Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([C:16]3[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[N:17]=3)[S:13][C:12]=2[CH:34]=1)(C)(C)C.C(O)(C(F)(F)F)=O.CO>ClCCl>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([C:16]3[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[N:17]=3)[S:13][C:12]=2[CH:34]=1
Reactant: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2ccc(NC(=O)OC(C)(C)C)cc2s1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2ccc(N)cc2s1
Reaction time: 20 h
Yield: 64 %

Procedure:
(2-{5-Methyl-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophen-6-yl)-carbamic acid tert-butyl ester (0.33 g, 0.66 mmol) is dissolved in dichloromethane (6 mL) and TFA (0.78 mL) is added. The solution is stirred for 20 hours before adding methanol. The mixture is passed through an SCX column. After eluting with methanol, 20% of 2.0 M NH3/MeOH in EtOAc is used to elute the product which is then chromatographed on silica gel, eluting with 2.0 M NH3/MeOH in dichloromethane 0-15%, to give the title compound as a yellow oil. (166 mg, 64% yield). ES+(m/z) 397 [M+H].
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.ClCC1C(C(F)(F)F)=NC=CC=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=O.N1C2C(=CC=CC=2)C2(C3C(=CC4OCCOC=4C=3)[O:53]C2)C1=O>>[N:4]1[CH:5]=[CH:6][N:7]=[CH:8][C:3]=1[CH2:2][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][C:37](=[O:53])[O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[CH2:22]1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: ClCc1cnccn1
Agent: FC(F)(F)c1ncccc1CCl
Product: O=C1COc2cc3c(cc2O1)[C@]1(CO3)CN(Cc2cnccn2)c2ccccc21

Procedure:
Following the procedure as described in Example 5.9, making non-critical variations using 2-(chloromethyl)pyrazine to replace 3-(chloromethyl)-2-(trifluoromethyl)pyridine, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, (8S)-1′-(pyrazin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2(1′H)-one was obtained (62%) as a colorless solid: mp 216-218° C.; 1H NMR (300 MHz, CDCl3) δ 8.65-8.62 (m, 1H), 8.58-8.50 (m, 2H), 7.27-7.15 (m, 2H), 7.09-7.01 (m, 1H), 6.91-6.85 (m, 1H), 6.51 (s, 1H), 6.31 (s, 1H), 5.13 (ABq, J=55.5, 16.1 Hz, 2H), 4.81 (ABq, J=81.0, 9.0 Hz, 2H), 4.24-4.09 (m, 4H); 13C NMR (300 MHz, CDCl3) δ177.5, 155.2, 151.2, 144.6, 144.2, 143.9, 143.8, 141.7, 138.3, 132.2, 128.8, 124.0, 123.7, 120.8, 111.7, 109.1, 99.4, 80.0, 64.5, 63.8, 58.0, 43.7; MS (ES+) m/z 387.8 (M+1); Anal. Calcd for C22H17N3O4: C, 68.21; H, 4.42; N, 10.85. Found: C, 67.81; H, 4.39; N, 10.84.
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CCOCC.C1COCC1>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) and stirred solution of n-BuLi (2.6 mL, 1.05 eq., 10.0 M in hexanes) in dry Et2O (20 mL) was added dropwise a solution of 2-bromothiazole (4.0 g, 24.4 mmol) in THF (10 mL) over a 10 minute period. After the yellow mixture had been stirred at −78° C. for 30 minutes, a solution of 1-Boc-4-piperidone (4.9 g, 1 eq.) in THF (20 mL) was added slowly. The mixture was then continued to stir for another 30 minutes before the reaction was quenched by addition of water (5 mL). The mixture was warmed to room temperature and extracted with EtOAc. The organic phase was separated, washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (45% EtOAc in hexanes) to afford the desired product as a thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])C(F)(F)F)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.[OH-:30].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:16])=[O:30])=[CH:7][N:8]2[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: [OH-]
Reactant: ICC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CC2CCCC2)c2cc(Cl)ccc12
Temperature: 60 °C
Yield: 98 %

