Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1>C(OCC)(=O)C.[Fe]>[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1OCc1ccccc1
Temperature: 76 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a mixture of iron powder (90.36 g, 1.62 mol) and acetic acid (10%, 400 mL) at 80° C. was added a solution of the title compound of Step A (40 g, 0.162 mol) in ethyl acetate (200 mL) dropwise with vigorous stirring. The reaction mixture was stirred further at 76° C. for 1 h. After the reaction was complete, the hot reaction mixture was filtered through Celite® (200 g) and the filter cake was washed with ethyl acetate (1000 mL). The filtrate was washed with water (3×200 mL), sodium bicarbonate solution (5%, 3×200 mL), dried (MgSO4) and concentrated to give the crude product. The product was purified by flash chromatography to give 24.76 g of the title compound of Step B. 1H NMR (CDCl3, 400 MHz): δ 7.41 (m,5H), 6.60 (m,3H), 5.04 (s,2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-])=O.O1CCCC1.C([O-])=O.[NH4+]>CO.[Pd]>[NH:9]1[C:10]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
5-nitroindole (1.0 g, 6.17 mmol) was dissolved in methanol (10 ml) and anhydrous tetrahydrofuran (10 ml) at room temperature and then, palladium/carbon (10%) of a catalystic amount and ammonium formate (2.0 g, 31.7 mmol) were added to be stirred slowly at room temperature for 30 minutes. After completing the reaction, the reacting solution was filtered through celite, washed with methanol, concentrated under reduced pressure and then, dropped a silica gel short column. Afterward, the residue was concentrated again under reduced pressure and triturated with isooctane. As a result, the present compound (0.45 g, productive yield 55%) was obtained as a solid phase.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH-].[Na+].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>C(O)C>[CH:15]1([CH2:14][O:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: NC(=O)c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccccc1OCC1CC1
Yield: 60.6 %

Procedure:
2-Hydroxybenzamide (5.17 g, 37.74 mmol) and sodium hydroxide (1.5 g, 37.5 mmol) in ethanol (20 ml) were refluxed for 1 h to give a clear solution. (Bromomethyl)cyclopropane (5.09 g, 37.7 mmol) was added and the mixture refluxed for 36 h. The solvent was evaporated and the residue triturated thoroughly with ether and water to give the above compound (4.37 g).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C:6]1[N:7]=[C:8]2[N:12]([CH:13]=1)[CH:11]=[C:10]([CH3:14])[S:9]2)C.C(O)C.C(OCC)C.[ClH:24]>>[ClH:24].[CH3:14][C:10]1[S:9][C:8]2=[N:7][C:6]([CH2:5][C:4]([OH:15])=[O:3])=[CH:13][N:12]2[CH:11]=1
Reactant: CCOC(=O)Cc1cn2cc(C)sc2n1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cc1cn2cc(CC(=O)O)nc2s1
Temperature: 25 °C
Yield: 93 %

Procedure:
Ethyl(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)acetate (151.3 g, 0.67 mol) was dissolved in 10% aqueous HCl (435 mL) and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and was concentrated in vacuo to give a yellow oil. Ethanol (100 mL) and diethylether (200 mL) were added and the resulting white precipitate was collected by filtration and dried in a vacuum oven overnight to give 144.3 g (93%) of final product, (2-methylimidazo[2,1-b][1,3]thiazol-6-yl)acetic acid hydrochloride). MS (ES+) 197.1 (M+H)+. 1H NMR (CD3OD) δ 2.48 (s, 3H), 3.88 (s, 2H), 7.81 (s, 1H), 7.85 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][O:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].CNN>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][O:10][NH2:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCON1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCON
Temperature: 25 °C
Reaction time: 72 h
Yield: 102.4 %

