Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:9]([CH3:10])[O:8][C@@H:6]([OH:7])[CH2:5][C@H:4]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14].[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].O.CC(C)=O>N1C=CC=CC=1>[CH3:1][O:2][C@H:3]1[C@H:9]([CH3:10])[O:8][CH:6]([O:7][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=2)[CH2:5][C@H:4]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CO[C@H]1[C@H](C)O[C@@H](O)C[C@H]1NC(=O)C(F)(F)F
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CO[C@H]1[C@H](C)OC(OC(=O)c2ccc([N+](=O)[O-])cc2)C[C@H]1NC(=O)C(F)(F)F
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
A solution of 1.64 g; 6.38 mmol of compound VII in 76 ml of anhydrous pyridine was treated at 0° C. under stirring with 2 g of p-nitrobenzoyl chloride. After 30 minutes at 0° C. and then 20 hours at room temperature, the reaction mixture was poured into iced water and extracted with chloroform; the combined chloroform extracts were washed successively with a 10% potassium bisulphate solution, 10% sodium bicarbonate solution and finally with water, after which it was dried over anhydrous sodium sulphate and then concentrated to a residue. The residue was chromatographed on a silica gel column. Elution with a chloroform: acetone mixture (95:5 by volume) gave 1.76 g (yield 68%) of 4-O-methyl-1-O-p-nitrobenzoyl-2,3,6-trideoxy-3-trifluoroacetamido-L-ribohexopyranose (VIII).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([NH:17][CH3:18])[C:14]([N+:19]([O-:21])=[O:20])=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1.[C:22](Cl)(=[O:24])[CH3:23].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([NH:17][CH3:18])[C:14]([N+:19]([O-:21])=[O:20])=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:22](=[O:24])[CH3:23])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: CNc1cc(OC)c(Oc2ccnc(N)c2)cc1[N+](=O)[O-]
Solvent: O
Solvent: ClCCl
Product: CNc1cc(OC)c(Oc2ccnc(NC(C)=O)c2)cc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-amine (1 eq) and disopropylethylamine (4 eq) in methylene chloride was brought to 0° C. Acetyl chloride (1.1 eq) was added dropwise and mixture stirred for 5 minutes. Reaction brought to room temperature and water added. Organic layer washed with brine, dried over sodium sulfate and concentrated to yield N-(4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-yl)acetamide. HPLC=3.21 min; MS: MH+=333.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1)=[O:13])[CH3:10]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:9]([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][Br:1])[N:15]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1cccc(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(CBr)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
Finely ground N-bromo-succinimide (29.4 g, 165.2 mmol) was added in several portions to a solution of 6-methyl-pyridine-2-carboxylic acid ethyl ester (24.7 g, 150.0 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.) in carbon tetrachloride (500 mL), and then benzoyl peroxide (100 mg, 0.4 mmol) was added. The mixture was heated at 84 degrees under nitrogen for approximately 40 h. Further portions of N-bromo-succinimide (14.8 g, 83.2 mmol) and then benzoyl peroxide (100 mg, 0.4 mmol) were added and heating was continued overnight. The reaction mixture was cooled to room temperature, filtered, evaporated, and purified by chromatography on silica gel using a Biotage system, eluting with 1:1 dichloromethane/hexane and dichloromethane to give 6-bromomethyl-pyridine-2-carboxylic acid ethyl ester (11.8 g, 32%) as a pale yellow oil. MS (MH+): 244/246. From HPLC, the purity was estimated at 85-90% and the material was used in the next step without further purification.
Reaction SMILES: O.[OH-].[Li+].[C:4]1([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)[CH:21]=2)[C:15]([O:17]C)=[O:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C1COCC1>[C:4]1([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:19]=[C:20]([O:22][C@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)[CH:21]=2)[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@H]2CCOC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)cc(O[C@H]2CCOC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
A solution of lithium hydroxide monohydrate (3.78 g; 90.0 mmol) in water (50 mL) was added to a solution of methyl 3-[(phenylmethyl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (10.0 g, 30 mmol) in THF (100 mL) and the mixture stirred at RT for 18 hours. The THF was removed in vacuo, the aqueous residue treated with 1M hydrochloric acid (90.0 mL) then extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give the desired material (9.00 g). 1H NMR δ (CDCl3): 2.0-2.2 (m, 2H), 3.7-3.95 (m, 4H), 4.85 (m, 1H), 5.0 (s, 2H), 6.65 (m, 1H), 7.15 (m, 1H), 7.25-7.4 (m, 6H); m/z 315 (M+H)+.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][CH3:12])[N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[F:13][C:14]1[CH:15]=[C:16]([CH2:24][CH2:25][CH:26]=O)[CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21]>>[F:13][C:14]1[CH:15]=[C:16]([CH2:24][CH2:25][CH:26]2[NH:9][CH2:8][CH2:7][N:5]3[C:4]([CH2:10][CH2:11][CH3:12])=[N:3][C:2]([I:1])=[C:6]23)[CH:17]=[CH:18][C:19]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=CCCc1ccc(C(F)(F)F)c(F)c1
Reactant: CCCc1nc(I)cn1CCN
Product: CCCc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)c(F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(4-iodo-2-propyl-imidazol-1-yl)-ethylamine (6.840 mmol) and 3-(3-fluoro-4-trifluoromethyl-phenyl)-propionaldehyde (2.195 g; 9.970 mmol) afforded 8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-1-iodo-3-propyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.81 min.; [M+H]+=481.75 g/mol.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16]([C:18]2[C:27]([NH:28]C(=O)OCC3C=CC=CC=3)=[CH:26][C:25]3[C:20](=[CH:21][C:22]([N:39]4[CH2:44][CH2:43][NH:42][C:41](=[O:45])[CH2:40]4)=[CH:23][CH:24]=3)[N:19]=2)=[O:17])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:28][C:27]1[C:18]([C:16]([NH:15][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:4]2[CH2:5][C@H:6]([CH3:8])[CH2:7][C@H:2]([NH2:1])[CH2:3]2)=[O:17])=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22]([N:39]1[CH2:44][CH2:43][NH:42][C:41](=[O:45])[CH2:40]1)[CH:21]=2
Reactant: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCNC(=O)C4)ccc3cc2NC(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCNC(=O)C4)ccc3cc2N)C1

