Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:33]=[CH:32][C:19]3[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=3[CH:17]=2)[C:4](=[O:34])[C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>[Pd].C(O)C.C(OCC)(=O)C>[CH2:30]([N:20]1[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]2[CH:17]=[C:16]([O:15][CH2:14][CH2:13][CH2:12][N:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:2][CH:3]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:4]3=[O:34])[CH:33]=[CH:32][C:19]1=2)[CH3:31]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)c(-c4ccccc4)c(Cl)c4ccccc43)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN3C(=O)C(c4ccccc4)Cc4ccccc43)ccc21
Reaction time: 6 h
Yield: 55.9 %

Procedure:
10% Palladium on carbon(20 mg) was added to an ethanol/ethyl acetate solution (1:1, 4 ml) of 7-[3-(4-chloro-2-oxo-3-phenyl-2H-quinoline-1-yl)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.19 g). The mixture was subjected to catalytic reduction at 50° C. under normal pressure for 6 hours. The reaction mixture was subjected to celite filtration to remove the catalyst. The filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether/hexane, thereby obtaining the title compound(0.1 g) as a white powder.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([N:11]([C:25](=[O:34])[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)[NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][CH3:23])([CH3:10])[CH3:9])(C)(C)C.[F-].[CH2:38]([N+](CCCC)(CCCC)CCCC)CCC.CCOCC>C1COCC1>[CH2:22]([C:15]1[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([NH:12][N:11]([C:8]([CH3:9])([CH3:10])[CH2:7][OH:6])[C:25](=[O:34])[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)=[CH2:38])[CH3:23]
Reactant: CCc1c(OC)cccc1C(=O)NN(C(=O)c1cc(C)cc(C)c1)C(C)(C)CO[Si](C)(C)C(C)(C)C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(NN(C(=O)c1cc(C)cc(C)c1)C(C)(C)CO)c1cccc(OC)c1CC
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 67 %

Procedure:
2.78 g (0.00526 mol) of 2-ethyl-3-methoxy-benzoic acid N′-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-N′-(3,5-dimethyl-benzoyl)-hydrazide were dissolved in 24 mL of THF. The mixture was cooled in an ice bath and 6.0 mL (0.006 mol) of a 1 M tetrabutyl ammonium fluoride solution in THF were added. The reaction was stirred at room temperature for 5-6 hours, and then 100 mL of Et2O were added and the reaction mixture was poured into ice water in a separatory funnel. The aqueous layer was further extracted twice with 25 mL of Et2O and the total ether layer was dried and concentrated. TLC of the product showed a new product (Rf 0.20) below some of the starting material. The product was purified by chromatography, eluting with 40-50% ethyl acetate/hexane to yield 1.42 g of pure 3,5-dimethyl-benzoic acid N′-[1-(2-ethyl-3-methoxy-phenyl)-vinyl]-N-(2-hydroxy-1,1-dimethyl-ethyl)-hydrazide. (67% yield). TLC: Rf=0.20. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.1-6.8 (m, 5H), 6.0 (d, 1H), 4.3 (d, 1H), 3.78 (s, 3H), 3.5 (d 1H), 2.4 (d, 1H) 2.29 (s, 6H), 2.2 (d, H), 1.56 (s, 3H), 1.45 (s, 3H), 1.00 (t, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)[CH2:10][NH:9][CH2:8][C:7]=2[CH:29]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:17][CH2:18][C@H:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:20][CH2:21]3)[CH2:10][N:9]([C:37](=[O:39])[CH3:38])[CH2:8][C:7]=2[CH:29]=1
Reactant: CC(=O)Cl
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](Oc4ccccc4)CC3)n1-2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](Oc3ccccc3)CC2)C1
Reaction time: 18 h

Procedure:
To a solution of trans-8-chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.071 g, 0.18 mmol) and triethylamine (0.048 ml, 0.35 mmol) in dichloromethane was added acetyl chloride (0.013 ml, 0.18 mmol) at room temperature. Stirring for 18 h was followed by partitioning between 1 M aqueous sodium hydroxide solution (50 ml) and dichloromethane (50 ml). The organic layer was separated. The aqueous layer was extracted with one 50-ml portion of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.039 g, 54%) as white solid.
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:3].[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[C:21]=1[OH:22])[CH:17]=O>>[OH:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:4](=[O:12])[CH:2]([CH3:1])[CH3:3])[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[C:21]=1[OH:22]
Reactant: CC(C)C(=O)Cc1ccccc1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: CC(C)C(=O)C(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1

Procedure:
The procedure described in Example 1 was repeated by using 2.96 g of 2-methyl-4-phenyl-3-butanone and 2.4 g of 3,4-dihydroxy-5-nitrobenzaldehyde. Yield 0.52 g, mp 151°-156° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[I-:12].[K+].Cl>[Cu](I)I.CN(C)P(N(C)C)(N(C)C)=O>[I:12][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: [I-]
Agent: I[Cu]I
Agent: Cl
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Ic1ccc2ccccc2c1
Temperature: 160 °C
Yield: 100 %