Procedure:
A mixture of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (300 mg, 1.21 mmol), potassium carbonate (419 mg, 3.03 mmol), and iodomethylcyclopentane (383 mg, 1.82 mmol) in N,N-dimethylformamide (4 mL) in a sealed reaction vessel was heated at 60° C. for 6 h. At this time, the reaction was cooled to 25° C. and partitioned between water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (15 mL), shaken, and separated. The organic layer was concentrated in vacuo to afford an orange oil. The resulting oil was treated with a 20% aqueous sodium hydroxide solution (7 mL) and was heated at 110° C. for 40 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (50 mL) and ethyl acetate (50 mL). This solution was treated with a 1N aqueous hydrochloric acid solution (20 mL), shaken, and separated. The organic layer was washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 6-chloro-1-cyclopentylmethyl-1H-indole-3-carboxylic acid (331 mg, 98%) as a yellow-orange solid: mp 181-184° C.; EI-HRMS m/e calcd for C15H16ClNO2 (M+) 277.0870, found 277.0873.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]([C:20](C(OCC)=O)(C(OCC)=O)[C:21]([O:23]CC)=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=[C:11]2[CH:36]([CH3:38])[CH3:37])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>C(O)C>[NH3:10].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=[C:11]2[CH:36]([CH3:38])[CH3:37])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCCCc2nc(C(C)C)n(Cc3ccc(Cl)c(Cl)c3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(CC(=O)O)CCCC2
Product: N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 132.9 %

