Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].CC([N-]C(C)C)C.[Br:32][C:33]1[N:38]=[C:37]([CH:39]=O)[CH:36]=[CH:35][CH:34]=1>C1COCC1>[Br:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([CH:39]=[CH:2][O:3][CH3:4])[N:38]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (34.5 g, 100.6 mmol) in THF (500 mL) at −10° C. was added LDA (60 mL, 2 mol/L). The mixture was stirred at −10° C. for 1 hour before addition of 6-bromopicolinaldehyde (10 g, 53.8 mmol) in THF (200 mL). The reaction mixture was then allowed to warm to room temperature and stirred at room temperature for 12 hours. The solution was then partitioned between water and ether. The aqueous fraction was separated and extracted twice with ether. The organic layers were washed with brine and dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product which was purified by chromatography (petroleum ether:ethyl acetate, 20:1) to give 2-bromo-6-(-2-methoxy-vinyl)-pyridine. (Yield 9.3 g, 80%). LC-MS: [M+H]+ 215.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:21])[CH3:22])[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=2[O:10][CH3:11])=[O:32])=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Reactant: O=C=Nc1ccc(Cl)cc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(Cl)cc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: CCCCCC.C([Li])CCC.[C:12](#[N:14])[CH3:13].C([O:17][C:18](=O)[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C>O1CCCC1>[CH2:21]([O:20][CH2:19][C:18](=[O:17])[CH2:13][C:12]#[N:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COCc1ccccc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCC(=O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 151.1 %

Procedure:
In a stream of argon, 156.2 ml (0.248 mole) of a solution of 1.6 moles of n-butyllithiumhexane was added to 150 ml of anhydrous tetrahydrofuran. The mixture was cooled to -78° C., and a solution of 15.8 ml (0.293 mole) of acetonitrile in 50 ml of anhydrous tetrahydrofuran was added dropwise. The mixture was stirred at -78° C. for 1 hour. A solution of 55.2 g (0.248 mole) of ethylbenzyloxyacetate in 100 ml of anhydrous tetrahydrofuran was added dropwise. The mixture was stirred at -78° C. for 15 minutes and at room temperature for 50 minutes. The mixture was then poured into 200 ml of ice water. The aqueous layer was washed with ether, acidified with concentrated hydrochloric acid, and extracted with ether. The ether layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 70.9 g of crude 4-benzyloxy-3-ketobutanenitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[S:15][CH:16]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.[H-].[Na+].CC1C=CC(S(O[CH:33]2[CH2:42][CH2:41][C:36]3([O:40][CH2:39][CH2:38][O:37]3)[CH2:35][CH2:34]2)(=O)=O)=CC=1>CN(C=O)C>[O:37]1[C:36]2([CH2:41][CH2:42][CH:33]([N:11]3[C:7]4[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=4[C:9]([C:12]4[CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[S:15][CH:16]=4)=[N:10]3)[CH2:34][CH2:35]2)[O:40][CH2:39][CH2:38]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reactant: COc1nccc2[nH]nc(-c3csc(C(N)=O)c3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a solution of 4-(4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (65.0 mg) in DMF (3 mL) was added sodium hydride (60% dispersion in mineral oil, 19.0 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (148 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (53.9 mg).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[O:15]([C:22]1[C:27]2[C:28]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:29][NH:30][C:26]=2[CH:25]=[CH:24][N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.Cl.Cl.[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]1[S:49][C:50]([CH2:53]N2CCC(CN)CC2)=[CH:51][N:52]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>C(#N)C>[O:15]([C:22]1[C:27]2[C:28]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][N:36]([CH2:53][C:50]4[S:49][C:48]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][N:42]=5)=[N:52][CH:51]=4)[CH2:35][CH2:34]3)=[N:29][NH:30][C:26]=2[CH:25]=[CH:24][N:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(Oc2nccc3[nH]nc(NCC4CCNCC4)c23)cc1
Reactant: NCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Oc2nccc3[nH]nc(NCC4CCN(Cc5cnc(-c6ccccn6)s5)CC4)c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
A solution of the compound prepared in Example 436 (0.053 g) and the compound prepared in Example 214 (0.039 g) in acetonitrile (1 mL) was stirred at room temperature for 30 minutes. Tetramethylammoniumtriacetoxy borohydride (0.094 g) was added and stirring at room temperature continued for 1 hour. The reaction mixture was quenched with aqueous saturated sodium bicarbonate. After stirring at room temperature for 20 minutes, hopeful product was extracted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, dried, evaporated in vacuo to an oil that was purified by column chromatography on silica gel (1-5% methanol in dichloromethane) to provide the title compound (0.008 g) with the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:18])[C:11]=1[O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:5]([O:7]C)=[O:6].[OH-].[Li+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:18])[C:11]=1[O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(OC2CCCC2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Cl)c(OC2CCCC2)c(Cl)c1
Yield: 82.1 %

