Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C(O)C.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: C1COCCN1
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCOCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a 10 mL reaction vial containing stir bar were added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.060 g, 0.160 mmol), ethanol (1.5 mL), and then morpholine (0.280 mL, 3.21 mmol) via syringe at once. The contents were capped, placed into a heat block, and heated at 120° C. for 18 h and then at 135° C. for 2 hr. After cooling to room temperature, the reaction mixture was diluted with water (40 mL), adjusted to pH 6-7, and stirred for 15 min. The contents were filtered and washed with water. The product was dried in vacuum oven at 50° C. for 5 hr. The product was obtained as 57 mg (79%). LCMS E-S (M+H)=425.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=6.57 Hz, 6H), 2.12 (s, 3H), 2.19 (s, 3H), 3.56-3.66 (m, 4H), 3.69-3.78 (m, 4H), 4.35 (d, J=4.80 Hz, 2H), 5.00 (quin, J=6.63 Hz, 1H), 5.89 (s, 1H), 7.13 (s, 1H), 8.03 (s, 1H), 8.65 (t, J=4.93 Hz, 1H), 11.56 (br. s., 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=4)[N:19]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:18]=3)[C:14]([C:40]#[N:41])=[CH:13][N:12]=2)[CH3:9])[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([C@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[C:23]([C:26]([F:29])([F:27])[F:28])[CH:24]=4)[N:19]([S:30]([C:33]4[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=4)(=[O:31])=[O:32])[CH:18]=3)[C:14]([C:40]#[N:41])=[CH:13][N:12]=2)[CH3:9])[CH2:6][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCC(O)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCC(=O)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
2-((R)-1-(4-hydroxycyclohexyl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (442 mg, 0.7561 mmol) was dissolved in dichloromethane (20 mL) and cooled down to 0° C. Dess-Martin periodinane (384.8 mg, 0.9073 mmol) was added and the reaction was allowed to warm up to room temperature. The mixture was stirred for 18 hours. The reaction mixture was partitioned between dichloromethane and a 1:1 saturated solution of sodium hydrosulfite and sodium hydrogen carbonate. The aqueous phase was further extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified on silica gel by flash column chromatography (ISCO Companion□, 40 g column, 0-20% EtOAc/DCM) to afford the title compound as a white solid (411 mg, 93% yield).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=[CH:14][S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:11]=2)[C:6]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[CH3:30])=[CH:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[C:18]1([S:15]([CH:14]=[CH:13][C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[NH:4][CH:5]=[C:6]3[CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[CH3:30])(=[O:17])=[O:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)n1cc(C[C@H]2CCCN2C)c2cc(C=CS(=O)(=O)c3ccccc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CS(=O)(=O)c3ccccc3)cc12
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A suspension of (R)-1-acetyl-5-(benzenesulfonylethenyl)-3-(N-methyl-pyrrolidin-2-ylmethyl)-1H-indole (220.8 g) in methanol (2.21 L) was treated with potassium carbonate (72.23 g) and stirred at ambient temperature. After about one hour active carbon (22.1 g) was added to the solution then water (660 mL) added slowly. The mixture was filtered and the filtrate heated to reflux and water (660 mL) added dropwise. The mixture was allowed to cool and crystallize, then further water was added slowly (3.31 1). The resulting solid was filtered, washed with 1:2 methanol:water mixture (2×200 mL) then dried in vacuo to give the title compound (149 g): mp, 84°-87° C. IR (KBr) 1600, 1450, 1290, 1145, 1085 cm-1 : 1H NMR (CDCl3) 8.4 (b, 1H), 8.0 (d, 2H), 7.8 (d, 1H), 7.7 (s, 1H), 7.6-7.5 (m, 3H), 7.3 (s, 2H), 7.05 (b, 1H), 6.75 (d, 1H), 3.15 (In, 2H), 2.6 (in, 1H), 2.45 (s, 3H), 2.4 (s, 1H), 2.2 (m, 1H), 2.0-0.5 (m, 4H); LRMS (TSP), m/z 381, 165, 133, 119.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]([CH2:25][O:26][C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[CH3:34])=[C:23]3[C:18]([NH:19][C:20]([CH3:38])([CH3:37])[C:21](=[O:36])[N:22]3[CH3:35])=[CH:17][CH:16]=2)=[C:11]([O:39][CH3:40])[CH:10]=1)(=[O:7])=[O:6].