Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][N:17]=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H][H]>C1COCC1.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([N:12]2[CH2:13][CH2:14][CH2:15][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:11]2)=[N:17][CH:18]=1
Reactant: [H][H]
Reactant: CN(C(=O)OC(C)(C)C)C1CCCN(c2ccc([N+](=O)[O-])cn2)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCCN(c2ccc(N)cn2)C1
Yield: 95 %

Procedure:
To a solution of tert-butyl methyl(1-(5-nitropyridin-2-yl)piperidin-3-yl)carbamate (1.03 g, 3.1 mmol) in THF (50 mL) was added Pd/C (10 wt. %, 500 mg). The reaction mixture was stirred under 1 atm of hydrogen for 16 h, filtered through celite and concentrated to afford the desired product (902 mg, 96%) as a red oil. ESI MS m/z 307 [C16H26N4O2+H]+
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1>O1CCCC1>[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]([OH:11])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Br)cc1
Yield: 88 %

Procedure:
Ethylmagnesium bromide (5.4 mL, 3 M solution in tetrahydrofuran) was added dropwise to the solution of 4-bromobenzaldehyde (2.0 g, 10.8 mmol) in tetrahydrofuran (30 mL) at −30° C. Then the resultant mixture stirred at room temperature for 4 hours. The reaction was quenched with saturated ammonium chloride aqueous. The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 1-(4-bromophenyl)propan-1-ol (2.0 g, 88%). 1H NMR (300 MHz, d6-DMSO): δ 7.49 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 5.20 (d, J=4.5 Hz, 1H), 4.45-4.41 (m, 1H), 1.63-1.53 (m, 2H), 0.80 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[OH:27][C:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:31]([C:28]5([OH:27])[CH2:30][CH2:29]5)=[O:32])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)C1(O)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1(O)CC1

Procedure:
The title compound, white solid (70 mg, 68%), MS (ISP) m/z=413.5 [(M+H)+], mp 164° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 1-hydroxy-cyclopropane-carboxylic acid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]12([CH2:34][CH2:35][C:36](O)=[O:37])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.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>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:36](=[O:37])[CH2:35][CH2:34][C:24]34[CH2:33][CH:28]5[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]5)[CH2:25]3)[CH2:31]4)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(O)CCC12CC3CC(CC(C3)C1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)CCC34CC5CC(CC(C5)C3)C4)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3-(adamantan-1-yl)propionic acid (10 mg) under the agency of HATU (25 mg) and N,N-diisopropylethylamine (22 μl) in dichloromethane (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[C:29](Cl)(=[O:31])[CH3:30]>C1COCC1>[C:29]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:15][CH2:14]2)[CH2:3][CH2:2]1)(=[O:31])[CH3:30]
Reactant: COc1ccc(C2CCN(CCC3CCNc4ccccc43)CC2)cc1OC
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(C2CCN(CCC3CCN(C(C)=O)c4ccccc43)CC2)cc1OC
Reaction time: 2 h

Procedure:
A solution of 2.5 g of 1-(2-(1,2,3,4-tetrahydroquinolin-4-yl)ethyl)-4-(3,4-dimethoxyphenyl)piperidine (dihydrochloride, m.p 235°-236°) in 35 ml of THF is treated with a solution of 0.9 g of a acetyl chloride in ml of THF, stirred for 2 hours at-50°, evaporated and worked up in the customary manner. 1-(2-(1,2,3,4-Tetrahydro-1-acetylquinolin-4-yl)ethyl)-4-(3,4-dimethoxyphenyl)piperidine is obtained.
Reaction SMILES: [C:1]12([CH2:11][NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:13]1[CH:18]=[C:17]([C:19]([OH:21])=O)[C:16]([S:22][S:23][C:24]2[C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][CH:14]=1>CN(C)C1C=CN=CC=1>[C:1]12([CH2:11][NH:12][C:30](=[O:32])[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:23][S:22][C:16]3[CH:15]=[CH:14][CH:13]=[CH:18][C:17]=3[C:19]([NH:12][CH2:11][C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[O:21])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)c1ccccc1SSc1ccccc1C(=O)O
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccccc1SSc1ccccc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Yield: 30.6 %

Procedure:
Prepared according to the method of Example 14 from 1-adamantanemethylamine (0.23 g), 4-dimethylaminopyridine (0.006 g) and 2,2′dithiosalicylic acid (0.2 g) to give the sub-title compound as an off-white solid (0.12 g).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:19])[NH:6][C:7]2[C:12]([C:13]=1O)=[CH:11][C:10]1[CH2:15][CH2:16][CH2:17][CH2:18][C:9]=1[CH:8]=2)(=O)[CH3:2].[NH2:20][NH2:21]>Cl.CC(N(C)C)=O.O>[CH3:2][C:1]1[NH:20][N:21]=[C:13]2[C:12]3[CH:11]=[C:10]4[CH2:15][CH2:16][CH2:17][CH2:18][C:9]4=[CH:8][C:7]=3[NH:6][C:5](=[O:19])[C:4]=12
Reactant: CC(=O)c1c(O)c2cc3c(cc2[nH]c1=O)CCCC3
Reactant: NN
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1[nH]nc2c1c(=O)[nH]c1cc3c(cc12)CCCC3
Temperature: 140 °C

