Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Nc1c(Cl)cccc1Cl
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
2,6-Dichloroaniline (2.84 g, 17.5 mmol) was dissolved in DMSO (5 mL) and 60% NaH (0.60 g, 15 mmol) was added. The mixture was stirred 30 min and then 2-chloro-5-nitrobenzonitrile (0.91 g, 5.0 mmol) in DMSO (5 mL) was added. The reaction darkened and warmed to 50°. After cooling to 23° the reaction was diluted with EtOAc (200 mL) and washed with H2O (3×), satd. aq. NaCl, and dried (Na2SO4), and concentrated to afford 1.45 g (94%) of the title compound as an ivory colored powder. 1H NMR (400) MHz. δ: 8.49 (finely split doublet, 1), 8.20 (dd, 1), 7.51 (d,2), 7.34 (d, 2), 6.41 (d, 1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([C:26]([N:28]1[CH2:32][CH2:31][C@H:30]([F:33])[CH2:29]1)=[O:27])[C@H:9]([CH:11]1[CH2:16][CH2:15][CH:14]([N:17](CC2C=CC=CC=2)[CH3:18])[CH2:13][CH2:12]1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-]>[F:33][C@H:30]1[CH2:31][CH2:32][N:28]([C:26]([C@@H:8]([NH:7][C:6](=[O:34])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C@H:9]([CH:11]2[CH2:16][CH2:15][CH:14]([NH:17][CH3:18])[CH2:13][CH2:12]2)[CH3:10])=[O:27])[CH2:29]1
Reactant: [H][H]
Reactant: C[C@@H](C1CCC(N(C)Cc2ccccc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNC1CCC([C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N2CC[C@H](F)C2)CC1

Procedure:
To a solution of the material prepared in Step B (0.18 g, 0.37 mmol) in methanol (100 mL) was added palladium(II) hydroxide (0.10 g). The mixture was placed under 3 atm of hydrogen at ambient temperature for 6 h, then filtered through Celite. The solution was concentrated in vacuo, affording the title compound as a clear oil. This material was used without further purification. LC/MS 386.3 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[N:27]([CH:28]5[CH2:30][CH2:29]5)[CH:26]=[N:25][N:24]=4)[CH:18]=3)=[O:15])[CH:9]=2)=[CH:4][CH:3]=1>C1(N)CC1>[CH:28]1([N:27]2[CH:26]=[N:25][N:24]=[C:23]2[C:19]2[CH:18]=[C:17]([NH:16][C:14]([C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[N:7][C:2]([NH:27][CH:28]5[CH2:30][CH2:29]5)=[CH:3][CH:4]=4)[CH:13]=[CH:12][N:11]=3)=[O:15])[CH:22]=[CH:21][CH:20]=2)[CH2:30][CH2:29]1
Reactant: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2ccc(Cl)nc2)ccn1
Agent: NC1CC1
Product: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2ccc(NC3CC3)nc2)ccn1
Temperature: 110 °C
Yield: 50 %

