Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[N:3]=1.[C:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH2:11][CH2:12][C:13]#[CH:14].C(N)(C)(C)C>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[OH:9][CH2:8][C:4]1[N:3]=[C:2]([C:14]#[C:13][CH2:12][CH2:11][C:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: OCc1cccc(Br)n1
Reactant: C#CCCC(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)(C)N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCC#Cc1cccc(CO)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 56.9 %

Procedure:
To a 200 mL round-bottom flask, 3.49 g of 2-bromopyridine-6-methanol, 3.0 g of t-butyl 4-pentynoate, 190 mg of BHT, 1.17 g of copper(I) iodide, 877 mg of tetrakis(triphenylphosphine)palladium(0), 2.72 g of t-butylamine and 56 mL of DMF were added, and the mixture was stirred under argon atmosphere at 80° C. for 6 hours. After the DMF was removed under reduced pressure from the reaction mixture, saturated aqueous sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by chromatography on silica gel (n-hexane-ethyl acetate=2:1) to give 2.76 g of t-butyl 5-(6-hydroxymethylpyridin-2-yl)pent-4-ynoate as a yellow oil.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:21]=[C:22]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31][CH:32](P(=O)(OCC)OCC)[C:33]3=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(O)C>O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31]/[C:32](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:33]3=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3cccc(F)c3)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4cccc(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
Lithium hydroxide (0.217 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.49 g) and diethyl [(3S,8aR)-3-(3-fluorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (1.9 g) in tetrahydrofuran (4 mL)-ethanol (16 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.76 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@H:25]3[CH2:28][C@H:27]([CH2:29][N:30]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.O.NN>C(O)C>[NH2:30][CH2:29][C@H:27]1[CH2:26][C@H:25]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9]2)[CH2:28]1
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CN2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4.15 g (7.83 mmol) of trans-2-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-isoindole-1,3-dione in 100 ml of dry ethanol are added dropwise at RT and under argon 5.87 g (5.7 ml; 117.5 mmol) of hydrazine monohydrate. After 20 min all the starting material is dissolved, and the reaction is complete after 20 h stirring at RT. The colorless precipitate is filtered off, and washed with ethanol. The filtrate is evaporated to dryness and the crude compound is purified by chromatography on silica gel (dichloromethane:methanol:NH4OHaqu.=90:10:1) to provide trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine. Analytical HPLC: tR=7.50 min (Grad 1); ES-MS: m/eo=400; 1H-NMR (CDCl3): 8.30/s (1H); 7.3-7.5/m (6H); 7.20/s (1H); 7.05-7.15/2 peaks (2H); 6.99/m (1H); 5.41/m (1H); 5.14/s (2H); 5.04/broad s (2H); 2.98/d (2H); 2.54-2.69/m (2H); 2.35-2.54/m (3H); 1.73/broad s (2H).
Reaction SMILES: [CH3:1][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Cl:27][C:28]1[CH:29]=[C:30]([C:35](=O)[CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:31]=[CH:32][C:33]=1[Cl:34].O>C1C=CC=CC=1>[Cl:27][C:28]1[CH:29]=[C:30]([C:35](=[CH2:1])[CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCC(=O)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: C=C(CCC(=O)OC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.8 %

Procedure:
1.75 g (49.0 mmole) of methyltriphenylphosphonium bormide and 5.50 g (49.0 mmole) of potassium t-butoxide were suspended in 200 ml of dried benzene, and the mixture was stirred at room temperature for 6 hours under a nitrogen atmosphere. At the end of this time, 8.50 g of methyl 4-(3,4-dichlorophenyl)-4-oxobutanoate [prepared as described in step (a) above] were dissolved in 40 ml of benzene, and the resulting solution was added to the reaction mixture. The mixture was then stirred for 1 hour. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and diethyl either ranging from 19:1 to 23:2 by volume as the eluent, to give 4.20 g of the title compound as a pale orange oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])[CH3:14]>C(O)=O.CO>[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[N:17]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH2:13][CH3:14])[CH3:11])[N:5]=1)[CH3:2])[CH3:14]
Reactant: CCc1ccccc1N
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: O=CO
Solvent: CO
Product: CCc1ccccc1N=C(C)c1cccc(C(C)=Nc2ccccc2CC)n1
Temperature: 50 °C
Reaction time: 24 h
Yield: 55.2 %