Procedure:
[2-(1,3-dioxo-1,3-dihydroisoindol-2-yloxy)-ethyl]-carbamic acid tert-butyl ester (0.842 g, 2.749 mmol) was dissolved in 20 ml of CH2Cl2 and methylhydrazine (150 μL, 2.776 mmol) was added at room temperature. As soon as methylhydrazine was added, a white precipitate was formed. The reaction was stirred at room temperature for 72 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide 0.496 g of a viscous oil (102% yield). The crude material was used without further purification.
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)C(OCC)=O)=[CH:11][C:10]=1[CH3:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO>[C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH2:15][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[CH:11][C:10]=1[CH3:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(c1ccc([N+](=O)[O-])cc1)c1cc(C)c(C(=O)c2ccccc2)n1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Cc2ccc([N+](=O)[O-])cc2)n(C)c1C(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Ethyl 2-(5-benzoyl-1,4-dimethylpyrrol-2-yl)-2-(4-nitrophenyl)acetate (8.2 g, 20.2 mmol) [prepared by proceeding as described in Example 1, Steps (a) and (b) ] was dissolved in a 1:1 mixture of methanol (200 ml). An aqueous solution of LiOH (250 mi 0.4 M, 100.9 mmol) was added and the mixture was stirred at 60° C. for 2 h. The organic solvents were evaporated in vacuo, the aqueous residue was acidified with 10% HCl, and the product was extracted into ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and concentrated under vacuum. Purification on a Florisil® column (hexane-ethyl acetate, 4:1) gave 4-[5-benzoyl-1,4dimethyl-1H-pyrrol-2-ylmethyl]-nitrobenzene (6.68 g, 99%) as a yellow solid. ##STR23##
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.ClC1C=CC=CN=1.ClC1N=C(C2C=CC=CC=2)C(C(OCC)=O)=CC=1.N[C:55]1[N:60]=[C:59]([NH:61][CH2:62][CH2:63][NH:64][C:65]2[CH:70]=[CH:69]C(C3NC=CN=3)=C(C3C=CC(Cl)=CC=3Cl)[N:66]=2)[CH:58]=[CH:57][C:56]=1[N+:84]([O-:86])=[O:85]>CC#N>[N+:84]([C:56]1[CH:57]=[CH:58][C:59]([NH:61][CH2:62][CH2:63][NH:64][C:65]2[N:66]=[C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:69][CH:70]=2)=[N:60][CH:55]=1)([O-:86])=[O:85]
Reactant: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: CCOC(=O)c1ccc(Cl)nc1-c1ccccc1
Agent: Clc1ccccn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Product: CCOC(=O)c1ccc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccccc1

Procedure:
ethyl 6-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)-2-phenylpyridine-3-carboxylate was prepared from ethyl 3-oxo-3-phenylpropanoate as the starting material and DDQ in the oxidation step. The final product is achieved directly from the chloropyridine by reacting ethyl 6-chloro-2-phenylpyridine-3-carboxylate with 2-(2-aminoethylamine)-5-nitropyridine in CH3CN and Hüing's base at 80° C. for 18 hours. The procedures are analogous to the general method for {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazolyl(2-pyridyl)]amine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([O:13]CC)=O.[CH3:16][NH2:17]>CO>[CH3:16][NH:17][C:11]([C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:13]
Reactant: CCOC(=O)c1cc2ccccc2n1C
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cc2ccccc2n1C
Temperature: 25 °C

