Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:32])[CH:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:14][O:15][Si](C(C)C)(C(C)C)C(C)C)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:15][CH2:14][CH:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:12]([NH:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:1]=[N:2][CH:3]=[CH:4]2)=[O:32]
Reactant: CC(C)[Si](OCC(C(=O)Nc1ccc2cnccc2c1)c1ccccc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc2cnccc2c1)C(CO)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To N-(isoquinolin-6-yl)-2-phenyl-3-(triisopropylsilyloxy)propanamide (E401) in THF cooled to 0° C. was added TBAF and this solution was stirred for 3 h at 0° C. The mixture was poured into EtOAc/NH4Cl(sat) and washed with NH4Cl(sat). The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (0-10% MeOH/CH2Cl2) gave pure 3-hydroxy-N-(isoquinolin-6-yl)-2-phenylpropanamide (E402).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[NH:38][C:39]([C:41]1[CH:50]=[CH:49][CH:48]=[C:47]2[C:42]=1[CH2:43][CH2:44][CH2:45][C@@H:46]2[NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[NH:40]>CN(C=O)C.CC(=O)OCC>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:40]=[C:39]([C:41]3[CH:50]=[CH:49][CH:48]=[C:47]4[C:42]=3[CH2:43][CH2:44][CH2:45][C@@H:46]4[NH:51][C:52](=[O:58])[O:53][C:54]([CH3:56])([CH3:55])[CH3:57])[N:38]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@@H]4NC(=O)OC(C)(C)C)no2)cc1C#N
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Prepared using General Procedure 2. To a stirring solution of 3-cyano-4-isopropoxybenzoic acid (556 mg, 2.72 mmol) in DMF (10 mL) was added HOBt (476.6 mg, 3.53 mmol) and EDCI (677.9 mg, 3.53 mmol). After stirring for 30 min, (S)-tert-butyl (5-(N-hydroxycarbamimidoyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate INT-10 (3.56 g crude, approximately 2.99 mmol) was added. After stirring at room temperature for an additional 90 min, the mixture was heated to 90° C. for 15 h. The mixture was diluted with EA and washed with NaHCO3. The combined organic layers were dried, concentrated, and chromatographed (EA/hexanes) to provide 1.89 g (46%) (S)-tert-butyl (5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate INT-12 as a white solid. LCMS-ESI (m/z) calculated for C27H30N4O4: 474.6; no M/Z observed, tR=4.23 min. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=2.1 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 7.92 (dd, J=7.7, 1.1 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.32 (dd, J=20.3, 12.6 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 4.94 (d, J=6.0 Hz, 1H), 4.88-4.72 (m, 1H), 3.23-3.08 (m, 1H), 3.07-2.94 (m, 1H), 2.06 (d, J=12.6 Hz, 1H), 1.97-1.78 (m, 3H), 1.53-1.43 (m, 15H). 13C NMR (101 MHz, CDCl3) δ 172.64, 169.40, 162.69, 155.43, 138.65, 137.55, 134.04, 133.83, 131.68, 129.55, 126.08, 125.97, 116.74, 115.20, 113.53, 103.87, 79.44, 72.69, 48.97, 29.73, 28.40, 21.68, 19.71, 14.14.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[CH2:1]([NH:8][C:9]1[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)NCc1ccccc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(NCc2ccccc2)n1

Procedure:
The reaction described in Preparation 42 was repeated, but using 5.02 g of benzylthiourea, 5.87 g of ethyl bromopyruvate and 50 ml of ethanol, giving the title compound as pale yellow needles.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[NH2:30].C(N(C(C)C)CC)(C)C.C(O)CC(C)C>C(OCC)(=O)C>[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[NH:30][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: NC1Cc2ccccc2C1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)CCO
Solvent: CCOC(C)=O
Product: Nc1nc(NC2Cc3ccccc3C2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
A mixture of 1.0 g of 2-chloroadenosine, 1.2 g of 2-indanylamine, and 1.6 ml of diisopropylethylamine and 1.0 ml of isoamyl alcohol is refluxed for 16 hours. The reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. After drying over magnesium sulfate the solvent is removed in vacuo and the residue is chromatographed on silica gel with 10:1 methylene chloride/ammonia saturated methanol as the eluent. The resulting product is recrystallized from methanol to afford 2-(2-indanylamino)-adenosine melting at 129°-132°.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[F:14])C.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:19]([O:18][C:16]([NH:15][CH:5]([CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[F:14])[C:4]([OH:23])=[O:3])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(Cc1cc(C)ccc1F)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(F)c(CC(NC(=O)OC(C)(C)C)C(=O)O)c1