Procedure:
Methyl 3,5-dichloro-4-(cyclopentyloxy)benzoate (2) (1.05 g, 3.63 mmol) and lithium hydroxide (174 mg, 7.26 mmol) were combined in THF (10 mL) and water (ca. 1.5 mL) was added dropwise until a solution formed. The resultant mixture was stirred at RT for 12 h. The THF was removed in vacuo and the residue acidified using aqueous HCl (1 M). The resultant precipitate was filtered to afford 3,5-dichloro-4-(cyclopentyloxy)benzoic acid (3) (820 mg, 82%): m/z 273 (M−H)− (ES−).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15][CH2:14]2.C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:1][C:2]1[N:7]=[C:6]([N:17]2[C:18]3[C:13](=[CH:12][C:11]([O:10][CH3:9])=[CH:20][CH:19]=3)[CH2:14][CH2:15][CH2:16]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1ccc2c(c1)CCCN2
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCCN2c1ccnc(Cl)n1
Temperature: 40 °C
Yield: 79.9 %

Procedure:
The reaction flask containing 2,4-dichloropyrimidine (372 mg, 2.5 mmol), 6-methoxy-1,2,3,4-tetrahydroquinoline (489 mg, 3 mmol) and diisopropylethylamine (0.52 mL, 3 mmol) in n-butanol (10 mL) was heated at 40° C. overnight. The solvent was evaporated, and the residue was purified by flash column chromatography to give 2-Chloro-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (551 mg, 80%). This intermediate (250 mg, 0.91 mmol) was then dissolved in dichloromethane and treated with BBr3 (1 M in dichloromethane) (1 mL, 1 mmol) at −78° C. The reaction mixture was slowly warmed up to room temperature and stirred for 1 hr, poured into water, extracted with dichloromethane. The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography to give 2-Chloro-4-(6-hydroxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (154 mg, 65%). To a stirred solution of 2-chloro-4-(6-hydroxy-3,4-dihydroquinolin-1(2H)-yl)pyrimidine (29 mg, 0.11 mmol) and 4-amino-N-(cyclopropylmethyl)benzenesulfonamide (27 mg, 0.12 mmol) in DMF (0.5 mL) was added p-toluenesulfonic acid (2 M in dioxane) (55 μL, 0.11 mmol). The reaction mixture was stirred at 90° C. overnight, then purified by HPLC to give the title compound (27 mg, 56%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[H-].[Na+].Br[CH2:25][CH2:26][CH3:27]>CN(C=O)C>[F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][N:8]([CH2:25][CH2:26][CH3:27])[C:9](=[O:11])[CH:10]=1
Reactant: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cc(C(=O)OCC)c(Nc2ccc(I)cc2F)cc1=O