Procedure:
A suspension of ethyl 1-methyl-1H-indole-2-carboxylate (27.10 g, 133.34 mmole) in 40% aqueous CH3NH2 (300 mL) and MeOH (30 mL) was stirred at RT. A solid tended to gradually creep up the walls of the flask, and was washed down periodically with MeOH. The flask was tightly stoppered to keep the material inside the flask. As the reaction proceeded, the solid dissolved, but eventually the product began to precipitate. The reaction was stirred at RT for 5 days, then was concentrated to remove approximately 200 mL of the solvent. The remaining residue was diluted with H2O (300 mL), and the solid was collected by suction filtration and washed with H2O. Drying at 50-60° C. in high vacuum left the title compound (23.45 g, 93%) as a faintly yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J=8.0 Hz, 1 H), 7.27-7.43 (m, 2 H), 7.10-7.20 (m, 1 H), 6.80 (s, 1 H), 6.10-6.30 (m, 1 H), 4.06 (s, 3 H), 3.01 (d, J=4.9 Hz, 3 H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>>[NH:11]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)[NH2:12]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Product: N#Cc1ccc(NN)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
A mixture of 6-chloro-nicotinonitrile (2.77 g, 20 mmol) and hydrazine hydrate (15 mL) was stirred at 100° C. for 3 h and evaporated. The residue was suspended in ether and filtered, then suspended in sodium bicarbonate solution and filtered, washing with water, and dried to provide 6-hydrazino-nicotinonitrile (1.25 g, 46% yield) as a tan solid. 1H-NMR (DMSO-d6, 500 MHz) 8.59 (s, 1H), 8.35 (s, 1H), 7.74 (d, 1H), 6.75 (s, 1H), 4.44 (s, 2H) ppm; MS (FIA) 135.1 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[C:19]3\[C:20](=[O:25])[NH:21][C:22](=[O:24])[S:23]\3)=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].CN(C1C=CC=CN=1)CCOC1C=CC(CC2SC(=O)NC2=O)=CC=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCOc2ccc(/C=C3/SC(=O)NC3=O)cc2)nc1
Agent: CN(CCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccccn1
Product: CCc1ccc(CCOc2ccc(C[C@H]3SC(=O)NC3=O)cc2)nc1

Procedure:
Biocatalytic reduction of 5-[1-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}-meth-(E)-ylidene]-thiazolidine-2,4-dione was investigated using literature procedures described for Rosiglitazone (J. Chem. Soc. Perkin Trans. I, 1994, 3319-3324).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1O>C(O)(=O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:12](=[O:13])[CH:11]=[CH:10]1
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Solvent: CC(=O)O
Product: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
A solution of 170 mg. of trans-Δ2 -PGE1 (prepared as described in Example 2) in 15 ml. of 90% acetic acid was stirred for 17 hours at a temperature of 57° to 60°C. The reaction mixture was concentrated under reduced pressure and the residue dissolved in diethyl ether, washed with water, dried, and concentrated under reduced pressure. The residue was further purified by column chromatography using 20 g. of silica gel and a cyclohexaneethyl acetate mixture (4:1) as eluent. The fraction containing trans-Δ2 -PGA1 was collected and concentrated. The product thus obtained was recrystallised from a cyclohexane-ethyl acetate mixture to obtain pure trans-Δ2 -PGA1 : yield 102 mg. (63%), m.p. 68°C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2](/[CH:14]=[CH:13]/[C:12]([O:11][CH3:10])=[O:15])=[CH:3][CH:4]=1)#[N:7]
Reactant: C=CC(=O)OC
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C#N)cc1
Temperature: 100 °C
Yield: 70.7 %

Procedure:
To a solution of 4-bromobenzonitrile (25 g, 0.136 mol) and methylacrylate (58.6 g, 0.682 mol) in dry DMF (250 mL) was added PPh3 (2.8 g, 0.0106 mol), Pd(OAc)2 (1.3 g, 0.00579 mol), sodium bicarbonate (18 g, 0.214 mol) and triethylamine (25 mL). The reaction mixture was heated to 100° C. for 16 h under nitrogen. The reaction mixture was cooled and the solid was filtered off. The filtrate was diluted with water (1 L) and the product was extracted with diethyl ether (4×200 ml). The combined organic layer was washed with water, brine, dried and evaporated to yield the crude product which was purified by chromatography (SiO2, PetEther/EtOAc (9.5/0.5) as eluent) to yield the title compound as a liquid (18 g, 71%). TLC: PetEther/EtOAc (9.5/0.5); Rf: 0.75
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reaction time: 8 h
Yield: 98 %

Procedure:
To a stirred solution of 2-chloro-3-nitrobenzoic acid (1.0 g, 5.0 mmol) in anhydrous methanol (10 mL) at 0° C. was added thionyl chloride (0.5 mL, 7.4 mmol) dropwise and the reaction mixture was stirred overnight at reflux. The mixture was diluted with methanol and concentrated under reduced pressure to remove the excess thionyl chloride. The residue was then re-dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, re-extracted with ethyl acetate, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 2-chloro-3-nitrobenzoate (1.1 g, 98%) as a white foam that was used in the next step without further purification: 1H NMR (300 MHz, DMSO-d6) δ 8.21 (d, J=1.5 Hz, 1H), 8.07 (dd, J=7.8, 1.5 Hz, 1H), 7.73 (t, J=8.1 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[H][H]>O1CCCC1.[Pd]>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(F)cc1F
Temperature: 100 °C
Yield: 98.1 %