[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[I-].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:41]([NH:48][CH2:2][CH2:3][CH2:4][S:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]([CH2:25][O:26][C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[CH3:34])=[C:23]3[C:18]([NH:19][C:20]([CH3:38])([CH3:37])[C:21](=[O:36])[N:22]3[CH3:35])=[CH:17][CH:16]=2)=[C:11]([O:39][CH3:40])[CH:10]=1)(=[O:7])=[O:6])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(OS(=O)(=O)CCCCl)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OS(=O)(=O)CCCNCc2ccccc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 50 °C
Reaction time: 5 h
Yield: 38.2 %

Procedure:
A mixture of 7-[4-(3-chloropropylsulfonyloxy)-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 1-54, 50.0 mg, 0.0846 mmol), benzylamine (92.4 μL, 0.846 mmol), and potassium iodide (16.9 mg, 0.102 mmol) was suspended in anhydrous N,N-dimethylformamide (0.4 mL) and stirred at 50° C. for 5 hours. After cooling down, ethyl acetate (50 mL) was added thereto. The organic layer was washed with water (50 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (21.4 mg) as a colorless amorphous product. (Yield 38%)
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.Cl[CH2:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[C:39]([O:41][CH3:42])=[O:40]>C(#N)C>[CH3:47][O:46][C:45]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=1[CH2:35][N:22]1[CH2:23][CH2:24][N:19]([C:17](=[O:18])[C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])=[CH:12][CH:13]=2)[CH2:20][CH2:21]1
Reactant: COC(=O)c1ccc(OC)c(CCl)c1
Reactant: O=C(Nc1ccccc1)Nc1ccc(C(=O)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccc(OC)c(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccccc4)cc3)CC2)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
1-Phenyl-3-(4-(piperazin-1-carbonyl)phenyl)urea (439 mg, 1.0 mmol) was stirred in acetonitrile (8 mL) at room temperature for 1 hour, N-Ethyl-N-isopropylpropan-2-amine (697 μl, 4 mmol) was added, followed by a solution of methyl 3-(chloromethyl)4-methoxy-benzoate (215 mg, 1.0 mmol) in acetonitrile (5 mL). The mixture was heated to 45° C. and stirred overnight. The mixture was concentrated under vacuum, diluted with dichloromethane (40 mL) and washed with saturated aqueous ammonium chloride (25 mL) and saturated aqueous sodium chloride (25 mL). The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum. The residue was submitted to silica chromatography (0-10% methanol in dichloromethane as eluant) to give the title compound (216 mg). MS (ESI) m/z 503.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5]2.[OH-].[K+].I[CH3:20]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:20])[C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5]2
Reactant: CI
Reactant: CCCCCCc1cc2cc(Cl)ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCc1cc2cc(Cl)ccc2n1C
Reaction time: 0.5 h

Procedure:
To the solution of 5-chloro-2-hexyl-1H-indole in DMSO was added KOH at RT and was stirred for 30 minutes. Then to this mixture, iodomethane was added and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product, 5-chloro-2-hexyl-1-methyl-1H-indole was purified by column chromatography.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]2([CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[CH:8]=[C:7]2[O:17]C)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCOCC1.O>[CH:1]1([CH2:4][CH2:5][C:6]2([CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[CH:8][C:7]2=[O:17])[CH2:3][CH2:2]1
Reactant: COC1=CC(=O)c2ccccc2C1(C)CCC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(CCC2CC2)C(=O)C=C(O)c2ccccc21
Temperature: 95 °C
Yield: 63.9 %

Procedure:
To a solution of Example 157C (1.06 g, 4.10 mmol) in dioxane (10 mL) was added 1 N NaOH (10 mL, 10 mmol) and the reaction mixture heated at 95° C. for 16 hours. After cooling the solution to room temperature, the reaction mixture was diluted with 50 mL of water, the pH adjusted to 2.0 with 1N HCl, and the aqueous layer extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. The product was purified by flash chromatography on SiO2 eluting with a 10-25% ethyl acetate/hexane gradient yielding the title compound (0.635 g, 64% yield) as a crystalline solid. 1H NMR (300 MHz, DMSO-d6): δ ppm −0.51 (m, 2 H)-0.02 (m, 2 H) 0.14 (m, 2 H) 0.46 (m, 1 H) 1.16 (s, 3 H) 5.42 (s, 1 H) 7.12 (t, J=7.35 Hz, 1 H) 7.34 (m, 2 H) 7.64 (d, J=7.35 Hz, 1H). MS (ESI+) m/z=243 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([F:39])([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH:32][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([F:39])([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(F)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)F)CN1C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
