Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[C:14]([C:27]([F:30])([F:29])[F:28])[CH:13]=3)[N:8]=[C:7]([C:31]#[N:32])[C:6]=2[N:5]=[CH:4]1.[CH2:33](I)[CH3:34].[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>C(#N)C>[CH2:33]([N:24]1[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([C:9]3[N:8]=[C:7]([C:31]#[N:32])[C:6]4[N:5]=[CH:4][N:3]([CH3:2])[C:11]=4[CH:10]=3)=[CH:13][C:14]=2[C:27]([F:29])([F:30])[F:28])[CH2:26][CH2:25]1)[CH3:34].[C:36]([OH:37])([C:27]([F:30])([F:29])[F:28])=[O:39]
Reactant: CCI
Reactant: O=C([O-])[O-]
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(CCOc2ccc(-c3cc4c(ncn4C)c(C#N)n3)cc2C(F)(F)F)CC1
Product: O=C(O)C(F)(F)F

Procedure:
1-Methyl-6-{4-[2-(piperidin-4-yl)-ethoxy]-3-(trifluoromethyl)-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile hydrochloride (20 mg)7 ethyl iodide (10 mg) and potassium carbonate (20 mg) in acetonitrile (1 ml) was stirred at room temperature for 20 hours. After removal of solid by filtration, filtrate was purified by HPLC to give 6-{4-[2-(1-ethylpiperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile as TFA salt.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH:16]3[CH2:17][N:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:31](=[O:36])[CH2:30]3)O1>>[ClH:1].[ClH:1].[N:12]12[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:18][CH:10]([C@@H:9]3[O:8][C:5]3[CH:4]=[CH:3][C:2]([C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[NH:32][C:31](=[O:36])[CH2:30]5)=[N:7][CH:6]=3)[CH2:11]1)[CH2:13]2
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Reactant: Clc1ccc(OC2C3CC4CC2CN(C4)C3)cn1
Product: Cl
Product: O=C1Cc2cc(-c3ccc(OC4C5CC6CC4CN(C6)C5)cn3)ccc2N1

Procedure:
Prepared from the product of Example 15B (185 mg, 0.699 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one using the microwave Suzuki coupling Method G and the salt formation Method H to provide the titled compound: 1H NMR (300 MHz, methanol-D4) δ ppm 1.93-2.00 (m, 2H), 2.23 (s, 1H), 2.39 (s, 1H), 2.43 (s, 1H), 2.56 (s, 2H), 3.58-3.78 (m, 8H), 5.09-5.16 (m, 1H), 7.10 (d, J=8.5 Hz, 1H), 7.73-7.82 (m, 2H), 8.10-8.23 (m, 2H), 8.57 (d, J=2.7 Hz, 1H). MS (DCI/NH3) m/e=362 (M+H)+. Anal. calcd. for C22H23N3O2.2HCl.H2O: C, 58.64; H, 6.02; N, 9.29. Found C, 58.64; H, 5.99; N, 9.11.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][OH:30])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([O:27][CH2:28][CH2:29][O:30][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C12CCC(OCCO)CC1COc1c(F)ccc(F)c12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97 %

Procedure:
A solution of 2-[10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-8-yloxy]-ethanol (1.09 g, 2.54 mmol) in CH2Cl2 (25 mL) at 0° C. was treated with Et3N (0.37 mL) and MsCl (0.65 mL), the reaction mixture was slowly warmed to room temperature. After 14 h, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo to afford the title compound (1.24 g, 97%): 1H NMR (CDCl3 400 MHz) δ 7.58 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.07 (m, 1H), 6.40 (m, 1H), 5.23 (dd, J=2.9, 11.7 Hz, 1H), 4.37 (dd, J=3.7, 4.4 Hz, 2H), 4.11 (d, J=11.7 Hz, 1H), 3.72 (m, 2H), 3.58 (m, 1H), 3.13 (s, 1H), 3.01 (m, 1H), 2.40 (m, 2H), 1.87 (m, 2H), 1.56 (ddd, J=1.6, 14.7, 14.7 Hz, 1H), 1.14 