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with NaH and bromopropane in DMF under the same conditions as for example 22, step A to give a crude solid which was purified by column chromatography on silica gel (50% EtOAc/hexanes as eluant). Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1-propyl-1,6-dihydro-3-pyridinecarboxylate was isolated as a white solid (54%), m.p. (EtOAc/hexanes) 147-150° C. 1H NMR [(CD3)2SO, 400 MHz] δ 9.29 (s, 1H), 8.50 (s, 1H), 7.76 (dd, J=10.1, 1.9 Hz, 1H), 7.60 (ddd, J=8.4, 2.0, 0.8 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.46 (d, J=1.3 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 3.85 (t, J=7.3 Hz, 2H), 1.62 (sextet, J=7.3 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H), 0.85 (t, J=7.4 Hz, 3H). Anal. Calcd for C17H18FIN2O3: C, 46.0; H, 4.1; N, 6.3. Found: C, 45.8; H, 3.9; N, 6.0.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12](C(=O)C(C2C3C(=NC=CC=3)NC=2)=O)[C@H:11](C)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:39]=[N:38][C:37]([O:40][CH3:41])=[C:36]2[C:32]=1[C:33]([C:42](=[O:46])[C:43]([O-:45])=O)=[CH:34][NH:35]2.[K+]>>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:43](=[O:45])[C:42]([C:33]2[C:32]3[C:36](=[C:37]([O:40][CH3:41])[N:38]=[CH:39][C:31]=3[O:30][CH3:29])[NH:35][CH:34]=2)=[O:46])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)[O-])c[nH]c12
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2ncccc12
Agent: [K+]
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c[nH]c12

Procedure:
Compound 5ao, N-(benzoyl)-N′-[(4,7-dimethoxy-6-azaindol-3-yl)-oxoacetyl]-piperazine was prepared by the same method used to prepare compound 5a but the starting material was Potassium (4,7-dimethoxy-6-azaindole-3-yl)-oxoacetate. The compound was purified by silica gel chromatography using EtOAc as the eluting solvent to give a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)=[N:10][N:11]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:12]=2[C:13]([F:16])([F:14])[F:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1C(F)(F)F
Yield: 33.6 %

Procedure:
4-(4-Fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (Example 1, Step 3) (2.11 g, 5.5 mmol) and ethyl bromoacetate (1.09 g, 6.5 mmol) were stirred vigorously in 15 mL dry DMF with finely powdered potassium carbonate (1.38 g, 10 mmol) under nitrogen at 25° C. for 3 hours. The mixture was diluted with ethyl acetate and filtered to remove solids. The organic filtrate was washed with two portions of water followed by brine, dried over MgSO4 and concentrated in vacuo. The desired isomer was isolated by chromatography on silica gel, using 10% ethyl acetate/90% heptane as the eluant, to give ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate as a white solid (0.87 g, 34%). Elemental analysis for C21H18N2F4SO4Calc'd: C, 53.62, H, 3.86, N, 5.96, S, 6.82. Found: C, 53.69, H, 3.97, N, 5.87, S, 7.05.
Reaction SMILES: O[C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>>[C:17]([C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1)(=[O:20])[CH2:18][CH3:19]
Reactant: CCC(=O)Cl
Reactant: CCCCCCCCC1(C)SC(=O)C=C1O
Product: CCCCCCCCC1(C)SC(=O)C=C1C(=O)CC
Yield: 48.1 %

Procedure:
From 32 (40 mg, 0.17 mmol) and propionyl chloride (20 μL, 0.22 mmol) following general procedure K was obtained 64 (23.1 mg, 47%) after flash chromatography (15% EtOAc/Hexanes). 1H NMR (300 MHz, CDCl3) δ 0.85 (t, J=7 Hz, 3H), 1.12-1.25 (m, 13H), 1.42-1.49 (m, 2H), 1.64 (s, 3H), 1.78-1.84 (m, 2H), 2.57 (q, J=7.5 Hz, 2H), 6.39 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 8.71, 14.0, 22.6, 25.1, 25.9, 27.9, 29.1, 29.3, 29.5, 31.8, 38.6, 60.4, 113.8, 169.1, 177.0, 179.9. IR (NaCl) 2928, 1787, 1688 cm−1; Analysis Calculated for C16H26O3S: C, 64.4; H, 8.78; Found: C, 64.3; H, 8.89.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]#[N:13].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([CH2:11][C:12]#[N:13])[CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Cc1c(CC#N)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(N)cccc1CC#N
Yield: 80.6 %