Add acetic anhydride (0.084 mL, 0.91 mmol) to a solution of (2S,5R)-5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-(2-fluoro-2-methylpropoxy)-morpholine-4-carboxylic acid tert-butyl ester (400 mg, 0.86 mmol) and triethylamine (0.81 mL, 130 mmol) in dry dichloromethane (10 mL) at room temperature and stir for 4 hours, concentrate and purify (silica gel cartridge chromatography, eluting with 2:1 to 1:2 hexanes:ethyl acetate), to give the desired compound as a white solid (0.37 g, 80%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(C)(C)C.CCOCC>[N:13]1([C:2]2[C:3]3[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: N#Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: N#Cc1c[nH]c2ncnc(N3CCCCC3)c12
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (54 mg/0.3 mmol) (prepared by the method of Townsend, et. al., J. Am. Chem. Soc., 1969, 91, 2102) suspended in 3.0 mL tert-Butanol was added piperidine (59 μL/0.60 mmol). The resulting mixture was then heated at reflux for 2.5 h and after cooling to room temperature, was transferred to a separatory funnel and diluted with ether (20 mL). The solution was extracted 2×10 mL with 1N HCl, the combined aqueous layers were adjusted to pH 7 with 2 N potassium hydroxide (KOH) solution forming a precipitate which was collected by filtration, washed with water and dried under reduced pressure to give 29 mg (42%) of the title compound as a colorless solid. Mp 209-211° C.; 1H NMR (400 MHz) (acetone-6) δ1.72-1.74 (m, 6H), 3.72-3.79 (m, 4H), 8.12 (s, 1H), 8.29 (s, 1H). LRMS: 228 (M+1).
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Br:7][C:5]1[N:6]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[Br:8]
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1c(-c2ccc(F)cc2)nc(Br)c1Br
Temperature: 110 °C
Yield: 86.5 %

Procedure:
A microwave vial was charged with 2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (881 mg, 2.0 mmol, Example 2, Step 2), 4-fluorophenyl boronic acid (308 mg, 2.2 mmol), aqueous Na2CO3 solution (6 ml, 2.0 M, 12.0 mmol) and DME (12 ml). The mixture was sparged with argon for 15 min, followed by addition of Pd(PPh3)4 (120 mg, 0.1 mmol). The reaction vial was sealed and heated at 110° C. for 20 minutes in a microwave reactor; the reaction was deemed complete by LCMS. The reaction mixture was partitioned between saturated Na2CO3 solution and EtOAc (10 ml/30 ml), the organic layer was separated, washed with brine (10 ml), dried (Na2SO4), and concentrated. The resulting residue was purified by flash column chromatography (SiO2; 100:0-80:20 hexanes-EtOAc) to furnish 4,5-dibromo-2-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (780 mg, 1.73 mmol, 87%) as a solid: 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.70 (m, 2H), 7.37 (app t, J=9.0 Hz, 2H), 5.33 (s, 2H), 3.52 (t, J=8.2 Hz, 2H), 0.83 (t, J=8.2 Hz, 2H), −0.06 (s, 9H).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=[CH2:12])[C:5](=[O:9])[CH:6](Br)[CH3:7])[CH:2]=[CH2:3].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[C:23]3[CH2:26][CH2:27][CH2:28][CH2:29][C:22]=3[C:21]2=[O:30])=[CH:16][C:15]=1[OH:31].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:21](=[O:30])[C:22]3[CH2:29][CH2:28][CH2:27][CH2:26][C:23]=3[C:24]2=[O:25])=[CH:16][C:15]=1[O:31][CH:6]([C:5](=[O:9])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:10][CH:11]=[CH2:12])[CH3:7]
Reactant: C=CCN(CC=C)C(=O)C(C)Br
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(CC=C)C(=O)C(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br

Procedure:
The reaction mixture was washed with water and dried and the solvent was distilled off to obtain 3.8 g. of N,N-diallyl α-bromopropionamide. The product was admixed with 3.5 g. of N-(4-bromo-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide, 2.2 g. of potassium carbonate, 1.8 g. of potassium iodide and 50 ml. of acetone.