Procedure:
To a solution of 2-tert-butoxycarbonylamino-3-(2-fluoro-5-methylphenyl)-propionic acid ethyl ester (7.7 g, 24 mmol) in 60 mL of THF and 60 mL of MeOH is added lithium hydroxide (1.5 g, 35.6 mmol) in H2O (15 mL). The reaction is stirred at room temperature for 1.5 hr after which time 1M HCl is added until the mixture reaches pH 4. The product is extracted into dichloromethane and the combine the organic layers are dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15](I)=[C:11]3[N:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CSC1N=C([Sn](CCCC)(CCCC)CCCC)C=CN=1.[CH:44]1([NH:49][C:50]2[N:55]3N=C(C4C=CC=CC=4)[C:58]([C:59]4C=CN=C(SC)[N:60]=4)=[C:54]3N=CN=2)[CH2:48][CH2:47][CH2:46][CH2:45]1.C1(NC2N3N=C(C4C=CC=CC=4)C=C3N=CN=2)CCCC1.ClC1C=C(C=CC=1)C(OO)=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.ClCCl.C1(N)CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)(=O)C>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]([C:59]4[CH:58]=[CH:54][N:55]=[C:50]([NH:49][CH:44]5[CH2:45][CH2:46][CH2:47][CH2:48]5)[N:60]=4)=[C:11]3[N:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Ic1c(-c2ccccc2)nn2c(NC3CCCC3)ncnc12
Reactant: CSc1nccc(-c2c(-c3ccccc3)nn3c(NC4CCCC4)ncnc23)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Agent: NC1CCCC1
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1ccc(-c2nn3c(NC4CCCC4)ncnc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
N-Cyclopentyl-8-iodo-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine (80 mg, 0.20 mmol) was dissolved in anhydrous toluene (5 mL). To this solution was added 2-(methylsulfanyl)-4-(tributylstannyl)pyrimidine (100 mg, 0.24 mmol,) and dichlorobis(triphenylphosphine)palladium (II] (14 mg, 0.1 equiv) and the resulting mixture heated at 100° C. for 24 hours. Ethyl acetate and water were added to the reaction mixture. The phases were separated and the organic phase washed with water, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate:hexane 1:1) gave an inseparable mixture of the desired N-cyclopentyl-8-[2-(methylsulfanyl)-4-pyrimidinyl]-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine contaminated with N-cyclopentyl-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine. This mixture was dissolved in dichloromethane (15 mL) and 3-chloroperoxybenzoic acid (113 mg, 57–86%) was added. The resulting reaction mixture was stirred at room temperature for 1 hour. Dichloromethane and saturated aqueous potassium carbonate were added and the phases separated. The organic phase was washed with additional saturated aqueous potassium carbonate, water, dried over magnesium sulfate, filtered and concentrated to give a foam. This foam was dissolved in cyclopentylamine and the solution was heated at 60° C. for 3 hours. The mixture was concentrated in vacuo and the residue purified by silica gel chromatography (ethyl acetate:hexane 1:1) to give 20 mg (23% for 3 steps) of N-cyclopentyl-8-[2-(cyclopentylamino)-4-pyrimidinyl]-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine as a white foam. 1H-NMR (CDCl3): δ 8.39 (s, 1H), 8.28 (d, 1H), 7.67 (m, 2H), 7.46 (3H), 6.71 (d, 1H), 5.01 (d, 1H), 4.64 (m, 1H), 3.80 (m, 1H), 1.2–2.3 (m, 16H); MS m/z 441 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[C:3]([C:11]2[S:12][C:13]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)c3ccccc3)s2)noc1C(F)(F)F
Yield: 70 %