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1O)OCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 100 g of 2-hydroxyphenylacetic acid, 75 cm3 of benzyl alcohol and 0.5 g of paratoluenesulphonic acid in 1400 cm3 of toluene is refluxed for 2 hours while removing the water formed. After cooling, treating with 3 g of animal black and filtering, the reaction mixture is concentrated to 150 cm3 and supplemented with 300 cm3 of isopropyl oxide. The crystals obtained by cooling to 0° C. are drained, washed and dried to give 82.5 g of benzyl 2-hydroxyphenylacetate. 174 g of potassium carbonate are added to a solution of 153 g of this ester in a mixture of 500 cm3 of 1,3-dibromopropane and 2500 cm3 of acetonitrile and the mixture is refluxed for 17 hours. The reaction mixture is cooled, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 500 cm3 of ethyl acetate and the organic phase is washed twice with 400 cm3 of water and twice with 250 cm3 of a saturated solution of sodium chloride and then dried and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 9 cm, height 55 cm), eluting with a cyclohexane and ethyl acetate mixture (95/5 by volume) and collecting fractions of 500 cm3. Fractions 12 to 18 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) to give 90 g of benzyl 2-(3-bromopropoxy)phenylacetate in the form of a yellow oil. A solution of 40 g of this product in 500 cm3 of acetonitrile is heated in an autoclave with 27 g of sodium iodide and 90 g of dimethylamine for 16 hours at 80° C. The reaction mixture is cooled, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by acid-base treatment to give 29.3 g of benzyl 2-(3-dimethylaminopropoxy)phenylacetate in the form of a yellow oil. Hydrogenation of this ester at atmospheric pressure at 40° C. in ethyl acetate in the presence of palladium hydroxide, followed by crystallization from ethyl acetate, lead to 17.5 g of 2-(3-dimethylaminopropoxy)phenylacetic acid in the form of white crystals; melting point 98° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:7][CH:6]=1)=O.[CH3:23][C:24]([S@@:27]([NH2:29])=[O:28])([CH3:26])[CH3:25]>C1COCC1.CCCCCC.CCOC(C)=O.C(O[Ti](OCC)(OCC)OCC)C>[CH3:23][C:24]([S@@:27](/[N:29]=[C:3](\[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:7][CH:6]=1)/[C:2]([F:22])([F:21])[F:1])=[O:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=C(c1ccc(OCCCCCC(F)(F)F)cc1)C(F)(F)F
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)[S@](=O)/N=C(\c1ccc(OCCCCCC(F)(F)F)cc1)C(F)(F)F
Yield: 65.8 %

Procedure:
To a solution of Intermediate 8B (717 mg, 2.184 mmol) and (S)-2-methylpropane-2-sulfinamide (529 mg, 4.37 mmol) in THF (10 mL) was added tetraethoxytitanium (1993 mg, 8.74 mmol) in THF (20 mL). The resulting mixture was reflux for 5 h. TLC (20% EtOAc in hexane) indicated the starting ketone was completely consumed. The solvent was evaporated to afford a yellow oil. This yellow oil was dissolved in EtOAc and then washed with saturated NaHCO3 (25 mL) and a large amount of white precipitation formed which was removed by filtering through a bed of Celite®. The white precipitation was rinsed with EtOAc. The combined EtOAc solution was washed again with saturated NaHCO3, dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography (40 g silica gel, eluted with EtOAc in hexanes) to afford Intermediate 8C (620 mg, 66%).