Reaction SMILES: C(OC(=O)[N:7]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[C:15]2[C:23]3[CH:22]=[N:21][CH:20]=[N:19][C:18]=3[N:17]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=2)=[CH:10][N:9]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[C:23]4[CH:22]=[N:21][CH:20]=[N:19][C:18]=4[NH:17][CH:16]=3)=[CH:10][N:9]=2)=[CH:37][CH:38]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(N(Cc3ccc(Cl)cc3)C(=O)OC(C)(C)C)nc2)c2cncnc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Clc1ccc(CNc2ccc(Cc3c[nH]c4ncncc34)cn2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(4-Chloro-benzyl)-5-[hydroxy-(7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-pyridin-2-yl-carbamic acid tert-butyl ester (43, 0.1 g, 0.16 mmol) was dissolved in 5 mL of acetonitrile and triethylsilane (0.25 mL, 1.6 mmol) was added followed by trifluoroacetic acid (0.12 mL,1.6 mmol). The reaction was stirred overnight at 80° C., then cooled and concentrated under vacuum. Ethyl acetate was added and the mixture was washed with 1 M potassium carbonate and brine. The organic portion was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with a gradient of 0-20% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound, which was further washed with a mixture of ethyl acetate in hexane (P-0001, 0.025 g, 44%). MS (ESI) [M+H+]+=349.9.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]#[N:37])[C:20]3[C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)C1C=CC=CC=1>[Pd].CCO.C1COCC1>[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]#[N:37])[C:20]3[C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1
Reactant: CCn1ccc2nc(C3CCCC(NC(=O)OCc4ccccc4)C3)n(Cc3ccccc3C#N)c2c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCn1ccc2nc(C3CCCC(N)C3)n(Cc3ccccc3C#N)c2c1=O
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A solution of {3-[3-(2-cyano-benzyl)-5-ethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]-cyclohexyl}-carbamic acid benzyl ester (66 mg, 0.13 mmol) in 1:3 EtOH/THF (8 mL) was hydrogenated over 10% Pd/C (70 mg, 0.065 mmol) at room temperature. After 2 h, the catalyst was removed by filtration, rinsing with MeOH, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography, eluting with 90:10:0.5 CH2Cl2/MeOH/NH4OH to give 2-[2-(3-amino-cyclohexyl)-5-ethyl-4-oxo-4,5-dihydro-imidazo[4,5-c]pyridin-3-ylmethyl]-benzonitrile (40 mg, 82% yield). The HCl salt was prepared by treating the amine in EtOAc with ethereal HCl (0.2 mL). 1H-NMR (CDCl3): δ 7.72 (dd, 1H, J=7.6, 1.2 Hz), 7.50 (t, 1H, J=7.6 Hz), 7.39 (t, 1H, J=7.6 Hz), 7.14 (d, 1H, J=7.2 Hz), 6.93 (d, 1H, J=7.6 Hz), 6.72 (dd, 1H, J=7.6, 2.0 Hz), 6.07 (m, 2H), 4.07 (m, 2H), 2.70 (m, 2H), 1.92 (m, 1H), 1.83 (m, 2H), 1.60 (m, 4H), 1.40 (m, 2H), 1.37 (dt, 3H, J=7.2, 3.2 Hz). MS: calculated for C22H25N5O+H 376.2; found: 376.2.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH:11]([F:13])[F:12])[N:7]([CH3:14])[N:6]=1)=O.[NH3:15]>>[C:3]([C:5]1[CH:9]=[C:8]([O:10][CH:11]([F:13])[F:12])[N:7]([CH3:14])[N:6]=1)(=[O:2])[NH2:15]
Reactant: N
Reactant: COC(=O)c1cc(OC(F)F)n(C)n1
Product: Cn1nc(C(N)=O)cc1OC(F)F

Procedure:
80.6 g (0.39 mole) 3-Methoxycarbonyl-5-difluoromethoxy-1-methylpyrazole and 300 ml aqueous ammonia (33%) was stirred under reflux for 1 hour. The reaction solution was cooled, the precipitate filtered off and washed with water and diisopropyl ether.