Procedure:
6-Chloro-N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)-3,4′-bipyridine-2′-carboxamide (60.0 mg, 0.144 mmol) was dissolved in cyclopropylamine (250 μL), and the mixture was heated to 110° C. for 2 days. The amine was removed under reduced pressure, and the residue was purified by reverse phase HPLC. The product (N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)-6-(cyclopropylamino)-3,4′-bipyridine-2′-carboxamide, 31.2 mg, 50% yield) was isolated as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[CH3:39][C:40]1[CH:44]=[C:43]([CH2:45][NH2:46])[O:42][N:41]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:46][CH2:45][C:43]1[O:42][N:41]=[C:40]([CH3:39])[CH:44]=1)=[O:5]
Reactant: Cc1cc(CN)on1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)on1
Reaction time: 8 h
Yield: 30.9 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 35 mg, 0.081 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.054 mL, 0.487 mmol), (3-methylisoxazol-5-yl)methanamine (16.38 mg, 0.146 mmol), and BOP (64.6 mg, 0.146 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.8 min) to give single enantiomer 2-hydroxy-N-((3-methylisoxazol-5-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (14.1 mg, 0.025 mmol, 30.8% yield): LCMS=526.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.13-8.24 (2 H, m), 7.66-7.78 (4 H, m), 7.53-7.66 (3 H, m), 6.04 (1 H, s), 5.19 (1 H, s), 4.51 (2 H, s), 2.22 (3 H, s); HPLC Peak=9.9 min (Analytical Method A).
Reaction SMILES: [N:1]1[N:9]2[C:4]([N:5]=[C:6]3[CH2:21][CH2:20][CH2:19]CC[C:7]3=[C:8]2[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:3][CH:2]=1.C(OC1C=CC(C2N3C(=CC=N3)N=C3C=2CCC3)=CC=1)C1C=CC=CC=1.[H][H]>[Pd]>[N:1]1[N:9]2[C:4]([N:5]=[C:6]3[C:7](=[C:8]2[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:19][CH2:20][CH2:21]3)=[CH:3][CH:2]=1
Reactant: Oc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: c1ccc(COc2ccc(-c3c4c(nc5ccnn35)CCC4)cc2)cc1
Product: Oc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1

Procedure:
Using the method described for the preparation of 4-(6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-yl)-phenol, the reaction of 8-(4-benzyloxy-phenyl)-6,7-dihydro-5H-1,4,8a-triaza-s-indacene and hydrogen in the presence of 10% Pd/C provided the title compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:13])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(Oc2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(Oc2ccc(F)cc2)c1
Yield: 91.8 %

Procedure:
EX-634B) 3-(4Fluorophenoxy)nitrobenzene (1.15 g, 4.93 mmol) from EX-634A was dissolved in ethanol (45 mL), and the solution was hydrogenated for 4 h in the presence of 5% palladium on charcoal. After the mixture was filtered through celite, the ethanol was removed in vacuo. The product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:10) to give 0.92 g (90%) of 3-(4fluorophenoxy)aniline as a yellow oil, 99% pure by HPLC analysis. HRMS calcd. for C12H11FNO: 204.0824 [M+H]+, found: 204.0837.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC.[CH3:54][N:55]1[C:59]([CH:60]=O)=[N:58][C:57]([CH3:62])=[N:56]1.CC1C=C(C)N2N=C(C=O)N=C2N=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:60][C:59]3[N:55]([CH3:54])[N:56]=[C:57]([CH3:62])[N:58]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: Cc1nc(C=O)n(C)n1
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: Cc1nc(CC2=C(O)CC(CCc3ccc(C(C)(C)C#N)c(F)c3)(C3CCCC3)OC2=O)n(C)n1

Procedure:
The title compound was prepared analogously to example A(1), where 2-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile from step 3 below, was substituted in place of 6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 2,5-Dimethyl-2H-[1,2,4]triazole-3-carbaldehyde was substituted instead of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in that example. 1H NMR (300 MHz, DMSO-d6): δ 1.49-1.69 (m, 8H), 1.72 (s, 6H), 2.06 (s, 3H), 2.11 (s, 3H), 2.12-2.13 (m, 2H), 2.34-2.42 (m, 1H), 2.55-2.66 (m, 3H), 2.80 (d, J=17 Hz, 1H), 3.42-3.65 (m, 2H), 7.08-7.18 (m, 2H), 7.35-7.40 (m, 1H). Anal. Calcd. For C27H33FN4O3.0.25H2O: C, 66.85; H, 6.96; N, 11.55. Found: C, 66.88; H, 6.99; N, 11.60. ESIMS (MH+): 481.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: NCCCCCCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NCCCCCCCCCCCCNc1ccccc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
34 g (0.216 mol) 2-nitro-chlorobenzene and 20 g 1,12-diaminododecane (0.10 mol) are mixed with 40 g potassium carbonate and 200 ml N,N-dimethylformamide (DMF). The mixture is heated with reflux while subjected to a vigorous stirring for four hours. Subsequently, the inorganic salts are filtered off and washed with a small amount of DMF. The entire DMF-phase is distilled under vacuum to remove substantially all DMF. The remanence is cooled, and 200 ml water are added while vigorously stirred. Subsequently, the water phase is decanted off, and the product is caused to crystallize by the addition of approximately 100 ml ethanol. The crystals are filtered off, washed twice with 25 ml ethanol and 100 ml petroleum ether followed by an air-drying of the product. Yield 21.8 g (49%), melting point 79° to 80° C.
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][C:10]3[CH:19]=[CH:18][C:17]([C:20](OC)=[O:21])=[CH:16][C:11]=3[N:12]([CH2:13][O:14][CH3:15])[C:7]=2[N:6]=[CH:5][CH:4]=1)#[N:2].[BH4-].[Li+]>O1CCCC1>[C:1]([C:3]1[C:8]2[S:9][C:10]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:11]=3[N:12]([CH2:13][O:14][CH3:15])[C:7]=2[N:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: COCN1c2cc(C(=O)OC)ccc2Sc2c(C#N)ccnc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCN1c2cc(CO)ccc2Sc2c(C#N)ccnc21
Yield: 69.1 %