Procedure:
2-Bromonapthalene (50.0 g, 242.0 mmol), copper iodide (230.0 g, 1210.0 mmol, 5 eq.), potassium iodide (200 g, 1210.0 mmol, 5 eq.) and hexamethylphosphoramide (500 mL) were stirred and heated to 160° C. for 8 h. This was cooled and added to 1N HCl (250 mL) then toluene (300 mL) and ether (300 mL) and the mixture filtered through celite. The organic layer was separated and washed with water (2×250 mL) dried over magnesium sulphate and concentrated to afford 2-iodonaphthalene (61.5 g, 59%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.46-7.52 (2H, m, ArH, 7.55-7.58 (1H, m, ArH), 7.68-7.74 (2H, m, ArH), 7.76-7.82 (1H, m, ArH), 8.22-8.26 (1H, m, ArH).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>>[CH3:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:25]1
Reactant: COC1CCCNC1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC1CCCN(c2nnc(N)nc2-c2ccccc2)C1
Yield: 4.2 %

Procedure:
6-(3-Methoxypiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (33 mg, 4%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.70 g, 2.78 mmol), K2CO3 (0.80 g, 5.85 mmol) and 3-methoxy piperidine HCl (0.52 g, 3.34 mmol) according to the general procedure of Example 2.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:44])=[O:43])=[CH:38][CH:37]=1>CN(C=O)C>[CH3:44][S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[C:6]2[CH3:14])=[CH:37][CH:38]=1)=[O:43]
Reactant: CS(=O)c1ccc(CBr)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)=O)cc1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.512 g, 2.51 mmol) in dry DMF (5.6 ml) at room temperature is treated with BEMP (1.17 ml, 4.01 mmol) dropwise. The reaction mixture is stirred at room temperature for 80 minutes and then treated with 1-bromomethyl-4-methanesulfinyl-benzene (0.934 g, 4.01 mmol). After stirring at room temperature for a further 2 hours, the reaction mixture is partitioned between ethyl acetate/ether (300 ml of a 1:1 mixture) and water (30 ml). The organic portion is separated and washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with DCM/methanol (10:1) to yield the titled product. (MH+ 357)
Reaction SMILES: [Na].CO.[Cl:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]([CH3:16])=[N:14][C:13]([OH:17])=[N:12]2)[CH:8]=[CH:9][CH:10]=1.Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CS(C)=O>[Cl:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]([CH3:16])=[N:14][C:13]([O:17][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:25])=[N:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1nc(O)nn1-c1cccc(Cl)c1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)C(C)Oc1nc(C)n(-c2cccc(Cl)c2)n1
Yield: 68 %

Procedure:
The process was carried out as was Example 9 above, starting with 0.8 g of sodium, 20 ml of methanol, 75 ml of dimethylsulfoxide, 7.8 g of 1-(3-chlorophenyl)-3-hydroxy-5-methyl-1,2,4-1H-triazole and 6.7 g of ethyl 2-bromopropionate. The yield was 7.8 g of the desired product, an oil.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:9][C:10]([F:39])([F:38])[C:11]1[CH:37]=[CH:36][C:14]([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[F:39][C:10]([F:9])([F:38])[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:30][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:31])=[O:32])=[O:21])=[CH:36][CH:37]=1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Reactant: CCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
In a stream of nitrogen and at 0° C. 0.16 ml (1.10 mmol) of hexanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 451 mg (1.00 mmol) of 3-(4-trifluoromethylbenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 8 and 249 mg (2.00 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 439 mg (yield: 80.0%) of the title compound.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:34])[CH:8](CN(CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:9][C:10]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:5])([CH3:4])[CH3:3].C([N:37](CC)CC)C>C(O)C.[Pd]>[C:2]([O:6][C:7](=[O:34])[CH:8]([NH2:37])[CH2:9][C:10]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)C(CN(Cc1ccccc1)Cc1ccccc1)CC1(C(=O)O)CCCC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)C(N)CC1(C(=O)O)CCCC1

Procedure:
3-(1-Carboxycyclopentyl)-2-(dibenzylaminomethyl)propanoic acid t-butyl ester hydrochloride (20.0 g; 41 mmol) in ethanol (160 ml) and triethylamine (2.0 ml) was hydrogenated over palladium (from 20% Pd(OH)2 /C; 20 g) at 60 p.s.i. (4.1 bar). After eighteen hours the mixture was filtered through arbicel, the solvent evaporated and the residue dried azeotropically with toluene. The required primary amino acid triethylamine salt, containing one mole equivalent of triethylamine hydrochloride was thus obtained as a white solid (16.21 g).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([OH:37])=O)[CH:33]=2)[N:28]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:27]=1.[NH2:57][C@@H:58]1[CH2:63][CH2:62][CH2:61][N:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:59]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([NH:57][C@@H:58]3[CH2:63][CH2:62][CH2:61][N:60]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:59]3)=[O:37])[CH:33]=2)[N:28]([C:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: O=C(O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc3c(c2)c(Br)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (3.1 mmol) was added to a suspension of 3-bromo-1-trityl-1H-indazole-5-carboxylic acid (1 g) in DMF (5 mL) and was stirred at room temperature for 15 minutes. A solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (415 mg) in DMF (5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.72 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[N:6]2[CH2:11][CH2:12]O.O=S(Cl)[Cl:24]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[N:6]2[CH2:11][CH2:12][Cl:24]
Reactant: Nc1ncnc2c1nc(CCc1cccnc1)n2CCO
Reactant: O=S(Cl)Cl
Product: Nc1ncnc2c1nc(CCc1cccnc1)n2CCCl
Reaction time: 12 h
Yield: 8 %