Reaction SMILES: [O:1]=[C:2]1[NH:24][C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][C:11]([C:14]4[CH:15]=[N:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[N:12][C:13]=3[C:4]=2[N:3]1[CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:27][CH2:26]1.[H-].[Na+].[CH3:43]I>CN(C)C=O>[CH3:43][N:24]1[C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][C:11]([C:14]4[CH:15]=[N:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[N:12][C:13]=3[C:4]=2[N:3]([CH:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])[CH2:29][CH2:30]2)[C:2]1=[O:1]
Reactant: CI
Reactant: O=C(OCc1ccccc1)N1CCC(n2c(=O)[nH]c3cnc4ccc(-c5cnc6ccccc6c5)nc4c32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C2CCN(C(=O)OCc3ccccc3)CC2)c2c3nc(-c4cnc5ccccc5c4)ccc3ncc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A suspension of compound 48 (6.6 g, 12 mmol) in N,N-dimethylformamide (200 mL) was cooled to 0° C. Sodium hydride (1.0 g, 25 mmol) was added, resulting in bright orange slush. The reaction mixture was stirred for 1 hr at 0° C. before adding methyl iodide (890 mL, 14 mmol). After 3 hours, the reaction was quenched with methanol (100 mL) and the solids were collected by filtration to afford benzyl 4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidine-1-carboxylate (compound 49) (5.0 g, 73%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH3:22].[CH3:23][S-:24].[Na+]>CN(C)C=O>[CH3:22][C:9]1[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:24][CH3:23])[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=1
Reactant: C[S-]
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCCCCCn1c(C)nc2c(N)nc3ccccc3c21
Temperature: 160 °C
Yield: 57.1 %

Procedure:
1-(6-Chlorohexyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.5 g, 8 mmol), sodium thiomethoxide (1.13 g, 15.5 mmol) and N,N-dimethylformamide (15 mL) were combined and heated at 160° C. for 3 hours. The reaction was quenched with water and the precipitate isolated to provide 1.5 g of 2-methyl-1-[6-(methylthio)hexyl]-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21]>O1CCOCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([O:22][CH3:23])=[O:21])(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Yield: 69 %

Procedure:
A solution of 5-chloro-3-methylbenzothiophene-2-sulfonyl chloride (50 mg, 0.178 mmol) and methyl 3-aminobenzoate (17 mg, 0.112 mmol) in aqueous dioxane (900 μL, 8:1 dioxane/water) was stirred at room temperature for 4 days. The reaction mixture was diluted with MeOH (1 mL) and the crude product was purified by reversed phase chromatography (ACE C8, 5 μm, 21×50 mm, flow 25 ml/min, 0.1% TFA in water/MeCN over 6 minutes). The title compound was obtained in 69% yield (30.5 mg). 1H NMR (500 MHz, MeOH-d4) δ ppm 2.49 (s, 3 H) 3.85 (s, 3 H) 7.35 (ddd, J=8.12, 7.31, 0.56 Hz, 1 H) 7.38 (ddd, J=8.12, 2.20, 1.58 Hz, 1 H) 7.46 (dd, J=8.65, 2.05 Hz, 1 H) 7.74 (dt, J=7.31, 1.58 Hz, 1 H) 7.82 (ddd, J=2.20, 1.58, 0.56 Hz, 1 H) 7.84 (dd, J=8.65, 0.56 Hz, 1 H) 7.85 (dd, J=2.05, 0.56 Hz, 1 H). MS (ESI+) m/z 396 [M+H]+.