Procedure:
To a solution of 0.19 g of methyl 4-cyano-10-(methoxymethyl)-10H-pyrido[3,2-b][1,4]-benzothiazine-8-carboxylate in dry tetrahydrofuran (5 ml) was added in a nitrogen atmosphere a solution of 0.026 g of lithium borohydride in tetrahydrofuran (10 ml) and the resulting mixture was heated under reflux for 20 minutes. After bringing back to room temperature, the mixture was extracted with 15 ml of water and 15 ml of acetic acid and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.12 g of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[CH:27]=3)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](Cl)(=[O:35])[CH3:34].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:27]=3)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(Cl)c3)c(-c3ccnc(N)c3)s2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(-c2sc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(Cl)c2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
To a solution of [4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-(3-chlorophenyl)-1,3-thiazol-5-yl]-2-pyridylamine (1.60 g, 3.40 mmol) in tetrahydrofuran (20 mL) were added acetyl chloride (0.25 mL, 3.52 mmol) and triethylamine (0.50 mL, 3.58 mmol) at 0° C. sequentially, and the resulting mixture was stirred at room temperature for 3 hours. Aqueous sodium hydrogen carbonate was added to the reaction mixture and extracted with ethyl acetate. The extracts were washed with brine, dried, and concentrated. The residue was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.), hexane-ethyl acetate=1:1) to give a title compound (1.79 g, yield 98%).
Reaction SMILES: Br[CH:2]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:20][C:21]([NH2:23])=[S:22].C([O-])(=O)C.[Na+]>>[CH:14]1([CH2:13][C:2]2[S:22][C:21]([NH2:23])=[N:20][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc(C(=O)C(Br)CC2CCCCC2)cc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(N)sc2CC2CCCCC2)cc1
Yield: 79.8 %