Procedure:
A mixture of benzyl [2-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(3-oxopiperazin-1-yl)quinolin-3-yl]carbamate (0.0086 g, 0.014 mmol) in 3.0 mL of MeOH was hydrogenated in the presence of 8 mg of 10% Pd on carbon under a balloon of hydrogen at room temperature for 1 h. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C25H31N8O2 [M+H]+: m/z=475.3. found: 475.4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([CH3:14])[CH:12]=O)[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl.[C:16]([CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](=O)[CH3:21])([OH:18])=[O:17].S(=O)(=O)(O)O>[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[CH2:12][C:11]([CH3:14])=[CH:10]2.[CH3:21][CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:19]1[C:16]([OH:18])=[O:17]
Reactant: CC(C=O)Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)C(Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Zn]
Product: CC1=Cc2cc(N)ccc2C1
Product: CC1C(C(=O)O)=Cc2ccccc21

Procedure:
Similarly, 5-amino-2-methylindene was prepared from the reductive cyclization of 3-(m-nitrophenyl)-2-methylpropionaldehyde with zinc and hydrochloric acid at elevated temperatures. Miller W. v. and Kinkelin G. Ber. 1886, 19, 1249 and 1520; Miller, W. v. and Rohde, G. ibid 1889, 22, 1830-1843. The difunctional 3-carboxy-4-phenyl-2-butanone reacted with excess sulfuric acid to give an unspecified yield of 1-methyl-2-carboxyindene. Roser, W. Ber. 1887, 20, 1574-1576.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-])=[O:9])=[CH:6][CH:5]=1.C1C=CC=CC=1.[N:20]1C=CC=C[CH:21]=1.C(Cl)(=O)C(Cl)=O>ClCCl.CO>[CH3:21][NH:20][C:8]([C:7]1[CH:11]=[CH:12][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:5][CH:6]=1)=[O:9]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1ccc(C(=O)OC)cc1
Reaction time: 0.25 h
Yield: 37 %