Procedure:
A mixture of Intermediate 9 (435 mg) and Sodium hydroxide, 2M aq (2.3 mL) in Ethanol (6 mL) was stirred at RT for 5 mins and then at 80° C. for 3 hr. The solvent was concentrated under vacuum, the residue suspended in acetic acid (6.00 mL) and heated at 120° C. for 2 hr. The solvent was removed under vacuum and the residue was purified by reverse phase chromatography using acetonitrile water with an ammonium carbonate modifier. The desired fractions were combined and concentrated under vacuum to give a white solid (210 mg). LC/MS MH+ 395, Rt 2.10 min (5 minute run).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][O:12][CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1F.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([O:12][CH3:13])[C:24]2[CH:23]=[CH:22][C:21]([N+:26]([O-:28])=[O:27])=[CH:20][C:19]=2[F:18])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:14]([F:17])([F:15])[F:16]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CONS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(c1ccc([N+](=O)[O-])cc1F)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a solution of 4-chloro-N-methoxy-3-(trifluoromethyl)benzenesulfonamide(0.58 g (2.00 mmol)) and 3,4-difluoronitrobenzene (0.66 ml (5.96 mmol)) in 5.0 ml of DMF, sodium hydride (60%, 0.09 g (2.25 mmol)) was added bit by bit with stirring under cooling with ice. The resulting mixture was stirred under cooling with ice for one hour and allowed to warm-up to room temperature. Water was added to the reaction mixture and the resulting mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.32 g (37%) of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.O.Cl.C(OCC)(=O)C>[C:30]1([NH:29][C:12]([CH:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:16][CH2:15]2)=[O:14])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccccc1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Part A: To a solution of N-Boc-isonipecotic acid (4.85 g, 21.2 mmol) in tetrahydrofuran (80 mL) at 25° C. was added carbonyl diimidazole (3.80 g, 23.3 mmol), and the reaction mixture was stirred for 1.00 h at 25° C. To the resulting mixture was added aniline (2.10 mL, 23.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) (3.20 mL, 21.2 mmol), and the solution was stirred at 25° C. for another 90 h. The reaction mixture was diluted with water, 1.00 N hydrochloric acid (80 mL), and ethyl acetate. The phases were separated, and the organic phase was washed with water (×2) and brine, dried over anhyd. sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-20% diethyl ether/methylene chloride) furnished tert-butyl 4-(phenylcarbamoyl)-piperidine-1-carboxylate (4.25 g) as a white solid; 1H NMR (300 MHz, CDCl3) δ 7.48 (d, 2H, J=8.0 Hz), 7.29 (t, 2H, J=8.0 Hz), 7.20 (br s, 1H), 7.08 (t, 1H, J=8.0 Hz), 4.16 (m, 2H), 2.75 (m, 2H), 2.35 (m, 1H), 1.89-1.61 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>N1C=CC=CC=1>[C:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ccccc12
Reactant: O=C(Cl)c1cccnc1
Solvent: c1ccncc1
Product: O=C(Oc1ccc(-c2cc(=O)c3ccccc3o2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.5 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed 2-(4-hydroxyphenyl)chromen-4-one (100 mg, 0.419 mmol), pyridine (5 mL) and nicotinoyl chloride (223 mg, 1.25 mmol). The reaction mixture was stirred for 24 h at rt under nitrogen. The solvent was removed under reduced pressure and crude product was purified by column chromatography using 50% EtOAc in hexane to give 100 mg of 4-(4-oxo-4H-chromen-2-yl)phenyl nicotinate (69%). MS (ES) m/z: 344.09 (M+1).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl.[NH2:5][OH:6].OC[CH:9]([N:18]1[CH:22]=[C:21]([C:23]#[N:24])[N:20]=[CH:19]1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[OH:6][NH:5][C:23]([C:21]1[N:20]=[CH:19][N:18]([CH:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:1][OH:2])[CH:22]=1)=[NH:24]
Reactant: C[O-]
Reactant: NO
Reactant: N#Cc1cn(C(CO)CCc2ccccc2)cn1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1cn(C(CO)CCc2ccccc2)cn1
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A powder of NaOMe (67.2 mg, 1.24 mmol) was added to a solution of hydroxylamine hydrochloride (86.4 mg, 1.24 mmol) in methanol (2 ml) at room temperature. After 30 minutes, 1-(1-hydroxy-4-phenyl-2-butyl)imidazole-4-carbonitrile (obtained in Example 12(2))(100 mg, 0.41 mmol) was added to the mixture and the resulting mixture was stirred at reflux for 2 h. After cooling, the insoluble material was removed and then the filtrate was evaporated. The residue was purified by silica gel (5 g) column chromatography eluting with chloroform/methanol (20:1) and concentrated in vacuo. The residue was triturated with isopropyl ether to give N-hydroxy-1-[1-hydroxy-4-phenyl-2-butyl]imidazole-4-carboximidamide (86.3 mg, 76.0%) as an amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7](F)=[C:8]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1)[CH3:2].[OH-:19].[K+]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:17][C:16](=[O:19])[C:11]3[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH:9]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCOc1ccc(F)c(-c2ccccc2C#N)c1
Agent: [K+]
Solvent: CO
Product: CCOc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon, 5-ethoxy-2-fluorophenylboronic acid (300 mg, 1.63 mmol), potassium phosphate (433 mg, 2.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 mmol) were dissolved in abs. N,N-dimethylformamide (8 ml), and the mixture was stirred at room temperature for 5 minutes. 2-Chlorobenzonitrile (112 mg, 0.82 mmol) was then added, and the reaction mixture was stirred at 160° C. for 4 h. After cooling to room temperature, water (>100 ml) was added and the aqueous phase was repeatedly extracted thoroughly with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered off and concentrated under reduced pressure. Purification of the residue that remained by column chromatography (gradient ethyl acetate/n-heptane) gave 5′-ethoxy-2′-fluorobiphenyl-2-carbonitrile (150 mg, 76% of theory) in the form of a colourless solid. 5′-Ethoxy-2′-fluorobiphenyl-2-carbonitrile (150 mg, 0.62 mmol) was then dissolved in methanol (5 ml), finely powdered potassium hydroxide (174 mg, 3.10 mmol) was added and the mixture was stirred under reflux conditions for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, water was added and the resulting precipitated solid was filtered off and dried. This gave 2-ethoxyphenanthridin-6(5H)-one (72 mg, 46% of theory) as a colourless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.58 (br. s, 1H, NH), 8.56 (d, 1H), 8.32 (d, 1H), 7.86 (d, 1H), 7.82 (dd, 1H), 7.64 (dd, 1H), 7.29 (d, 1H), 7.13 (dd, 1H), 4.17 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[N:2]1.[NH2:8][CH2:9][C:10]1[CH:37]=[CH:36][C:13]([CH2:14][N:15]([CH2:26][C:27]2[NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]=2)[CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[BH4-].[Na+]>CO>[NH:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[CH2:26][N:15]([CH2:14][C:13]1[CH:36]=[CH:37][C:10]([CH2:9][NH:8][CH2:6][C:3]2[CH:4]=[CH:5][NH:1][N:2]=2)=[CH:11][CH:12]=1)[CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: O=Cc1cc[nH]n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNCc2cc[nH]n2)cc1)Cc1nc2ccccc2[nH]1
Yield: 59.8 %