Procedure:
105 g of 2,4-difluorocinnamic acid from Example 5 were dissolved in 450 ml of tetrahydrofuran and reacted with 5 g of palladium on active carbon with stirring at 100° C. and a hydrogen pressure of 50 bar. After a constant pressure had been achieved, the mixture was cooled to room temperature, the pressure was released, the palladium catalyst was filtered off and the solvent was removed by distillation. After drying in vacuo, 104.1 g of 3-(2,4-difluorophenyl)-propionic acid (98% of theory; melting point: 100-102° C.) were obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[C:9]1(=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[O:10]1>CCO>[OH:8][CH:5]1[CH2:6][CH2:7][CH:2]([N:1]2[C:9](=[O:10])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:18])[CH2:3][CH2:4]1
Reactant: NC1CCC(O)CC1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Yield: 60 %

Procedure:
A mixture of 4-aminocyclohexanol (3.9 g, 34 mmol) and isobenzofuran-1,3-dione (4.9 g, 34 mmol, 1.0 eq) in 100 mL of EtOH was heated at reflux for 2 days. EtOH was removed and the residue was purified by column chromatography on silica gel (eluent with DCM) to give 2-(4-hydroxycyclohexyl)isoindoline-1,3-dione as white solid (5.0 g, 59%). MS: m/z 246.0 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[C:9]([C:19]#[CH:20])=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11]>CN1C(=O)CCC1.C(OCC)(=O)C>[Br:7][C:8]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[C:10]2[C:9]=1[CH:19]=[CH:20][NH:11]2
Reactant: C#Cc1c(N)cc(C(F)(F)F)cc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1cc(Br)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of potassium tert-butoxide (1.33 g) in NMP (30 mL) was added a solution of 3-bromo-2-ethynyl-5-(trifluoromethyl)aniline (1.56 g) in NMP (5 mL) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.08 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(C(F)(F)F)=O>[CH:10]1[CH:11]=[CH:12][C:7]([CH:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[C:5]2[NH:1][CH:2]=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: c1cc[nH]c1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C(c2ccc[nH]2)c2ccc[nH]2)cc1

Procedure:
Gas Chromatography. We previously reported that the GC trace of the crude reaction mixture, obtained with TFA catalysis, shows three major peaks.16 The GC trace of the crude reaction mixture obtained with 0.1 equiv of InCl3 and a pyrrole:benzaldehyde ratio of 100:1 for 1 h also shows three major peaks (FIG. 2A) that are assigned as 1 (tR=16.4 min), 2 (tR=17.0 min) and 3 (tR=21.8 min) based on comparison with authentic samples. Closer scrutiny of the same GC trace upon amplification of the scale reveals a number of additional minor peaks (FIG. 2B). The appearance and intensity of these minor peaks depend on the reaction conditions (catalyst, reaction time, and pyrrole:benzaldehyde ratio). For example, some of the minor peaks seen in InCl3 catalyzed reactions are not observed in TFA catalyzed reactions.
Reaction SMILES: [N+](C1C=CC(CBr)=CC=1)([O-])=O.S([O-])([O-])=O.[Na+].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:19].[N+:24]([C:27]1[CH:37]=[CH:36][C:30]([CH2:31][S:32]([O-])(=[O:34])=[O:33])=[CH:29][CH:28]=1)([O-:26])=[O:25].[Na+]>O>[N+:24]([C:27]1[CH:37]=[CH:36][C:30]([CH2:31][S:32]([Cl:19])(=[O:34])=[O:33])=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)[O-])cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=S([O-])[O-]
Agent: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Temperature: 90 °C
Yield: 83 %