Procedure:
Monomethylterephthalate (Aldrich, 5.0 g, 0.028 mol) was added to 80 mL of dry benzene in a 250-mL round-bottom flask under argon and fitted with a calcium chloride drying tube. Dry pyridine (4.4 g, 0.056 mol) was added and the mixture was stirred for 15 min. Oxalyl chloride (3.66 g, 0.029 mol) was added by drop over 10 min. The mixture bubbled vigorously during the addition and a heavy white precipitate formed. The mixture was vigorously stirred for 40 min and followed by TLC (three solvent systems: dichloromethane, 2% methanol, and 5% methanol). Anhydrous methylamine was bubbled into the mixture for 10 min. The precipitate dissipated somewhat and the solution color changed from colorless to green and finally to yellow. The mixture was then stirred overnight. The remaining white precipitate was collected on a filter and washed with benzene. The filtrate was washed with water and dried over sodium sulfate. The drying agent was removed by filtration, washed with benzene, and the solvent concentrated to give a white solid. The solids were combined and dissolved in 300 mL dichloromethane. The solution was washed 3 times with 5% HCl, 3×5% sodium bicarbonate, 3×water, 1×brine, and then dried over sodium sulfate. The drying agent was removed by filtration and the filtrate concentrated to give a white solid which was dried in vacuo. This white solid was recrystallized from methanol to give 2 g (37%) of methyl 4-(methylaminocarbonyl)benzoate, mp 126° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH3:47])[N:44]=[C:43]([CH2:48][CH3:49])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH3:47])[N:44]=[C:43]([CH2:48][CH3:49])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K34) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (421 mg, 88%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([OH:9])([CH3:8])[CH2:4][C:5]([OH:7])=O.[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:5](=[O:7])[CH2:4][C:3]([OH:9])([CH3:8])[C:2]([F:1])([F:11])[F:10])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: CC(O)(CC(=O)O)C(F)(F)F
Product: CC(O)(CC(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1)C(F)(F)F

Procedure:
Following the procedure of Example 9, making variations only as required to use 4,4,4-trifluoro-3-hydroxy-3-methylbutyric acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (50.1% yield). 1H NMR (300 MHz, CDCl3) δ 8.07, 7.96, 6.98, 6.23, 4.05-3.52, 2.90, 2.47, 1.53-1.43, 0.76, 0.46, 0.09. MS (ES+) m/z 430 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[C:25]5=[O:33])[C:19]=4[CH3:34])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Br[CH2:36][CH2:37][CH2:38][C:39](Cl)=[O:40].[H-].[Na+].O>C1COCC1.C(Cl)Cl>[CH3:34][C:19]1[C:20]([N:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:33])=[CH:21][CH:22]=[CH:23][C:18]=1[C:7]1[C:6]2[C:5]3[C:13](=[CH:14][C:2]([N:1]4[CH2:36][CH2:37][CH2:38][C:39]4=[O:40])=[CH:3][CH:4]=3)[NH:12][C:11]=2[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=1
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(N)ccc4c23)cccc1N1Cc2ccccc2C1=O
Reactant: O=C(Cl)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(N5CCCC5=O)ccc4c23)cccc1N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 72.5 %

Procedure:
A solution of 7-amino-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 54-14, 60 mg, 0.134 mmol) in THF (3 mL) was treated with TEA (0.019 mL, 0.134 mmol) and a solution of 4-bromobutanoyl chloride (24.92 mg, 0.134 mmol) in DCM (1 mL). The mixture was stirred at rt for 40 min, then was diluted with DCM, washed with water, dried and concentrated. The residue was dissolved in THF (5 mL) and added to a suspension of sodium hydride (60% oil dispersion, 40 mg, 1.000 mmol, pre-washed with hexane) in THF (5 mL). The mixture was stirred at rt overnight, then was heated at 65° C. for 30 min. The mixture was cooled to rt, poured into water and extracted with EtOAc. The organic phase was dried and concentrated, and the residue was purified by column chromatography (eluting with a gradient from 99:0.9:0.1 to 90:9:1 DCM-methanol-28% aqueous ammonium hydroxide) to provide 4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-7-(2-oxopyrrolidin-1-yl)-9H-carbazole-1-carboxamide (50 mg, 66%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 10.67 (1 H, s), 7.96 (1 H, d, J=7.47 Hz), 7.91 (1 H, s), 7.74 (1 H, d, J=7.91 Hz), 7.62-7.67 (1 H, m), 7.52-7.58 (2 H, m), 7.45-7.48 (2 H, m), 7.38-7.42 (1 H, m), 7.22 (1 H, dd, J=8.79, 1.76 Hz), 7.11 (2 H, d, J=7.91 Hz), 4.86 (2 H, s), 3.90-4.02 (2 H, m), 2.66 (2 H, t, J=8.13 Hz), 2.16-2.25 (2 H, m), 1.94 (3 H, s). Mass spectrum m/z 515.3 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4]1)[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC1Nc2ccccc2-c2ccccc21
Solvent: c1ccncc1
Product: CCC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)cc1
Yield: 86.8 %