Procedure:
(2-Methyl-3-nitro-phenyl)-acetonitrile (16.6 g ) was dissolved in 400 ml of ethyl acetate and 0.83 g of 10% palladium on carbon (Degussa type) was added; and the reaction mixture was placed under 50 lb/in2 of hydrogen on the Parr shaker for 4 hr. The catalyst was filtered off; the solvent was evaporated; and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate:hexane (2:3), yielding 11.1 g of (3-amino-2-methyl-phenyl)-acetonitrile as a white solid. ##STR119##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18](O)=[O:19])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1.C(N(CC)CC)C>ClCCl>[CH3:43][N:40]1[CH2:41][CH2:42][CH:37]([C:31]2[C:30]3[C:34](=[CH:35][CH:36]=[C:28]([NH:27][C:18](=[O:19])[CH2:17][C:10]4[C:11]5[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)=[CH:8][CH:9]=4)[CH:29]=3)[NH:33][CH:32]=2)[CH2:38][CH2:39]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)Cc1ccc(-c2ccncc2)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Cc4ccc(-c5ccncc5)c5ccccc45)cc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.1 %

Procedure:
A stirred suspension of 4-(pyridin-4-yl)naphth-1-ylacetic acid (D7, 0.18 g, 0.7 mmole) in dichloromethane (15 ml) was treated with oxalyl chloride (0.18 ml, 2.1 mmole), then stirred at room temperature for 3 hours, before evaporating to dryness. The solid residue was suspended in dichloromethane (15 ml), cooled to 0° C. and treated with a solution of 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole (D2, 0.13 g, 0.56 mmole) in dichloromethane (15 ml). The mixture was stirred at 0° for 1 hour and then a solution of triethylamine (0.25 ml) in dichloromethane (5 ml) was added dropwise. The mixture was allowed to warm to room temperature and stir overnight, then evaporated to dryness and the residue subjected to flash chromatography on silica gel eluting with CH2Cl2/MeOH/NH4OH (100:5:0.5 to 100:10:1 gradient elution) to afford the title compound as a pale cream powder (0.04 g).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[F:42])[CH:37]=[O:38].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:34]4[CH:35]=[C:36]([CH:37]=[O:38])[CH:39]=[CH:40][C:41]=4[F:42])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C=O)ccc4F)cc23)CC1
Temperature: 160 °C

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane (3.0 mL) and H2O (1.0 mL) was added 3-bromo-4-fluorobenzaldehyde (264 mg, 1.30 mmol), and K2CO3 (360 mg, 2.60 mmol) in microwave tube. The reaction mixture was degassed for 5 min before addition of tetrakis(triphenylphosphosphine) palladium (0) (48 mg, 0.043 mmol). The reaction was heated in a microwave for 30 min at 160° C. The organic layer was separated and concentrated. The residue was dissolved in MeOH until solid precipitated to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-formylphenyl)-1H-indole-7-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2cc(Cl)cc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
The product from Example 193a (1.06 g, 5.2 mmol), N-(4-hydroxyphenyl)acetamide (0.70 g, 4.5 mmol) and K2CO3 (0.79 g, 5.7 mmol) in DMF (14 ml) was heated at 110° C. for 6 hours. The reaction mixture was cooled to room temperature, diluted with H2O and then extracted with EtOAc. The extract washed with H2O and brine, dried over MgSO4, filtered and concentrated under vacuum giving the crude title compound as a pale brown crystal, which was purified by washing with i-Pr2O to give the desired product as pale brown crystal (1.28 g, 92%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:17])([CH3:16])[NH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N+:13]([O-])=O.[H][H].C1(C)C=CC(S(O)(=O)=O)=CC=1>[Pd].CO>[F:12][C:10]1[CH:11]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:13][C:3](=[O:2])[C:4]([CH3:17])([CH3:16])[NH:5]2
Reactant: COC(=O)C(C)(C)Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC1(C)Nc2cc(F)ccc2NC1=O