Procedure:
Using General Procedure B: A solution of pyrazol-3-carboxaldehyde (26.6 mg, 0.28 mmol) and (4-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (110 mg, 0.28 mmol) in MeOH (2.0 mL) was stirred overnight at room temperature. NaBH4 (21.2 mg, 0.56 mmol) was added and the resultant mixture stirred for an additional 15 minutes. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 100:1:1) afforded the desired amine (80 mg, 60%) as a white foam.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:15]([OH:17])=O.[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[NH:21][CH3:22]>>[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[N:21]([CH3:22])[C:15]([C:2]1[S:1][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1)=[O:17]
Reactant: CNc1ccc(F)cc1F
Reactant: O=C(O)c1cc2c(s1)-c1ccccc1OCC2
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(F)cc1F

Procedure:
Following General Procedure C, 156 is prepared from 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid and 2,4-difluoro-N-methylaniline. MS: (ESI+) 371.9
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:11])=[C:4]2[CH:10]=[CH:9][N:8]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1c(Br)cnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(F)c(Br)cnc21
Reaction time: 0.33 h
Yield: 59.3 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (5.3 g, 24.7 mmol) was placed in DMF (53 mL) at 0° C. NaH (1.18 g, 29.6 mmol) was then added and stirred for 20 minutes. Benzenesulfonyl chloride (3.47 mL, 27.1 mmol) was then added next, and the reaction was stirred at 0° C. for 30 minutes. Water was then added, and the resulting solid was filtered and dried. The crude solid was then triturated in 1:1 hexane:EtOAc to give 5-bromo-4-fluoro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.2 g, 59.4% yield).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Zn](CC)CC.CN([C@@H](C1C=CC=CC=1)C1C2C(=CC=CC=2)C=CC=1O)[C@H](C1C=CC=CC=1)C.[Cl:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[CH:46]=[O:47]>C1(C)C=CC=CC=1>[Cl:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[C@@H:46]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:47]
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccccc1Cl
Agent: CC[Zn]CC
Agent: C[C@@H](c1ccccc1)N(C)[C@@H](c1ccccc1)c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Product: O[C@H](c1ccccc1)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 10 h
Yield: 91.3 %

Procedure:
PhB(OH)2 (122 mg, 1.0 mmol) and ZnEt2 (334 μL, 3.25 mmol) in toluene (1 mL) is charged to a 10 mL flask under a nitrogin atmosphere. This mixture is heated to 60° C. and stirred for 10 h with a magnetic stirrer. Then the mixture is cooled to 0° C. and 1-{(S)-[methyl-((S)-1-phenyl-ethyl)-amino]-phenyl-methyl}-naphthalen-2-ol (prepared as described by Chan et al., J. Org. Chemistry 2003, 68, 1589-1590; 14.7 mg, 0.04 mmol) in toluene (0.5 mL) and DiMPEG (100 mg, 0.05 mmol) in toluene (0.5 mL) is added. After stirring for additional 15 min, the solution is cooled to −15° C. and 2-chlorobenzaldehyde (70.0 mg, 0.5 mmol) in toluene (1 mL) is added. After stirring 15 h at −15° C., the reaction is quenched with 1 N HCl (2 mL) and the mixture is extracted with EtOAc (5 mL), dried over anhydrous Na2SO4 and the solvent is removed in vacuo. The purification of the residue by flash chromatography (EtOAc/hexane, 1:10) gives (R)-(2-chlorophenyl)-phenylmethanol in about 94.3% ee and about 91.3% yield (the ee value is determined by HPLC using a Chiralcel OD-H column).
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:16])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)C.C[O-].[Na+].[CH3:20][N:21]([CH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([NH:29][NH2:30])=O)[CH3:22].Cl.CC(O)C>C(O)C.CCOCC>[ClH:1].[CH3:20][N:21]([CH3:22])[CH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:26]([C:27]2[N:16]=[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:10][CH:11]=3)[NH:30][N:29]=2)[CH:25]=1
Reactant: CCOC(=N)c1ccc(C(F)(F)F)cc1
Reactant: CN(C)Cc1cccc(C(=O)NN)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: CC(C)O
Product: CN(C)Cc1cccc(-c2n[nH]c(-c3ccc(C(F)(F)F)cc3)n2)c1
Reaction time: 0.5 h
Yield: 10.5 %