Procedure:
A solution of 6-ethyl-5,6-dihydrophenanthridine (14 g, 69.2 mmol) and 4-methoxybenzenesulfonyl chloride (17.2 g, 83 mmol) in pyridine (100 ml) was heated at 80° C. overnight. The solvent was evaporated in vacuo; and the crude product was purified by preparative column chromatography on silica gel, eluting with a gradient and mixture of dichloromethane-hexane (50:50 to 100:0). After evaporation of the solvent, the residue was crystallized from diethyl ether, yielding the title compound (22.8 g, 60.1 mmol, 87%) as a colorless, crystalline solid, which was characterized by LCMS (ES+, FA, CV=5) and 1H NMR.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[C:17]#[N:18]>>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:15]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][C:16]=3[C:17]#[N:18])[C:4]=2[CH:3]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: Fc1ccc2c(c1)NCCO2
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 28.6 %

Procedure:
A 250 ml round bottom flask charged with 6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (5.00 g, 32.6 mmol) was dried under high vacuum and placed under nitrogen prior to the addition of THF (131 ml). The solution was cooled in an ice water bath for 10 mins prior to the addition of sodium hydride (60% in mineral oil) (1.436 g, 35.9 mmol), added carefully in two portions 5 mins apart. The resulting suspension was stirred for 15 min at 0° C. then 90 min at room temp yielding a brownish suspension. To the suspension was added 2-fluoro-5-(trifluoromethyl)benzonitrile (6.79 g, 35.9 mmol) at room temperature. The mixture was stirred at 60° C. overnight affording about 75% conversion according to LC-MS. The dark solution was cooled in an ice water bath and carefully added to a stirred flask of water/ice/NH4Cl which was extracted with EtOAc (2×). The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The crude residue was purified with a 120 g ISCO gold column (load column loaded with crude brown oil directly with DCM rinsing) ramping EtOAc in heptane (0-25%, then isocratic at 25%) providing product cleanly (3.65 g, yellow solid) as well as a large portion which coeluted with starting amine and other minor impurities. The mixture was dried under reduced pressure and passed through a 25 g SCX-2 column, then a second 25 g SCX-2 column since after the first wash some dark materials eluted through. DCM was used as the eluent providing 2-(6-fluoro-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-5-(trifluoromethyl)benzonitrile as a tan solid (3.0 g) (6.65 g total, 63%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.84-3.91 (m, 2 H) 4.26-4.31 (m, 2 H) 6.53 (dd, J=9.93, 2.89 Hz, 1 H) 6.64 (ddd, J=9.00, 7.82, 2.93 Hz, 1 H) 6.90 (dd, J=8.95, 5.33 Hz, 1 H) 7.55 (d, J=8.71 Hz, 1 H) 7.76 (ddd, J=8.71, 2.25, 0.59 Hz, 1H) 7.95 (dd, J=1.57, 0.68 Hz, 1 H). m/z (ESI) 323.1 (M+H)+.
Reaction SMILES: BrC1C=C(N2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[N:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[C:13]3C(CC)=C2)C=CC=1C#N.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35]O.C(C1C2C(=NC=CC=2C2C=NC3C(C=2)=CC=CC=3)N([C:58]2[CH:65]=[CH:64][C:61]([C:62]#[N:63])=[C:60]([NH:66][CH2:67][CH2:68][CH2:69][CH2:70][OH:71])[CH:59]=2)C=1)C>>[CH2:34]([C:33]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][C:18]=2[C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:31]([C:59]2[C:60]([NH:66][CH2:67][CH2:68][CH2:69][CH2:70][OH:71])=[C:61]([CH:64]=[CH:65][CH:58]=2)[C:62]#[N:63])[CH:32]=1)[CH3:35]
Reactant: CCc1cn(-c2ccc(C#N)c(NCCCCO)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: CCc1cn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: NCCCCO
Product: CCc1cn(-c2cccc(C#N)c2NCCCCO)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 38 %