Procedure:
Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and benzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (10 then 20%) as eluant to afford product as a colorless solid (118 mg, 70%). 1H NMR (CDCl3) 2.33 (d, J=1.3, 3 H), 7.43-7.59 (m, 4 H), 7.62 (d, J=4.0, 1 H), 7.80-7.83 (m, 2 H). 13C NMR 7.9, 118.7 (q, J=271), 128.8, 128.9, 129.4, 133.0, 134.8, 136.3, 137.7, 145.8, 155.5 (q, J=40), 157.9, 188.0. 19F NMR −63.1. LC/MS 7.29 min, [M+1]+ 338.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[C:25]([O:32][CH3:33])=[CH:26][C:27]([CH2:30][OH:31])=[N:28][CH:29]=1.[OH-].[Na+]>C(Cl)Cl>[Br:23][C:24]1[C:25]([O:32][CH3:33])=[CH:26][C:27]([CH:30]=[O:31])=[N:28][CH:29]=1
Reactant: COc1cc(CO)ncc1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(C=O)ncc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
Dess-Martin reagent (1.14 g) was added at 0° C. to a methylene chloride (5 mL) solution of (5-bromo-4-methoxypyridin-2-yl)methanol (450 mg) synthesized by the method described in Organic Process Research & Development 2000 4,473. The reaction solution was agitated at 0° C. for 1 hour and further agitated at room temperature for 1 hour. 1N sodium hydroxide solution was added to the reaction solution, the organic layer was separated, and washed with a saturated sodium chloride solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 1:1), and 300 mg (67%) 5-bromo-4-methoxypyridine-2-carbaldehyde was obtained. The physical properties of the compound are as follows.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[C:23]4[O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:31])[CH:5]=[CH:4][N:3]=1.[OH:32][CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1>>[CH:21]1[C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][C:23]=2[C:18]([C:16]([NH:15][C:13]2[CH:12]=[CH:11][C:10]([CH3:31])=[C:9]([CH:14]=2)[NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:32][CH:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[N:7]=2)=[O:17])=[CH:19][CH:20]=1
Reactant: CN1CCC(O)CC1
Reactant: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1Nc1ccnc(Cl)n1
Product: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1Nc1ccnc(OC2CCN(C)CC2)n1

Procedure:
Using an analogous procedure to that described in Example 8, 2-chloro-4-[5-(4-dibenzofuranylcarbonylamino)-2-methylanilino]pyrimidine was reacted with 4-hydroxy-N-methylpiperidine. The reaction mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent followed by increasingly polar mixtures of methylene chloride and methanol containing 1% aqueous ammonium hydroxide solution. There was thus obtained the title compound; NMR Spectrum: (DMSOd6) 1.56 (m, 2H), 1.84-2.1 (m, 4H), 1.97 (s, 3H), 2.17 (s, 3H), 2.53 (m, 2H), 4.78 (m, 1H), 6.22 (d, 1H), 7.18 (d, 1H), 7.38-7.58 (m, 4H), 7.77 (d, 1H), 7.86 (m, 2H), 7.93 (d, 1H), 8.19 (d, 1H), 8.28 (d, 1H); Mass Spectrum: M+H+ 507.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[N:16]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH2:17]1.[Na+].[Cl-]>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:26]2[CH2:25][CH2:24][CH:23]([N:16]3[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH2:17]3)[CH2:28][CH2:27]2)[N:7]=1
Reactant: OC1CCCN(C2CCNCC2)C1
Reactant: Clc1ncnc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OC1CCCN(C2CCN(c3ncnc(Cl)n3)CC2)C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
200 mg (1.27 mmol) of 2,4-dichloro-1,3,5-triazine are dissolved in 2 ml of acetonitrile, cooled to 0° C., 176 μl of triethylamine and 223 mg (1.27 mmol) of 1,4′-bipiperidinyl-3-ol are added. The reaction mixture is stirred at 0° C. for 2 h and subsequently at room temperature for 48 h. Sat. NaCl solution is subsequently added, and the mixture is extracted three times with ethyl acetate. The combined organic phases are washed with 1N NaOH and water, dried over Na2SO4 and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:17]([NH:24][C@@H:25]([CH2:27][C:28](O)=[O:29])[CH3:26])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:28](=[O:29])[CH2:27][C@H:25]([NH:24][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH3:26])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: C[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Product: C[C@H](CC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)NC(=O)OC(C)(C)C