Procedure:
A mixture of 4-nitrobenzyl bromide (100.0 g 0.46 mol), sodium sulphite (84.8g, 0.67 mol) and water (316 ml) was heated at 90° C. for 5 h. The solution was cooled and the resultant solid filtered and washed with diethyl ether. The product was dried under vacuum at 60° C. (95 g, 86%). Phosphorus pentachloride (78 g, 0.375 mol ) was added to sodium 4-nitrobenzyl sulphonate (60 g, 0.25 mol) and the mixture heated at 90° C. for 2 h. The mixture was cooled and volatile material removed under vacuum. The residue was dissolved in dichloromethane (500 ml) and water (150 ml). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and evaporated to give 4-nitrobenzyl sulphonyl chloride (48.9 g, 83%) which was pure by 1H NMR. Methylamine gas was bubbled through a solution of 4-nitrobenzyl sulphonyl chloride (37.9 g, 0.16 mol), in dichloromethane (325 ml), until uptake had ceased (0.5 h). The resulting solid was filtered, washed with H2 and dried under vacuum to give the title-sulphonamide (32.5 g, 88%), δ(250MHz, D6 -DMSO) 2.61 (3H, s, Me), 4.55 (2H, s, CH2), 7.06 (1H, s, NH), 7.66 (2H, d, J=8.7Hz, Ar-H), 8.25 (2H, d, J=8.7Hz, Ar-H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19](=[O:24])[NH:20][CH2:21][CH2:22][OH:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[O:23]=[CH:22][CH2:21][NH:20][C:19](=[O:24])[O:18][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(NCCO)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.1 %

Procedure:
A solution (30 ml) of oxalyl chloride (1.72 ml, 20.0 mmol) in dichloromethane was added dropwise to a solution (10 ml) of dimethyl sulfoxide (2.84 ml, 40.0 mmol) in dichloromethane at −78° C., and the mixture was stirred at the same temperature for 5 min. A solution (45 ml) of benzyl(2-hydroxyethyl)carbamate (1.95 g, 10.0 mmol) in dichloromethane was added to the reaction mixture and the mixture was further stirred for 15 min. Triethylamine (6.93 ml, 50.0 mmol) was added, and the mixture was stirred for 5 min. The temperature was raised to room temperature and the reaction mixture was stirred for 1.5 hrs. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (7:3-3:2, v/v) to give the title compound (930 mg, 48%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]([CH:34]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1)[CH3:35])([F:33])[C:29]([F:32])([F:31])[F:30].[F:45][C:46]([F:55])([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:47][NH2:48]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:42][CH2:41][C:40]1[CH:39]=[CH:38][C:37]([O:36][CH:34]([C:28]([F:27])([F:33])[C:29]([F:30])([F:31])[F:32])[CH3:35])=[CH:44][CH:43]=1.[F:45][C:46]([F:55])([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:47][NH2:48]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(Oc1ccc(CN)cc1)C(F)(F)C(F)(F)F
Agent: NCC(F)(F)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C(F)(F)C(F)(F)F

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (9 g, 21.1 mmol) with 4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamine isomer 2 (11.4 g, 42.3 mmol) in anhydrous toluene (270 mL). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 4:1 gradient) to obtain 7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine isomer 2 (9.5 g, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2([C:11]#N)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CC[O:25]C(C)=O.OS(O)(=O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2([CH:11]=[O:25])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: N#CC1(c2ccnc(Br)c2)CC1
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CC1(c2ccnc(Br)c2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a chilled (−78° C.) solution of 1-(2-bromopyridin-4-yl)-cyclopropanecarbonitrile (1.16 g, 5.2 mmol) in toluene (30 mL) is added a 1 M solution of diisobutylaluminum hydride (DIBAH) (10.4 mL) in toluene. The mixture stirred at −78° C. for 1 hour and is then warmed to room temperature. After 1 hour, EtOAc (30 mL) is added, followed by 1 M aqueous solution of H2SO4 (30 mL). The organic phase is separated and the aqueous layer is extracted with EtOAc (3×50 mL). The combined organic layers are dried over MgSO4, filtered and concentrated to afford crude 1-(2-bromopyridin-4-yl)-cyclopropanecarboxaldehyde which is used without purification. MS m/z 226.5, 228.5