Procedure:
A mixture of 3-acetyl-4-hydroxy-6,7,8,9-tetrahydrobenzo[g]quinolin-2(1H)-one (1-5) (2.0 g, 7.8 mmol, 1 equiv), hydrazine (0.40 mL, 0.41 g, 13 mmol, 1.6 equiv), and catalytic concentrated hydrochloric acid solution (2 drops) in DMA (30 mL) was heated at 140° C. under nitrogen for 16 h. The solution was cooled and diluted with water (30 mL). The precipitate was filtered, washed with hexanes (3×100 mL), and dried to yield 3-methyl-2,5,7,8,9,10-hexahydro-4H-benzo[g]pyrazolo[4,3-c]quinolin-4-one (1-6) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 13.51 (s, 1H), 10.99 (s, 1H), 7.70 (s, 1H) 7.04 (s, 1H), 2.78 (m, 4H), 2.59 (s, 3H), 1.76 (m, 4H). LRMS m/z (M+H) 254.4 found, 254.1 required.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:18]1([N:15]2[CH2:16][CH2:17][CH:12]([C:10]3[N:11]=[C:7]4[N:8]([C:3]([NH:31][CH2:32][CH2:33][NH:34][C:35]5[N:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=5)=[N:4][C:5]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=5[Cl:28])=[CH:6]4)[N:9]=3)[CH2:13][CH2:14]2)[CH2:19][CH2:20]1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: Clc1ccc(-c2cc3nc(C4CCN(C5CC5)CC4)nn3c(Cl)n2)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(C5CC5)CC4)nn23)nc1
Temperature: 130 °C

Procedure:
21 mg (0.10 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(1-cyclopropylpiperidin-4-yl)[1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 45A), 40 mg (0.10 mmol) of 6-[(2-aminoethyl)-amino]pyridin-3-carbonitrile hydrochloride (Example 2A) and 0.10 ml (0.57 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 32 mg (62% of theory) of the product as a solid.
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][C:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(Br)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
A mixture of 0.95 g (3.8 mmol) 2-isopropylanthraquinone, 0.81 g (4.6 mmol) N-bromosuccinimide (NBS) and 6 mg benzoyl peroxide in 7 mL CCl4 was refluxed for 2 h under N2 with mild stirring. After cooling to room temperature, the solution was filtered through glass wool and then the CCl4 was removed under vacuum to yield a yellow liquid that solidified upon cooling. 1H-NMR showed the conversion to be complete and so the product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[I:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:32]=[C:31]([NH:30][C:27]4[CH:26]=[CH:25][C:24]([I:23])=[CH:29][CH:28]=4)[N:33]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1ccc(I)cc1
Solvent: O=[N+]([O-])O
Product: O=C1Cc2cnc(Nc3ccc(I)cc3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(4-iodo-phenyl)-guanidine nitrate were converted to I-36 (62%): HRMS Calcd. for C18H12ClIN4O: 462.9822, Found 462.9818.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]([F:44])([F:43])[C:9]1[CH:10]=[C:11]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:12][N:13]([C:30]1[N:31]=[N:32][N:33]([CH3:35])[N:34]=1)[C@H:14]1[CH2:20][CH2:19][CH2:18][NH:17][C:16]2[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:23]([CH3:25])=[CH:24][C:15]1=2.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH2:5]([O:4][C:2]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:14]([N:13]([CH2:12][C:11]2[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=[C:9]([C:8]([F:7])([F:44])[F:43])[CH:10]=2)[C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)[C:15]2[CH:24]=[C:23]([CH3:25])[C:22]([C:26]([F:28])([F:27])[F:29])=[CH:21][C:16]1=2)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(C)c(C(F)(F)F)cc21
Reaction time: 2 h
Yield: 65.9 %