Procedure:
tert-Butyl(R)-4-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-4-oxobutan-2-ylcarbamate was prepared from (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol and Boc-D-beta-homoalanine using the conditions described in Example 1, Step 2. MS (ESI+)=425.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([OH:21])[C:18]([CH3:22])=[CH:17][C:16]=2C2(C3C=CC=CC=3)C3C(=CC=CC=3)NC2=O)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(S(Cl)(=O)=O)=CC=1)(C)(C)C.NC1C=CC(C)=C(O)C=1>ClCCl.N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:22])=[C:19]([OH:21])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C2(c3ccccc3)C(=O)Nc3ccccc32)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1O
Agent: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(N)cc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1O
Reaction time: 8 h
Yield: 78 %

Procedure:
As another non-limiting example, 4-tert-butyl-N-[5-hydroxy-4-methyl-2-(2-oxo-3-phenyl-2,3-dihydro-1H-indol-3-yl)-phenyl]-benzenesulfonamide (compound 1430) was synthesized by adding dropwise 4-tert-butyl-benzenesulfonyl chloride (8 g, 34 mmol) in 5 mL dichloromethane to a stirring solution of 5-Amino-2-methyl-phenol (4 g, 32 mmol) in 20 mL pyridine and letting the mixture spin overnight at room temperature. The resulting mixture was concentrated in vacuo and the product was purified by column chromatography to yield 8 g (78%) of 4-tert-butyl-N-(3-hydroxy-4-methyl-phenyl)-benzenesulfonamide. A mixture of 3-hydroxy-3-phenyl-1,3-dihydro-indol-2-one (3.9 g, 17 mmol), 4-tert-butyl-N-(3-hydroxy-4-methyl-phenyl)-benzenesulfonamide (7 g, 22 mmol) and p-toluenesulfonic acid (6.5 g, 32 mmol) in dichloroethane was refluxed for 12 hours. The resulting mixture was cooled to room temperature to yield a colorless solid. The solid was filtered and purified using column chromatography to yield 8 g (88%) of the desired product (compound 1430).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20]Cl)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][N:22]3[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CNCCNC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CCl)c3ccccc32)cc1
Product: Cc1ccc(S(=O)(=O)n2cc(CN3CCCNCC3)c3ccccc32)cc1

Procedure:
Using essentially the same procedure as described in example 127, 1-(4-methylbenzenesulfonyl)-3-chloromethyl-1H-indole was reacted with homopiperazine to obtain the above derivative.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=O)=[C:20]([N+:23]([O-:25])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.O.O.C([O-])(=O)C.[Na+]>O1CCCC1.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]4=[CH:26][O:25][N:23]=[C:20]4[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nocc4c3O2)cc1
Reaction time: 48 h