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:25]1([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:39][C:36]3[CH:37]=[CH:38][C:33]([O:32][CH2:31][CH2:30][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:34][CH:35]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ccccc1CNc1cccn2nc(Nc3ccc(OCCN4CCCC4)cc3)nc12)S(C)(=O)=O

Procedure:
N-Methyl-N-[2-({2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-phenyl]-methanesulfonamide was prepared from N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (48.0 mg, 0.233 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.026 g, 24%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.79 (d, J=6.7 Hz, 1H), 7.55-7.45 (m, 3H), 7.38-7.28 (m, 3H), 6.92 (d, J=8.9 Hz, 2H), 6.65 (t, J=7.5 Hz, 1H), 6.51 (s, 1H), 6.36 (d, J=7.7 Hz, 1H), 5.21 (t, J=5.7 Hz, 1H), 4.72 (d, J=6.1 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H), 3.31 (s, 3H), 3.00 (s, 3H), 2.90 (t, J=5.9 Hz, 2H), 2.66-2.59 (m, 4H), 1.85-1.77 (m, 4H). MS=536 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:24][CH2:23][CH:22]3[CH:18]([CH2:19][NH:20][CH2:21]3)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:24][CH2:23][CH:22]3[CH:18]([CH2:19][N:20]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:21]3)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4CNCC4C3)n2)cn1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4CN(C(=O)CC#N)CC4C3)n2)cn1
Temperature: 45 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To a solution of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(octahydro-1H-isoindol-5-yl)pyrimidine-2,4-diamine (470 mg, 1.35 mmol), 2-cyanoacetic acid (246.7 mg, 2.90 mmol) in a mixture of DCM (40 mL) and DMF (10 mL) were added EDCI (505.2 mg, 2.64 mmol) and HOAT (325.4 mg, 0.30 mmol). After addition, the reaction mixture was stirred at 45° C. for 3 h, quenched with H2O (30 mL) and extracted with DCM (200 mL×3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as beige solid (228.4 mg, 40.8%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[OH:20][C:21]1[C:26]([CH2:27][CH2:28][CH3:29])=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=1[C:31](=[O:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:31]([C:22]1[CH:23]=[CH:24][C:25]([O:30][CH2:2][C:3]2[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)=[O:8])=[CH:5][CH:4]=2)=[C:26]([CH2:27][CH2:28][CH3:29])[C:21]=1[OH:20])(=[O:33])[CH3:32]
Reactant: N#Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCc2ccc(C(=O)Nc3ccc(C#N)cc3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
Add 4-chloromethyl-N-(4-cyano-phenyl)-benzamide (1.00 g, 3.69 mmol) to a solution of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (717 mg, 3.69 mmol) in dimethylformamide (14 mL). After 10 minutes add potassium carbonate (766 mg, 5.54 mmol) and cesium carbonate (1.204 g, 3.69 mmol). Stir at room temperature for one hour, then heat to 70° C. for 1.5 hours. Cool, and partition between ethyl acetate (100 mL) and water (100 mL). The organic phase is washed twice with water, brine, dried, and concentrated to dryness. The resulting residue is purified by silica gel column chromatography, eluting with 1:1 hexane:ethyl acetate to afford the title compound (820 mg, 52%): 1H NMR (CDCl3) δ 0.97 (t, 3H), 1.58 (m, 2H), 2.56 (s, 3H), 2.73 (m, 2H), 5.25 (s, 2H), 6.46 (d, 1H), 7.56-7.60 (m, 3H), 7.68 (d, 2H), 7.79 (d, 2H), 7.88-7.94 (m, 3H), 12.77 (s, 1H).