Procedure:
One 9 of 2,6-diacetylpyridine and 3.0 ml of 2-ethylaniline were added to a round-bottom flask with 30 ml of methanol. A stirbar and 5 drops of 97% formic acid were added, and the flask was sealed and the solution was stirred for 24 hours at 50° C. The flask was then cooled to room temperature and placed in a freezer at −30° C. After 1 day, yellow crystals had formed. The crystals were isolated by filtration and identified by 1H NMR as the desired product (1.25 g, 55.2%). 1H NMR (CDCl3): δ8.38(d, 2, Hpyr), 7.86(t, 1, Hpyr), 7.20(m, 4, Haryl), 7.07(t, 2, Haryl), 6.65(d, 2, Haryl), 2.49(q, 4, Hbenzyl), 2.35(s, 6, N—C—CH3), 1.14(t, 6, CH2CH3).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([NH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[CH:20]=[CH:21][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:33])[F:34])[CH:18]=2)[CH:25]=1
Reactant: O=C(O)c1cccc(Nc2cccc(C(F)(F)F)c2)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Nc2cccc(C(F)(F)F)c2)c1
Yield: 66.6 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(3-(trifluoromethyl)phenylamino)benzamide was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.220 g; 0.951 mmol), 3-(3-(trifluoromethyl)phenylamino)benzoic acid (0.294 g; 1.05 mmol), HATU (0.470 g; 1.24 mmol) and N,N-diisopropylethylamine (0.439 mL; 2.38 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.290 g (65%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([CH3:16])=[C:7]([CH:15]=1)[C:8]([O:10][CH:11]([CH2:13][CH3:14])[CH3:12])=[O:9])[CH3:2].[CH3:17][C@@:18]([C:23]([NH2:25])=[O:24])([CH:20]([CH3:22])[CH3:21])[NH2:19].[S]>ClC1C=CC=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([C:16]2[NH:25][C:23](=[O:24])[C:18]([CH:20]([CH3:22])[CH3:21])([CH3:17])[N:19]=2)=[C:7]([CH:15]=1)[C:8]([O:10][CH:11]([CH2:13][CH3:14])[CH3:12])=[O:9])[CH3:2]
Reactant: CCc1cnc(C)c(C(=O)OC(C)CC)c1
Reactant: CC(C)[C@](C)(N)C(N)=O
Agent: [S]
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: CCc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)OC(C)CC)c1
Yield: 72.4 %

Procedure:
A mixture of 2.2 g of sec-butyl 5-ethyl-2-methylnicotinate (10 mmol), 1.3 g of a-methylvalinamide (10 mmol) and 2.0 g of sulfur (62 mmol) in 2.5 g of chlorobenzene (114 wt%) is magnetically stirred at reflux temperatures for 24 hours. The reaction is cooled, diluted with methylene chloride, and filtered to remove unreacted sulfur. The filtrate is chromatographed on silica gel using 2:1 hexane-ethyl acetate as eluant to afford 2.5 g of the title product (72% yield) as a solid; recrystallization from ether-hexane gives mp 83°-87° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:19](CC)CC)C.C(OC(Cl)=O)C(C)C.N>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH2:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)CCNC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.05 h

Procedure:
111.7 g of benzyloxycarbonyl-β-alanine were dissolved in 1 liter of dimethylformamide, cooled to -20° C, treated with 70 ml of triethylamine and 67 ml of chloroformic acid isobutyl ester and stirred at -20° C for 3 minutes. Dry ammonia gas was led into this mixture until the pH rose to 11, care being taken that the temperature did not, exceed -10° C. The mixture was stirred for a further 30 minutes at room temperature, filtered and the filtrate concentrated in vacuo. The residue was recrystallised from water. Yield: 91 g; melting point 162°-165° C.
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:19]([O-])([O-])[O:20][CH2:21][CH3:22].C(OC(=O)C)(=O)C>>[F:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([C:6](=[CH:19][O:20][CH2:21][CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 150 °C
Yield: 94.3 %

Procedure:
A mixture of ethyl α-(2,3,4,5-tetrafluorobenzoyl)acetate (0.7 g), ethyl orthoformate (0.67 g) and acetic anhydride (0.74 g) is heated at 150° C. for 1.5 hour. After the reaction, the volatile material is distilled off at 120° C. under reduced pressure with a water pump to give ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxyacrylate (0.8 g) as a mixture of cis and trans isomers.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]1[C:20]([C:21](OCC)=[O:22])=[C:19]([CH3:26])[N:18]=[C:13]12.C(OCC)(=O)C>O1CCCC1>[Cl:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]1[C:20]([CH2:21][OH:22])=[C:19]([CH3:26])[N:18]=[C:13]12
Reactant: CCOC(=O)c1c(C)nc2c3cccc(Cl)c3ccn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc2c3cccc(Cl)c3ccn2c1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.5 %