Procedure:
19.7 g (87.4 mmole) of stannous chloride dihydrate was added to a solution of 6.62 g (17.5 mmole) of (2R)-(8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl 4-methylbenzenesulfonate in 400 mL of 1:1 tetrahydrofuran/methanol followed by the addition of 23.8 g (0.17 mole) of sodium acetate trihydrate. The mixture was stirred under nitrogen for a period of 48 hours. The solvent was removed in vacuo and replaced with an equal amount of methylene chloride and the solution was washed with 400 mL portions of saturated aqueous sodium bicarbonate and saturated brine and dried over magnesium sulfate. After the solution was filtered and concentrated in vacuum, the crude oil obtained was column chromatographed on silica gel with methylene chloride as eluant and the product fractions were combined and evaporated in vacuum to give 4.47 g (71%) of the (R)-enantiomer of the title compound as a light yellow solid, m.p.109-110° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].[F:11][C:12]1[CH:20]=[CH:19][C:18](I)=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:11][C:12]1[CH:20]=[CH:19][C:18]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1cc(I)ccc1F
Reactant: C#Cc1cncc(OC)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(C(N)=O)c2)c1
Temperature: 60 °C
Yield: 88.8 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (70 mg, 0.10 mmol), copper (I) iodide (38 mg, 0.20 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (350 mg, 2.6 mmol) to a solution of 2-fluoro-5-iodobenzamide, (prepared as described in PREPARATION 44), (0.54 g, 2.0 mmol) in triethylamine (3.1 mL, 30.3 mmol) and heat at 60° C. for 18 h. Cool to room temperature and concentrate. Purify by silica gel chromatography, eluting with 100:0 to 0:100 dichloromethane:ethyl acetate, to give the title compound as a white solid (480 mg, 68%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.O.[CH3:17][N:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([N:18]([CH3:19])[CH3:17])=[N:21][CH:22]=2)[C:11]=1[CH3:12]
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccc(N(C)C)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2-(N,N-dimethylamino)pyridine-5-boronic acid hydrate (0.335 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 1.3 h to give 5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-N,N-dimethylpyridin-2-amine as a yellow solid. Mass Spectrum (ESI) m/e=344.1 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[C:10]1([CH3:29])[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl>C(Cl)CCl>[Cl:5][CH2:6][C:7]([C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[CH2:28][CH:20]([NH:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([CH3:29])=[CH:15][CH:14]=1)(=[O:17])=[O:18])[CH2:21]2)=[O:8]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(S(=O)(=O)NC2Cc3ccccc3C2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)NC2Cc3ccc(C(=O)CCl)cc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25.4 g (0.19 mol) of anhydrous aluminium chloride are suspended in 80 ml of ethylene chloride and 11.1 g (0.095 mol) of chloroacetyl chloride are added. 22.8 g (0.079 mol) of 2-p-toluenesulphonamido-indane are then added and the mixture is stirred for 2 hours at room temperature. The product is then decomposed by means of ice and hydrochloric acid and the reaction product is isolated from the organic phase and recrystallised from ethyl acetate/cyclohexane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[C:7]([Cl:13])[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[Cl:20].[Li]CCCC.CN([CH:29]=[O:30])C>C1COCC1>[Cl:13][C:7]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]([Cl:20])[C:4]2[C:9](=[C:10]([F:12])[CH:11]=[C:2]([CH:29]=[O:30])[CH:3]=2)[N:8]=1
Reactant: Fc1cc(Br)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)c2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Temperature: -72 °C
Reaction time: 0.33 h

Procedure:
A yellow solution of 6-bromo-2,4-dichloro-8-fluoro-3-phenylquinoline (1.01 g, 2.72 mmol, Intermediate 46, step a) in THF (10 mL) was stirred at −72° C. while n-BuLi (1.15 mL, 2.59 M in hexane, 2.99 mmol) was added dropwise under argon. The resulting homogeneous dark solution was stirred at −72° C. for 20 min, and was then treated with DMF (0.273 mL, 3.53 mmol) dropwise. The homogeneous dark reaction was stirred at −72° C. for 25 min, and was then removed from the cold bath and stirred under ambient conditions for 30 min. The dark homogeneous solution was quenched with 5 M NH4Cl (10 mL) and the aqueous layer was extracted with EtOAc (3×8 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated, and the residue was flash chromatographed with a 20% DCM/heptane to 100% DCM gradient to provide the title compound as a yellow powder.