Procedure:
A mixture of N-(5-fluoro-2-nitrophenyl)-2-methylalanine methyl ester (XI, EXAMPLE 7, 11.2 g), palladium on carbon (10%, 0.63 g), and methanol (350 ml) is shaken under 44 psi of hydrogen pressure for 1.5 hr. Additional palladium on carbon (10%, 0.23 g) is added and the mixture is shaken at 36 psi for another 45 min. p-Toluenesulfonic acid (0.46 g) is added and the catalyst is filtered off. The filtrate is concentrated to about 150 ml and warmed at 800 for 75 min. The solvent is then removed under reduced pressure and the residue is chromatographed on silica gel (700 ml) eluting with dichloromethane/methanol (98/2). aaa a solid. The product is crystallized from methanol/dichloromethane/hexane to give the title compound, mp 148.5°-149.0°; NMR (CDCl3) 1.42, 3.80, 6.40, 6.46, 6.66 and 8.35 δ.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])[CH:5]=1)([O-])=O.[OH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:13]1([C:11]([NH:10][C:6]2[CH:5]=[C:4]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20]4)[CH:9]=[CH:8][N:7]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: O=C(O)c1cnc2ccc(O)cc2c1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccn1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cc2c1
Temperature: 150 °C

Procedure:
N-(4-Nitropyridin-2-yl)cyclopropanecarboxamide (Int-23, 150 mg, 0.722 mmol), 6-hydroxyquinoline-3-carboxylic acid (Int-15, 150 mg, 0.794 mmol), and cesium carbonate (706 mg, 2.17 mmol) were weighed into a 2-5 mL microwave vial. N,N-dimethylformamide (3.5 mL) was added and the vial was capped. The reaction mixture was heated in the microwave for 3 h at 150° C. The vial was allowed to cool to room temperature and the cap was removed. The reaction mixture was diluted with water (5 mL) and stirred for a few minutes. The resulting clear solution was acidified by addition of 1N HCl and extracted three times with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. A solid precipitated in the extracts, was isolated by filtration and found to be the product. Solid product was combined with product isolated by extraction (0.245 g, 97%). LC-MS: (FA) ES+ 350; 1H NMR (400 MHz, d6-DMSO) δ ppm 13.67-13.47 (m, 1H), 10.92 (s, 1H), 9.30 (d, J=2.1 Hz, 1H), 8.98 (d, J=2.0 Hz, 1H), 8.25 (d, J=5.7 Hz, 1H), 8.21-8.17 (m, 1H), 8.01-7.99 (m, 1H), 7.75 (dd, J=9.1, 2.7 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 6.81 (dd, J=5.7, 2.4 Hz, 1H), 1.95 (tt, J=7.6, 7.6, 4.9, 4.9 Hz, 1H), 0.81-0.67 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)[CH2:3]1.[CH:18]1([N:23]2[C:27]([NH2:28])=[C:26]([C:29]([NH2:31])=[O:30])[C:25]([CH2:32][CH3:33])=[N:24]2)[CH2:22][CH2:21][CH2:20][CH2:19]1.CS(O)(=O)=O>C(Cl)Cl>[CH:18]1([N:23]2[C:27]3=[N:28][C:13]([C:12]4[CH:15]=[CH:16][CH:17]=[C:10]([O:9][CH:4]5[CH2:5][CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3]5)[CH:11]=4)=[N:31][C:29](=[O:30])[C:26]3=[C:25]([CH2:32][CH3:33])[NH:24]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CN1CCCCC(Oc2cccc(C=O)c2)C1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(OC4CCCCN(C)C4)c3)nc(=O)c1-2
Yield: 44.9 %

Procedure:
A mixture of 3-(1-methyl-3-hexahydroazepinyloxy)benzaldehyde (0.79 g, 3.4 mol), 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.5 g, 2.2 mmol), methanesulfonic acid (0.25 ml) and xylenes (25 ml) was refluxed overnight. The solvent was stripped, the residue was dissolved in CH2Cl2 and purified by column chromatography on silica gel eluting with ether, then acetone, then 0.5% Et3N/acetone to afford 0.43 g (45%) of 1-cyclopentyl-3-ethyl-6-[3-(1-methyl-3-hexahydroazepinyloxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 195-196° C.