Procedure:
Lithium aluminum hydride (0.668 g) was added portionwise to a solution of 7-chloro-3-ethoxycarbonyl-2-methylimidazo[2,1-a]isoquinoline (5.1 g) in tetrahydrofuran (100 ml) with ice-cooling under nitrogen atmosphere and the mixture was stirred at room temperature for 1.5 hours. After an addition of ethyl acetate, the mixture was evaporated in vacuo and the residue was extracted with hot ethanol. The extract was treated with activated charcoal and evaporated in vacuo. The residue was recrystallized from 90% ethanol to give 7-chloro-3-hydroxymethyl-2-methylimidazo[2,1-a]isoquinoline (1.94 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:11]C(=O)C(C)(C)C)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[NH2:11]
Reactant: CC(C)(C)C(=O)Nc1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of N-(3-fluoro-4-nitro-phenyl)-2,2-dimethyl-propionamide (87.0 g, 0.36 mol) in CH2Cl2 (400 mL) and 6N hydrochloric acid (800 mL) was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with 1000 mL of ethyl acetate and potassium carbonate (500.0 g) was added portion wise. The aqueous solution was separated and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed by evaporation under reduced pressure; the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to afford 3-fluoro-4-nitroaniline (56.0 g, 99%). 1H NMR (300 MHz, CDCl3) δ 8.07 (t, J=8.7 Hz, 1 H), 7.86 (dd, J=2.1, 13.2 Hz 1 H), 7.59 (brs, 2 H), 7.22 (s, 1 H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([CH2:13][C:14](OC)=[O:15])[CH:10]=[CH:11][CH:12]=1.[BH4-].[Li+].O>ClCCl>[OH:15][CH2:14][CH2:13][C:9]1[CH:8]=[C:7]([N:3]2[CH2:4][CH2:5][NH:6][C:2]2=[O:1])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)Cc1cccc(N2CCNC2=O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Product: O=C1NCCN1c1cccc(CCO)c1
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
Methyl [3-(2-oxo-1-imidazolidinyl)phenyl]acetate was dissolved in dry dichloromethane (10 vol). Lithium borohydride (2M solution in THF, 4.3 vol) was added dropwise over 1 hour at 20° C. The resulting suspension was stirred at 20° C. for 2.5 hours. Water (2 vol) is added dropwise at 20° C. over 60 minutes. The resulting suspension was concentrated to 2 vol and aqueous ammonium chloride solution (7%, acidity corrected with 10% hydrochloric acid to pH 3, 3 vol) was added. The suspension was stirred at 20° C. for 2 hours then filtered. The filter-cake was washed thoroughly with aqueous ammonium chloride solution (7%, acidity corrected with 10% hydrochloric acid to pH 3, 2 vol) and water (2 vol) until the filtrate had an acidity of pH 7. The filter-cake was dried at 80° C. to give the title compound (75% th.).
Reaction SMILES: [NH4+].[N+:2]([C:5]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[S:16]([O-:19])(=[O:18])=[O:17])([O-])=O>C(O)(=O)C.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:2][C:5]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[S:16]([OH:19])(=[O:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1cc(Cl)c(Cl)cc1S(=O)(=O)[O-]
Agent: [Ti+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(C(F)(F)F)ccc1Oc1cc(Cl)c(Cl)cc1S(=O)(=O)O

Procedure:
The 2-(2-nitro-4-trifluoromethylphenoxy)-4,5-dichlorobenzenesulfonic acid, ammonium salt (5 g, 11.2 mmol) was dissolved in acetic acid (75 mL). The mixture was diluted with water (75 mL), and a 20 % aqueous solution of titanium trichloride (65 mL) was added. After aqueous workup the crude product was flash chromatographed (silica gel, methylene chloride/ethanol/ammonium hydroxide) to give the title compound. 1H NMR (400 MHz, CD3OD) δ8.02 (s, 1H), 7.17 (d, 1H), 7.12 (d, 1H), 6.94 (dd, 1H), 6.87 (s, 1H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C(NC(C)C)(C)C.[Li].F[B-](F)(F)F.[CH+:17]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=[CH:18]1>O1CCCC1>[CH:22]1([CH2:2][C:1]#[N:3])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=[CH:23]1
Reactant: c1ccc[cH+]cc1
Reactant: CC#N
Agent: F[B-](F)(F)F
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CCC1C=CC=CC=C1
Reaction time: 0.33 h
Yield: 25.6 %