Procedure:
According to Example 1(6), a crude product of 4-{(3-ethyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}-2-(4-hydroxybutylamino)benzonitrile was prepared using compound (41h) instead of compound (1e) and using 4-amino-1-butanol instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (74) (the second stage yield: 38%) was prepared as a white solid using 4-{3-ethyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}-2-(4-hydroxybutylamino)benzonitrile instead of compound (1f).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[F-:12].[K+]>CS(C)=O>[Cl:1][C:2]1[N:9]=[C:8]([F:12])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(F)c(F)nc1Cl
Temperature: 20 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
To 2,6-dichloro-5-fluoronicotinonitrile (50 g, 262 mmol) was added spray-dried potassium fluoride (30 g, 516 mmol) followed immediately by the addition of anhydrous DMSO (125 mL). The reaction mixture was stirred at 20° C. for 16-20 hours. The progress of the reaction was closely monitored by HPLC. When the product concentration reached maximum (˜79%), the reaction was worked up immediately. Ethyl acetate (1000 mL) was added to the reaction mixture followed by the addition of ice (50 g). Water (500 mL) was then slowly added with cooling to ensure the temperature did not exceed 25° C. The organic phase and the aqueous phase were separated. The organic phase was washed with water (400 mL). Active carbon (12 g, Darco G-60, 100 mesh) was added and the mixture was stirred for 2 hours. The mixture was filtered through a pad of Celite. The filtrate was washed with water (400 mL) and concentrated by rotary evaporation to a volume of about 120 mL. The concentrate was diluted with heptane (150 mL) and the resulting solution was concentrated to a volume of about 150 mL, which resulted in precipitation of solid product. The mixture was stirred for 30 minutes at room temperature and filtered. The filter cake was washed with heptane (100 mL) and dried to afford the title compound (29.5 g, 65%). 1H NMR (500 MHz, CDCl3) δ ppm 7.92-7.96 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8](N)=[C:7]([F:12])[CH:6]=1)[CH3:2].C(#N)C.[ClH:17].N([O-])=O.[Na+].[S:22](=[O:24])=[O:23]>CC(O)=O.O.O.[Cu](Cl)Cl.O>[Cl:17][S:22]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:6][C:7]=1[F:12])(=[O:24])=[O:23]
Reactant: Cl
Reactant: O=S=O
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(S(=O)(=O)Cl)c(F)c1
Temperature: -5 °C
Reaction time: 0.58 h
Yield: 74 %

Procedure:
4-amino-3-fluoro-benzoic acid ethyl ester (490 mg, 2.7 mmol) was dissolved in acetonitrile (20 mL, 400 mmol) at ambient temperature. The solution was cooled to −5° C. in an acetone bath. 37% HCl (37:63, HCl:water, 2 mL) was added slowly. A solution of sodium nitrite (203 mg, 2.94 mmol) in water (1 mL, 60 mmol) was added slowly. The reaction mixture turned orange over the course of the addition. After addition was complete, the reaction mixture was stirred at 0° C. for 35 min. A 0° C. solution of sulfur dioxide in AcOH (8:25, sulfur dioxide:AcOH, 20 mL) was added followed by copper(II) chloride dihydrate (460 mg, 2.7 mmol). No gas evolution was evident. The mixture warmed to ambient temperature and stirred for 1.5 hours. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The concentrate contained a large excess of AcOH. The residue was diluted with acetonitrile and water, frozen, and lyophilized to afford a mauve powder (559 mg, 74%).