Procedure:
A procedure similar to step 5 of Example 6 was used. 2-bromo-3-cyclohexyl-1-(4-methoxy-phenyl)-propan-1-one prepared in the step 3, thiourea and anhydrous sodium acetate were used as starting materials, refluxed for 3 hours, followed by post-treatment to give a crude product, which was purified under a reduced pressure by silica gel column chromatography eluted with petroleum ether and ethyl acetate at a ratio of 3:1 (V:V) to obtain a product as a white solid in a yield of 79.8%, mp: 118-119 └. 1H-NMR (CDCl3, 400 MHz) δ: 0.80˜0.92 (2H, m), 1.05˜1.25 (3H, m), 1.40˜1.50 (1H, m, CH), 1.60˜1.80 (5H, m), 2.59 (2H, d, J=7.04 Hz, CHCH2Ar), 3.83 (3H, s, OCH3), 5.55 (2H, br, NH2), 6.93 (2H, d, J=6.72 Hz, ArH), 7.44 (2H, d, J=6.72 Hz, ArH); EI-MS m/e (%): 302.2 (M+, 59), 219.1 (100), 177.1 (44); HREI-MS Calcd. for C17H22N2OS: 302.1453. found: 302.1450. Anal. Calcd. for C17H22N2OS: C, 67.51; H, 7.33; N, 9.26. found: C, 67.41; H, 7.47; N, 9.24.
Reaction SMILES: [F:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([N+:8]([O-])=O)=[CH:6][CH:7]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: COc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1c(F)ccc(N)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3-fluoro-2-methoxy-6-nitrophenyl)phenylamine (322 mg, 1.2 mmol) in EtOAc (5 mL) was added palladium on carbon (30 mg, 10% by wt) and the reaction mixture stirred at RT under an atmosphere of hydrogen for 4 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo to give the title compound as a white solid which darkened to red on standing (284 mg, 100%). 1H NMR 400 MHz δ (CDCl3): 7.24-7.18 (2H, m), 6.88-6.78 (2H, m), 6.71-6.66 (2H, m), 6.43 (1H, dd, J=9.0, 4.5 Hz), 5.50 (1H, br s), 3.77 (3H, d, J=1.7 Hz), 3.64 (2H, br s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2]1.[H-].[Na+].[CH2:23](Br)[C:24]#[CH:25].[Cl-].[NH4+]>CN(C)C=O.O>[CH:18]([O:17][CH:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:25][C:24]#[CH:23])[CH:2]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:19])[CH3:20]
Reactant: C#CCBr
Reactant: CCOC(=O)C(Cc1c[nH]c2ccccc12)OC(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1cc(CC(OC(C)C)C(=O)OCC)c2ccccc21
Reaction time: 0.5 h

Procedure:
0.23 g of Ethyl 3-(1H-indol-3-yl)-2-isopropoxypropionate was dissolved in 5 ml of N,N-dimethylformamide, and 34 mg of 60% sodium hydride was added under ice-cooling. The reaction solution was stirred for 30 minutes under ice-cooling, then 0.09 ml of propargyl bromide was added, and stirring was continued at room temperature for 16 hours. The reaction solution was cooled with ice, treated with water and ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography (9% ethyl acetate-hexane), to give 0.18 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[NH2:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=1
Reactant: CN(C)c1ccc(C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN(C)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.9 %

Procedure:
Commercially available 4-dimethylaminobenzonitrile 18i (2 g, 13.7 mmol) dissolved in 15 ml of ether was added dropwise at 0° C. to LiAlH4 (2 equiv., 1 g) suspended in diethyl ether (40 ml). The mixture was stirred at room temperature for 24 hours. The reaction was quenched by addition of water and filtrated and the salts were washed with ether. The organic phase was separated, anhydrified and evaporated giving 1.85 g of a pale yellow oil. Yield=90% 1HNMR (DMSO, 200 MHz) δ 1.60 (2H, bs), 2.84 (6H, s), 3.57 (2H, s), 6.67 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.6 Hz)
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:10]=1[Cl:11].ClC1C=C(Br)C=CC=1Cl.C(OCC)C.[CH3:27][N:28]1[CH2:33][CH:32]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1>C(OCC)C.O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:32]2[CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: CCOC(=O)C1=CCN(C)CC1
Reactant: Clc1ccc(Br)cc1Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C)CC1c1ccc(Cl)c(Cl)c1
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a suspension of magnesium (10.76 g) in diethyl ether (110 mL) was added a trace amount of iodine. About 1/10 amount of a solution of 3,4-dichlorobromobenzene (100 g) in diethyl ether (110 ml) was added slowly at 35-40° C., and the mixture was vigorously stirred until the reaction started. Once the initiation was occurred, the rest of 3,4-dichlorobromobenzene/diethyl ether solution was added slowly with cooling to maintain the reaction temperature at 35-40° C. When everything was added, and the mixture was stirred at 40° C. for 1 hr, then cooled to 0° C. To the reaction mixture was added copper iodide(I) (12.6 g), and the compound (56.2 g) obtained in step 1 was slowly added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, and further at room temperature for 1 hr. The reaction mixture was poured into water (40 mL), diethyl ether (500 mL) was added, and the precipitate was removed by decantation. The reaction solution was washed with aqueous ammonium chloride solution and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20% ethyl acetate/hexane→>2.5% aqueous ammonia/17.5% methanol/ethyl acetate) to give crude ethyl 3-(3,4-dichlorophenyl)-1-methylpiperidine-4-carboxylate (cis/trans mixture) (75.5 g) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].C1(C)C=CC=CC=1.CC(C)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>O.CC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([N:25]=[N+:26]=[N-:27])=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)c1cc(F)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cc(F)ccc1[N+](=O)[O-]