Procedure:
To an ethanolic suspension of 4-trifluoromethyl-benzimidic acid ethyl ester hydrochloride salt (761 mg, 3.0 mmol, 1.5 eq.) was added sodium methoxide (162 mg, 3 mmol) in ethanol (20 ml.) and the resulting mixture stirred for 30 min.at r.t. 3-dimethylaminomethyl-benzoic acid hydrazide (386 mg, 2.0 mmol) in ethanol was then added at 20° C., followed by heating to reflux for 16 hrs. Upon cooling, the product mixture was filtered, solvent was evaporated and the residue subjected to preparative reversed-phase HPLC purification using a YMC ODS-AQ column (20×50 mm) and a (0.1% trifluoroacetic acid) water-acetonitrile gradient (25 ml/min. flow rate). The pure fractions were concentrated and the product obtained was converted to the hydrochloride salt in ether by addition of excess 5N HCl/iPrOH solution (1 ml) followed by solvent evaporation and high vacuum drying to afford the title compound (79 mg, 0.21 mmol, 10% yield) as a white foam. MS: m/e=347.4 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[C:4]=1[CH3:18])=[O:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:18][C:4]1[C:5]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:15])=[CH:16][CH:17]=2)=[C:6]([CH3:8])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: Cc1[nH]c(C=O)c(C)c1-c1ccc(C(=O)O)cc1
Reactant: C1COCCN1
Product: Cc1[nH]c(C=O)c(C)c1-c1ccc(C(=O)N2CCOCC2)cc1

Procedure:
4-(5-Formyl-2,4-dimethyl-1H-pyrrol-3-yl)-benzoic acid was reacted with morpholine using General Amidation Procedure 1 to give 3,5-dimethyl-4-[4-(morpholine-4-carbonyl)-phenyl]-1H-pyrrole-2-carbaldehyde. MS m/z 313 [M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[C:13]([CH:21]=[O:22])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].O1CC[CH2:35][CH2:34]1>C(N(CC)CC)C.[Cu](I)I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:34][CH3:35])=[CH:17][CH:18]=3)[C:13]([CH:21]=[O:22])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cc(Br)ccc32)cc1
Reactant: C#CCCCCCCCC
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1ccc2c(c1)c(C=O)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 65 °C
Reaction time: 168 h
Yield: 50.8 %

Procedure:
To a degassed mixture of 1-(4-methylphenylsulfonyl)-5-bromoindole-3-carboxaldehyde (36.9 g), 1-decyne (16.8 g), in dry triethylamine (200 ml) and dry tetrahydrofuran (150 ml) was added, 1 mole percent of copper (II) iodide and 2 mole percent of bis(triphenylphosphine)palladium (II) chloride. The reaction mixture was stirred at 65° C. for 7 days. The solution was evaporated, and the residue was flash chromatographed (silica gel: 4:1, dichloromethane:heptane). The appropriate fractions were collected and evaporated. The residue was recrystallized from hexane to give 23.1 g (50.8%) of product, mp 84°-86° C.