Procedure:
Add ethyl chloroformate (0.0223 mL, 0.233 mmol) dropwise to a solution of (S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine (0.0430 g, 0.0778 mmol) (Example 3, Step 18) and pyridine (0.0190 mL, 0.233 mmol) in dichloromethane (1 mL) at room temperature under an atmosphere of nitrogen and stir for 2 h. Dilute the reaction mixture with ethyl acetate (10 mL) and wash with 1.0 N hydrochloric acid (10 mL) and water (3×10 mL). Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue using column chromatography on silica gel, eluting with ethyl acetate/hexanes (0-20%), to provide the title compound (0.0320 g, 65%). MS (ES+): 625 (M+H).
Reaction SMILES: B#B.C1COCC1.[Br:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16](O)=[O:17])[CH:12]=[N:13][CH:14]=1.O>C1COCC1.C(OCC)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][OH:17])[CH:12]=[N:13][CH:14]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 23.9 %

Procedure:
A solution of Diborane-THF complex (1.0 M in THF, 7.5 mL, 7.5 mmol) was added dropwise to a solution of 5-bromo-3-pyridinylacetic acid (1080 mg, 5 mmol) in dry THF at 0° C. The resulting mixture was allowed to warm to room temperature. After 15 h, the reaction mixture was cooled to 0° C. and water (10 mL) was added dropwise. The reaction mixture was diluted with ethyl acetate (100 mL). The organic layer was separated, washed with brine, dried over Na2SO4. After filtration and concentration, the residue was purified by flash column and afforded of the title compound as colorless solid (241 mg). 1HNMR (CDCl3, 400.342 MHz) δ 2.89 (t, J=6 Hz, 2H), 3.92 (t, J=6 Hz, 3H), 7.99 (s, 1H), 8.46 (s, 1H), 8.60 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH:6]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)[N:19]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:18]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[CH3:2].[CH:37]([N-]C(C)C)(C)C.[Li+].IC.O>O1CCCC1.O1CCCC1.CCCCCCC>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([CH3:37])[CH:6]([C:17]1[C:25]2[C:20](=[C:21]([CH2:26][S:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)[N:19]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:18]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CC(c1ccc(C(F)(F)F)cc1)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)C(c1ccc(C(F)(F)F)cc1)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
1.60 g (3.07 mmol) of the compound from Example 26A were dissolved in tetrahydrofuran at −78° C., and 3.2 ml (6.44 mmol) of a 2N solution of lithium diisopropylamide in tetrahydrofuran/n-heptane were slowly added dropwise. After 5 min, 0.40 ml (6.44 mmol) of iodomethane was added, and the mixture was stirred at −78° C. for 2 h and then warmed to RT over the course of a further 2 h. The reaction solution was mixed with water, the phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, the solid was filtered off, and the solvents were removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient) to result in 1.20 g (73% of theory) of the title compound as mixture of diasteromers.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>>[F:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[C:7]([CH3:11])[C:8]([N+:17]([O-:19])=[O:18])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(F)c1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])ccc(F)c1C(=O)O
Temperature: -2.5 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
A solution of 2-fluoro-6-methylbenzoic acid (2 g, 12.98 mmol) in concentrated H2SO4 (15.77 ml, 295.85 mmol) was cooled to −5° C. in an acetone/ice bath in air. A mixture of concentrated nitric acid (1.08 ml, 16.87 mmol) and concentrated H2SO4 (1 ml, 18.76 mmol) was added dropwise to the reaction mixture at −5 to 0° C. over 15 minutes. The pale yellow reaction mixture was stirred at −5 to 0° C. for 30 minutes before being poured onto ice (100 g). The resulting precipitate was filtered and dissolved in EtOAc (50 ml) and the organic phase was washed with deionized water (25 ml) followed by brine (25 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give 2 g (77%) of 6-fluoro-2-methyl-3-nitrobenzoic acid as a white solid. LC-MS 99%, 1.31 min (3 minute LC-MS method), m/z=198.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 8.04 (dd, J=9.1, 5.0 Hz, 1H), 7.16 (t, J=8.6 Hz, 1H), 2.63 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:17]2[CH2:18][CH2:19][N:14]([CH:11]([CH3:13])[CH3:12])[CH2:15][CH2:16]2)=[O:7])[CH:8]=[CH:9][N:10]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)c1ccnc(Cl)c1
Product: CC(C)N1CCN(C(=O)c2ccnc(Cl)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Step A of Example 9 using 2-chloro-isonicotinic acid and 1-isopropyl-piperazine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 4-fluoro-2-methylbenzoic acid (32.5 g) in conc. sulfuric acid (50 ml) was added dropwise conc. nitric acid (8.4 ml) at 0° C., and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice-water (500 ml), and the mixture was extracted with diisopropyl ether (300 ml), and the organic layer was washed with water, and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated under reduced pressure to give the title compound (40.0 g).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([I:9])=[CH:7][N:6]=[C:5](N)[CH:4]=1)[CH3:2].N([O-])=O.[Na+].[OH-].[Na+].[ClH:17]>O>[Cl:17][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]([I:9])=[CH:7][N:6]=1
Reactant: Cl
Reactant: CCc1cc(N)ncc1I
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
4-ethyl-5-iodopyridin-2-amine (15.0 g, 60.48 mmol) was dissolved in 140 mL conc. HCl. NaNO2 was dissolved in 40 mL of water and added drop wise to the above solution at 0° C. Care was taken to prevent the temperature of the reaction mixture from rising above 0° C. When all of the NaNO2 solution was added, the reaction mixture was allowed to warm up to room temperature and was stirred for a further 2 h at room temperature. Progress of the reaction was monitored by GC and HPLC. The reaction mixture was then re-cooled to 0° C. and the pH was adjusted to pH=12 by the addition of sat. NaOH. The mixture was extracted with dichloromethane (2×200 mL) and the solvent removed under vacuum. The crude was purified by silica gel column chromatography eluting with 5% ethyl acetate/hexanes. 8.0 g of desired product was obtained after purification (49% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[C:3]=1[CH3:12].[F:13][C:14]1[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH2:29][F:30])(=[O:26])=[O:25])=[CH:21][CH:20]=[C:19]([F:31])[C:15]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:1][C:2]1[NH:11][C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:16](=[O:17])[C:15]3[C:19]([F:31])=[CH:20][CH:21]=[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH2:29][F:30])(=[O:25])=[O:26])[C:14]=3[F:13])[CH:9]=[C:4]2[C:3]=1[CH3:12]
Reactant: Cc1[nH]c2ncc(N)cc2c1C
Reactant: O=C(O)c1c(F)ccc(NS(=O)(=O)CCCF)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)CCCF)c3F)cc2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.8 %