Reaction SMILES: CN(C)[CH:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:4]#[N:5].Cl.[NH2:14]O.[C:16]([OH:19])(=O)C>>[NH2:14][C:16]1[O:19][N:5]=[CH:4][C:3]=1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: NO
Reactant: CN(C)C(C#N)c1cccnc1
Reactant: CC(=O)O
Agent: Cl
Product: Nc1oncc1-c1cccnc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of α-(dimethylamino)-α-(3-pyridyl)acetonitrile (5.19 g, 30 mmol) in acetic acid (40 ml) was added hydroxylamine hydrochloride (2.8 g, 40 mmol). The reaction mixture was stirred at 100° C. for 1 hour, cooled to room temperature and concentrated in vacuo. Water (50 ml) was added and the reaction mixture neutralized with solid potassium carbonate. The precipitated compound was filtered washed with water and dried giving the title compound in 4.2 g yield.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[H-].[Na+].F[C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:27]=1[F:36]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]([C:26]4[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:27]=4[F:36])[C:18](=[O:22])[CH:17]=3)[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: CCc1cnc(N2CCC(Oc3cc[nH]c(=O)c3)CC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4F)c(=O)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
A suspension of 4-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-2(1H)-one (127 mg, 0.424 mmol, prepared according to procedures described in Example 230 Step C substituting 2-chloro-5-ethylpyrimidine (Aldrich) for 2-chloro-5-cyclopropylpyrimidine), sodium hydride (60 wt % mineral oil, 21 mg, 0.51 mmol) and DMF (5 mL) was purged with Argon and then stirred at room temperature for 1 h. To the reaction was added 1,2-difluoro-4-(methylsulfonyl)benzene (90 mg, 0.47 mmol, Matrix Scientific) and then heated at 110° C. for 1 h. The resulting mixture was quenched with H2O and extracted with EtOAc. The organic layer was concentrated in vacuo to a yellow solid. The solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2) to yield 91 mg of the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (s, 2 H), 7.83-7.91 (m, 2 H), 7.64 (dd, J=8.53, 6.78 Hz, 1 H), 7.13 (dd, J=7.53, 1.00 Hz, 1 H), 6.08 (dd, J=7.65, 2.64 Hz, 1H), 6.03 (d, J=2.51 Hz, 1 H), 4.54-4.63 (m, 1 H), 4.16-4.27 (m, 2 H), 3.60-3.70 (m, 2 H), 3.12 (s, 3H), 2.49 (q, J=7.53 Hz, 2 H),1.97-2.15 (m, 2 H),1.78-1.97 (m, 2H),1.21 (t, J=7.53 Hz, 3 H). MS (ESI) 473 (M+H).
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([O:23][CH2:24][C:25]3[CH:50]=[CH:49][C:28]([O:29][CH2:30][C:31]4[N:32]=[C:33]([C:37]5[CH:42]=[CH:41][C:40]([CH2:43][C:44]([O:46]CC)=[O:45])=[CH:39][CH:38]=5)[O:34][C:35]=4[CH3:36])=[C:27]([O:51][CH3:52])[CH:26]=3)=[N:14][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[C:1]([C:5]1[S:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([O:23][CH2:24][C:25]3[CH:50]=[CH:49][C:28]([O:29][CH2:30][C:31]4[N:32]=[C:33]([C:37]5[CH:38]=[CH:39][C:40]([CH2:43][C:44]([OH:46])=[O:45])=[CH:41][CH:42]=5)[O:34][C:35]=4[CH3:36])=[C:27]([O:51][CH3:52])[CH:26]=3)=[N:14][N:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:16]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(C(C)(C)C)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2csc(C(C)(C)C)n2)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a mixture of ethyl {4-[4-({4-[({4-[(E)-2-(2-tert-butyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (0.77 g), tetrahydrofuran (9 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give {4-[4-({4-[({4-[(E)-2-(2-tert-butyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as crystals (0.59 g, yield 80%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 113-115° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)([O-:3])=[O:2].[SH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CSCc1ccccc1[N+](=O)[O-]

Procedure:
