=[CH:16][CH:15]=3)=[CH:32][CH:31]=2)[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: CCCC[P+](CCCC)(CCCC)Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: O=Cc1ccc(C=Cc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
Potassium tert-butoxide (0.044 mol, 44mL 1M solution in THF) was added to a mixture of terephthalaldehyde mono-(diethyl acetal) (Sigma-Aldrich) (9.98 g, 0.048 mol) and 4-(diphenylamino)benzyltributylphosphonium bromide (21.6 g, 0.040 mol) in anhydrous THF (200 mL) in a 500 mL round bottom flask equipped with a reflux condenser, addition funnel and nitrogen inlet. After the addition was complete, the mixture was refluxed for 2 hours, and then cooled to RT. Aqueous HCl (20 mL, 3M) was then added and the mixture was stirred an additional hour. The product was extracted with methylene chloride (3×100 mL) and the combined organic solution dried with MgSO4. The solvent was removed by rotovaporization and the crude product purified by silica gel column chromatography (1:1 hexane:methylene chloride) yielding the pure product as a bright yellow solid (13 g, 87%). 1H NMR δ: 7.02-7.85 (m, 18 Ar—H, 2 vinyl H), 9.96 (s, 1H, CHO).
Reaction SMILES: [S:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[CH2:10][C:9](=[O:13])[NH:8]3)[N:3]=[CH:2]1.[C:14]([O:17][CH:18](OCC)OCC)(=O)[CH3:15]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[CH2:14]([O:17][CH:18]=[C:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]3[C:12]=2[S:1][CH:2]=[N:3]3)[NH:8][C:9]1=[O:13])[CH3:15]
Reactant: CCOC(OCC)OC(C)=O
Reactant: O=C1Cc2c(ccc3ncsc23)N1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: CCOC=C1C(=O)Nc2ccc3ncsc3c21

Procedure:
To a 250-ml round bottom flask was added a stir bar, 6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one (Procedure B, 4.0 g, 0.021 mol), 40 mL of glacial acetic and diethoxymethyl acetate (17.0 g, 0.105 moles). The flask was fitted with a reflux condensor and charged with nitrogen. The reaction was heated to reflux for 8 h. The flask was cooled, the stir bar was removed and the reaction was concentrated to a wet solid. The solid was triturated with a solution of ether and ethanol. The mixture was filtered, the solid was washed with an ethanol-ether solution, and the solid was dried under vacuum to yield 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one: 1H NMR (DMSO-d6): δ 10.5 (s, 1H), 9.1 (s, 1H), 7.8 (d, 1H), 7.7 (s, 1H), 7.0 (d, 1H), 4.5 (q, 2H), 1.4 (t, 3H); APCI-MS m/z 245 (M−H)−.
Reaction SMILES: CON(C)[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17])=[O:5].C[Li].[C:27](O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)C>[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:15][S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17])(=[O:5])[CH3:27]
Reactant: CON(C)C(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 4 h
Yield: 16 %

Procedure:
A solution of N-methoxy-N-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (160 mg) in anhydrous tetrahydrofuran (10 mL) was cooled to −70° C. under nitrogen atmosphere. A solution (1.8 mL) of 1.2M-methyllithium in diethyl ether was added dropwise. The temperature of the solution was gradually raised from −70° C. to 0° C., and the mixture was stirred for 4 hr. The reaction mixture was poured into aqueous citric acid solution, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10-3:7), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (22 mg, yield 16%) as colorless crystals. melting point 241-243° C.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:39]1[C:47]2[N:46]=N[NH:44][C:43]=2[CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[CH:10]1[C:11]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:44][C:43]3[CH:42]=[CH:41][CH:40]=[CH:39][C:47]=3[NH2:46])=[O:24])=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)CCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)CCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
6-(2-(9H-fluoren-9-ylidene)acetamido)hexanoic acid (335 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (353 mg, 83% yield) as a brown solid. 1H NMR (DMSO-d6) δ1.37 (m, 2H, CH2), 1.55 (m, 2H, CH2), 1.63 (m, 2H, CH2), 2.32 (t, J=8.0 Hz, 2H, CH2CO), 3.25 (m, 2H, NCH2), 4.81 (s, 2H, benzene-NH2), 6.51 (t, J=8.0 Hz, 1H, Ar—H), 6.69 (d, J=8.0 Hz, 1H, Ar—H), 6.87 (t, J=8.0 Hz, 1H, Ar—H), 7.08 (s, 1H, ═CH—CO), 7.13 (d, J=8.0 Hz, 1H, Ar—H), 7.31 (m, 2H, Ar—H), 7.41 (t, J=8.0 Hz, 2H, Ar—H), 7.76 (d, J=8.0 Hz, 1H, Ar—H), 7.81 (m, 2H, Ar—H), 8.53 (t, J=4.0 Hz, 1H, CONH), 8.69 (d, J=8.0 Hz, 1H, Ar—H), 9.09 (s, 1H, benzene-NH). LC-MS (m/z) 426 (M+1).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CC(C)=O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: O=C(O)c1ccc(CCBr)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCc1c(OCCc2ccc(C(=O)O)cc2)ccc(C(C)=O)c1O

Procedure:
A mixture of 1 g (5.55 mmoles) of 2,4-dihydroxy-3-propylacetophenone, 1.27 g (5.55 mmoles) of para-(β-bromoethyl)benzoic acid, 2.4 g of potassium carbonate, and 50 ml of dry acetone was stirred and refluxed for 3 days. The reaction flask was cooled and the stirred mixture was diluted with H2O and acidified with 6N HCl. Extraction with ethyl acetate and drying with Na2SO4 afforded the crude product after evaporating the ethyl acetate in vacuo. Pure 4-β-(4-acetyl-3-hydroxy-2-propylphenoxy)ethyl benzoic acid was isolated by flash chromatography on silica gel eluting with 5% MeOH/CH2Cl2 containing 0.1% acetic acid.