Procedure:
A solution of 5-fluoro-2-nitrobenzoyl chloride (52 g, 0.256 mol) in a toluene (50 mL) and acetone (60 mL) mixture is added dropwise to a solution of sodium azide (19.55 g, 0.301 mol) in water while maintaining the reaction mixture temperature below 30° C. The resultant solid is collected and the filtrate is extracted with ether. The organic extracts are combined, washed with water, dried over anhydrous magnesium sulfate and concentrated by blowing air over the solution to obtain additional solids. The solids are combined, slurried in an acetone/water (1:3) solution, filtered and dried to give the title product as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][N:18]=[C:17]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:16]=23)[C@H:10]([F:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][N:18]=[C:17]3[N:24]([S:27]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:16]=23)[C@H:10]([F:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)[C@H](F)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)[C@H](F)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A stirred solution of trans-4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (0.231 g, 0.445 mmol) in ethyl acetate (5 ml) was treated with 10% palladium on activated carbon (0.025 g, 0.023 mmol) and stirred at 50° C. overnight. The mixture was then filtered through Celite, washed with copious methanol and concentrated under vacuum to give 201 mg (92%) of trans-4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester that was used without further purification. LCMS (Method F): RT=0.88 min, m+H=490.0; 1H NMR (400 MHz, DMSO) δ=8.06-7.99 (m, 2H), 7.72-7.64 (m, 1H), 7.60 (s, 3H), 7.54-7.46 (m, 1H), 6.87-6.79 (m, 1H), 5.33-5.22 (m, 1H), 4.60-4.33 (m, 3H), 4.13-4.07 (m, 1H), 3.80-3.66 (m, 1H), 3.26-3.03 (m, 2H), 1.96-1.87 (m, 1H), 1.41 (s, 9H), 1.37-1.32 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:20][C:21]1[CH:28]=[C:27]([F:29])[C:24]([CH:25]=O)=[C:23]([F:30])[CH:22]=1.OS([O-])(=O)=O.[Na+]>ClCCl.O>[Br:20][C:21]1[CH:28]=[C:27]([F:29])[C:24]([CH2:25][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:23]([F:30])[CH:22]=1
Reactant: C1CCNC1
Reactant: O=Cc1c(F)cc(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Fc1cc(Br)cc(F)c1CN1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.2 %

Procedure:
Pyrrolidine (25 mL, 0.30 mol) and sodium triacetoxyborohydride (64 g, 0.30 mol) were added in portions to a stirred solution of Intermediate 18a, 4-Bromo-2,6-difluorobenzaldehyde (53.5 g, 0.24 mol) in dichloromethane (500 mL) on ice bath. The reaction mixture was intensively stirred for 12 h at RT. Water (400 mL) was added followed by addition of 5M aq. NaHSO4 to attain pH˜2. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×200 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH˜10, and extracted with CHCl3 (2×300 mL). The organic extract was washed with brine, dried over anhydrous Na2SO4 (100 g) and evaporated in vacuo to give the title compound (52.5 g, 79%, 0.19 mol). LC/MS data: 275.9 and 277.9 (M+H)+ (calculated for C11H12BrF2N, 276.13). 1H NMR data (DMSO-d6): 7.40-7.48 (m, 2H Ar—H), 3.66 (s, 2H, Ar—CH2), 2.38-2.46 (m, 4H pyrrolidine (CH2)2N), 1.61-1.71 (m, 4H, CH2CH2CH2CH2).