Procedure:
2,3-Dimethyl-1H-pyrrolo[2,3-b]pyridin-5-amine (0.048 g, 0.298 mmol), 2,6-difluoro-3-(3-fluoropropylsulfonamido)benzoic acid (0.097 g, 0.328 mmol), EDCI (0.063 g, 0.328 mmol) and HOBt (0.040 g, 0.298 mmol) were dissolved in DMF (1.6 mL) and stirred at room temperature for 16 hours. The reaction mixture was directly purified by reverse phase HPLC to give N-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(3-fluoropropylsulfonamido)benzamide (0.043 g, 33%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 11.24 (s, 1H), 10.80 (s, 1H), 9.93 (br s, 1H), 8.18 (d, 2H), 7.61-7.46 (m, 1H), 7.35-7.19 (m, 1H), 4.68-4.56 (m, 1H), 4.56-4.44 (m, 1H), 3.29-3.16 (m, 2H), 2.32 (s, 3H), 2.23-2.04 (m, 5H); m/z (ES-MS) 441.1 (98.2%) [M+1]. One methyl peak was hidden under solvent signal.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23](/[CH:25]=[CH:26]/[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)#[N:24].N12CCCN=C1CCCCC2.C(#N)C>>[C:23]([CH2:25][CH:26]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[N:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1)#[N:24]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C#N)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CC1
Temperature: 55 °C
Yield: 88.6 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 0.0317 mol), tert-butyl 4-[(E)-2-cyanovinyl]piperidine-1-carboxylate (10.7 g, 0.0430 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (470 uL, 0.0032 mol) in acetonitrile (100 mL, 2 mol) was heated at 55° C. overnight. The solvent was removed by rotary evaporation to give an orange foam. The resultant material was chromatographed with 0-100 ethyl acetate/hexane to give 15.5 g white solid/foam (100% yield). 1H NMR (400 MHz, CDCl3): δ 8.93 (1H, s); 8.41 (1H, s); 8.38 (1H, s); 7.45 (1H, d); 6.85 (1H, d); 5.75 (2H, s); 4.32 (2H, m); 4.15 (1H, br); 3.6 (2H, t); 3.22-3.05 (2H, m); 2.95-2.6 (2H, m); 2.15 (1H, m); 1.95 (1H, m); 1.45 (9H, s); 1.35 (3H, m); 0.97 (3H, t); 0 (9H, s). LCMS (M+1): 552.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:4]=1[C:5]([Cl:17])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C#N)ccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1C(=O)Cl
Reaction time: 1 h
Yield: 100 %

Procedure:
2-Methoxy-4-cyanobenzoic acid (Tetrahedron Letters, 1986, 27(49), 5997-6000) (1 g, 5.6 mmol) was dissolved in CH2Cl2 (20 ml). Oxalyl chloride (1.5 ml, 8.2 mmol) was rapidly introduced into the solution and a drop of DMF was added. A vigorous reaction took place with the abundant evolution of gaseous products. The solution was stirred for 1 h then allowed to stand over night. Solvent was removed using a rotary evaporator to leave 1.1 g of an off white solid (5.6 mmol, yield 99%) that was used without further purification.