Procedure:
To a solution of anhydrous acetonitrile (3.12 mL, 56.2 mmol, 1 eq.) in tetrahydrofuran (281 mL, 0.2 M) was added lithium diisopropylamine (1.8 M in heptane/ethylbenzene/tetrahydrofuran, 31.2 mL, 56.2 mmol, 1 eq.) at −78° C. After 20 minutes at −78° C., tropylium tetrafluoroborate (10 g, 56 mmol, 1 eq.) was added. After 10 minutes, the reaction was concentrated in vacuo and the residue was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide a brown oil, which was purified by silica gel chromatography (Gradient: 0% to 10% ethyl acetate in heptane) to provide #61 (1.88 g, 25%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.69-6.71 (m, 2H), 6.27-6.32 (m, 2H), 5.28-5.33 (m, 2H), 2.61 (d, J=7.2 Hz, 2H), 2.26-2.34 (m, 1H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38][NH2:39]>O1CCCC1.ClCCl>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:33])[NH:39][CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCC(=O)O
Reactant: CN(C)CCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)CCCCCCCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
1,1′-Carbonyldiimidazole (118 mg, 0.73 mmol) was added to a solution of acid 3 (200 mg, 0.66 mmol) in a mixture of tetrahydrofuran (5 mL) and dichloromethane (1 mL). The resulting solution was stirred at ambient temperature for 4 h. 3-(Dimethylamino)propylamine (0.10 mL, 0.79 mmol) was then added and stirring continued for 14 hours at room temperature. The solvent was then removed under vacuum. The resulting residue was dissolved in dichloromethane (10 mL) and washed sequentially with aqueous sodium bicarbonate (1×10 mL), and then water (1×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 4 (154 mg, 61%) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 1.27 (m, 12H), 1.57 (br, 14H), 1.56-1.65 (m, 2H), 1.67-1.74 (m, 2H), 2.16 (t, 2H, J=7.5 Hz), 2.32 (s, 6H), 2.51 (t, 2H, J=6.7 Hz) 3.29-3.33 (m, 2H), 4.51 (br, 1H); m/z (ESI) 386 [C21H43N3O3+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:19]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1cccc2cnccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1cccc2cnccc12)c1ccccc1
Temperature: 0 °C
Yield: 103.6 %

Procedure:
To a solution of 5-hydroxyisoquinoline (15.0 g, 103 mmol) in dichloromethane (300 ml) was added triethylamine (10.9 g, 108 mmol), and the mixture was cooled to 0° C. Under stirring, benzoyl chloride (15.2 g, 108 mmol) was added dropwise and the temperature was raised to room temperature. After stirring for 6 hours at room temperature, dichloromethane was added. The solution was washed with saturated aqueous solution of sodium hydrogencarbonate, then dried over anhydrous magnesium sulfate and solvent was distilled off, thereby affording 26.6 g of the title compound as a light brown liquid. Yield quantitative. 1H-NMR (DMSO-d6, δ): 7.68(2H, t, J=7.3 Hz), 7.75(1H, d, J=5.9 Hz), 7.79-7.85(3H, m), 8.12-8.16(1H, m), 8.28(2H, d, J=7.3 Hz), 8.55 (1H, d, J=5.9 Hz), 9.45(1H, s).
Reaction SMILES: CC[Mg+].[Br-:4].C1C=CC(C(C2NC=CC=2)C2NC=CC=2)=CC=1.C[C:23]1[CH:37]=[CH:36][C:26]([C:27](=[O:35])[S:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1>C1COCC1>[Br:4][C:23]1[CH:37]=[CH:36][C:26]([C:27](=[O:35])[S:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Sc2ccccn2)cc1
Reactant: [Br-]
Agent: CC[Mg+]
Agent: c1ccc(C(c2ccc[nH]2)c2ccc[nH]2)cc1
Solvent: C1CCOC1
Product: O=C(Sc1ccccn1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
Exemplified for 1-(4-Methylbenzoyl)-5-phenyldipyrromethane (2a). A solution of EtMgBr (50.0 mL, 50.0 mmol, 1.0 M in THF) was added via syringe to a stirred solution of 1a (4.44 g, 20.0 mmol) in THF (20 mL) under argon. The mixture was stirred for 10 min at room temperature and then cooled to −78° C. A solution of 6a (4.58 g, 20.0 mmol) in THF (20 mL) was added. The mixture was stirred for 10 min at −78° C. Then the cooling bath was removed, the mixture was stirred for 20 min, and then the reaction was quenched with saturated aqueous NH4Cl (150 mL). The mixture was diluted with THF (10 mL), washed with water (100 mL), and then dried (Na2SO4). Removal of solvents and chromatography [silica (6×24 cm), CH2Cl2 (2300 mL)] afforded a golden amorphous solid (5.82 g, 86%): mp 69-70° C.; 1H NMR δ 2.43 (s, 3H), 5.55 (s, 1H), 5.95-6.01 (m, 1H), 6.05-6.09 (m, 1H), 6.14-6.18 (m, 1H), 6.67-6.71 (m, 1H), 6.79-6.82 (m, 1H), 7.20-7.35 (m, 7H), 7.72-7.76 (m, 2H), 8.05-8.22 (brs, 1H), 9.50-9.68 (brs, 1H); Anal. Calcd for C23H20N2O: C, 81.15; H, 5.92; N, 8.23. Found: C, 80.74; H, 5.74; N, 8.25.