A mixture of o-nitrobenzylchloride (17.2 g), methyl mercaptoacetate (8.9ml), and potassium carbonate (27.6 g) was refluxed with stirring in acetone (200 ml) for 6 hours. The reaction mixture was filtered and evaporated to leave the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>C1COCC1.C(OCC)(=O)C>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:4]([C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([CH3:28])[CH:30]=2)([C:3]([O:2][CH3:1])=[O:17])[CH2:5][CH2:6]1)=[O:11])([CH3:14])([CH3:16])[CH3:15]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)c2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a cold (−78° C.) solution of methyl N-tert-butoxycarbonyl-piperidine-4-carboxylate (0.25 g, 1.03 mmol; Example 3, Step B) in anhydrous THF (10 mL), a solution of sodium bis(trimethylsilyl)amide (1.2 mL, 1M, 1.2 mmol) was added over a period of 5 min. The resultant mixture was stirred at −78° C. for 1 h., and 3-methylbenzoyl chloride (135 μL, 1.02 mmol) was added. The reacting mixture was allowed to warm up to room temp. and stirred overnight. The product mixture was diluted with ethyl acetate and washed with brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 8-10% ethyl acetate in hexane gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O.C1(C)C=CC=CC=1>[Pt].C(O)C>[NH2:15][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:5]=1[NH:4][CH2:3][C:2]([OH:1])([CH3:18])[CH3:19])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(O)CNc1c(N)cnc2ccccc12

Procedure:
Using the method of Example 26, 7.0 g (0.027 mole) of 4-(2-hydroxy-2-methylpropylamino)-3-nitroquinoline, 1 g of platinum on charcoal, 200 ml of toluene and 150 ml of ethanol was hydrogenated on a Paar apparatus. The solution was filtered, then evaporated to dryness to provide 3-amino-4-(2-hydroxy-2-methylpropylamino)quinoline was a solid residue. To the residue was added 50 ml of triethyl orthoformate and 5 drops of formic acid. The solution was heated at 135° to 140° C. for one hour, then allowed to stand for about 16 hours. The product was separated by filtration, dissolved in hydrochloric acid and reprecipitated with sodium hydroxide solution. The product was recrystallized from ethanol to provide 1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline, m.p. 169°-170° C. Analysis: Calculated for C14H15N3O.H2O: %C, 64.8; %H, 6.6; %N, 16.2; Found: %C, 65.1; %H, 6.6; %N, 16.4.
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(Cl)(Cl)Cl>[N:22]1([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]4=[N:4][N:3]([C:27]5[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=5[CH2:29][N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[C:2](=[O:1])[C:6]4=[CH:7]3)=[CH:17][CH:18]=2)[CH:26]=[CH:25][CH:24]=[N:23]1
Reactant: O=Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(3-Oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzaldehyde (Example 529, 0.15 g, 035 mmol) and pyrrolidine (0.031 mL, 0.38 mmol, 1.1 equiv) were combined in 1,2-dichloroethane (2 mL) and treated with powdered 4 Å molecular sieves (0.15 g, 1 wt equiv) and acetic acid (0.099 mL, 1.7 mmol, 5 equiv). After stirring vigorously for 20 minutes at ambient temperature, the mixture was treated with sodium triacetoxyborohydride (0.11 g, 0.52 mmol, 1.5 equiv) portionwise over 2 minutes. After stirring for 90 minutes, the mixture was treated with sodium bicarbonate (7 mL, aqueous saturated) and stirred for 5 minutes. The mixture was diluted with chloroform (20 mL), filtered and the organic filtrate was washed once with sodium bicarbonate (10 mL, aqueous saturated) and brine (10 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 90:10; chloroform:methanol; then 92:8; chloroform:methanol containing 10% ammonium hydroxide), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.12 (1H, br s), 8.46 (1H, dd, J=2.5, 0.4 Hz), 8.32 (1H, s), 8.20 (1H, d, J=8.1 Hz), 7.84 (2H, d, J=8.8 Hz), 7.78 (1H, d, J=8.3 Hz), 7.73 (1H, d, J=1.7 Hz). 7.65-7.60 (2H, m), 7.53 (1H, t, J=7.4 Hz), 7.48 (2H, d, J=8.6 Hz), 7.45-7.33 (2H, m), 6.53 (1H, dd, J=2.5, 1.8 Hz), 5.77 (2H, s), 3.63 (2H, br m), 2.36 (4H, br m), 1.63 (4H, br m) ppm; low resolution mass spectrometry (ES+) m/z 501.0 [(M+H)+; calculated for C31H29N6O: 501.2].