Procedure:
0.45 g of 2-(6-amino-8-(2-pyridin-3-yl-ethyl)-purin-9-yl)ethanol were cooled to −20° C. and 6 ml of SOCl2 were added. The temperature was gradually risen to 50° C. and the mixture was stirred at this temperature for 12 hours. The excess of SOCl2 was evaporated and the residue was taken up in dichloromethane washed with saturated aqueous NaHCO3 dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (CHCl3:MeOH 50:1) to give 40 mg (8%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:24]#[N:25])=[CH:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=3)[N:14]=[C:13]([CH3:22])[C:12]=2[CH3:23])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)O1.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.CN(C=O)C>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:22])[C:12]([CH3:23])=[C:11]2[N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:34]3[CH:35]=[N:36][NH:37][CH:38]=3)[CH:10]=2)[C:6]([C:24]#[N:25])=[CH:7]1
Reactant: Cc1nc2ccc(Cl)cc2c(-n2cc(C#N)c3ccc(Br)cc32)c1C
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: CN(C)C=O
Product: Cc1nc2ccc(Cl)cc2c(-n2cc(C#N)c3ccc(-c4cn[nH]c4)cc32)c1C
Temperature: 25 °C

Procedure:
A solution of 6-bromo-1-(6-chloro-2,3-dimethylquinolin-4-yl)-1H-indole-3-carbonitrile (0.2 g, 0.49 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.188 g, 0.97 mmol), and Pd(PPh3)4 (0.056 g, 0.049 mmol) in a 2M aqueous solution of Na2CO3 (1.5 mL) and DMF (5 mL) was stirred at 100° C. overnight. After this time the reaction mixture was allowed to cool to rt and poured into ice water. The resulting precipitate was filtered and purified via flash column chromatography to give 1-(6-chloro-2,3-dimethylquinolin-4-yl)-6-(1H-pyrazol-4-yl)-1H-indole-3-carbonitrile. 1H NMR (500 MHz, chloroform-d) δ ppm 8.02 (1H, d, J=9.0 Hz), 7.82 (1H, d, J=8.3 Hz), 7.64 (2H, m), 7.58 (2H, m), 7.49 (1H, dt, J=8.3, 0.7 Hz), 6.96 (1H, d, J=2.4 Hz), 6.82 (1H, s), 2.76 (3H, s), 2.01 (3H, s). Mass Spectrum (ESI) m/e=398 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=3)[S:8][C:7]=2[CH:33]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[S:8][C:7]=2[CH:33]=1
Reactant: COC(=O)COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: COC(=O)COc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl][4-carbomethoxymethoxyphenyl]methanone (250 mg, 0.54 mmol) was converted to the title compound by the procedure of Example 3 using 0.24 mL (3.25 mmol) of ethanethiol and 505 mg (3.79 mmol) of aluminum chloride except the total reaction time was 0.5 hours and the workup of the reaction went as follows: the mixture was poured into a mixture of brine/ethyl acetate and extracted with ethyl acetate. The residual solid remaining in the reaction vessel was dissolved in a minimal amount of methanol and added to the ethyl acetate extracts. The combined organic extracts were washed thoroughly with brine, dried (magnesium sulfate), filtered, and concentrated. Purification by radial chromatography (2 mm, silica gel, 40% methanol in ethyl acetate) gave 140 mg methyl ether cleaved product as a yellow solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:8]([NH2:21])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:22][C:11]1[N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:21])[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=2
Reactant: CCCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
2-(Butyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (9.45 g) was dissolved in chloroform (50 ml) and cooled to 0° C. (ice-bath). To this solution was added portion wise N-bromosuccinimide (6.07 g) keeping the temperature below 3° C. This gave a dark green solution, stirred at 2.5° C. for 30 mins. before allowing to warm to room temperature and then stirring for 6 hours. The reaction mixture was then washed with water (100 ml, twice). Organic phase was dried/separated using a hydrophobic frit and evaporated to give a dark brown gum which was purified by silica chromatography (120 g) (ISCO) using a gradient elution of 0-50% ethyl acetate:cyclohexane to afford the title compound as a pale yellow solid (8.37 g).
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.CSC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=O)([CH3:21])[CH3:20])=[CH:14][CH:13]=1.C[O-].[Na+]>C(#N)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C:19]([CH3:21])([CH3:20])[CH2:22][C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[CH2:7][O:6]2)=[CH:16][CH:17]=1
Reactant: CC(C)(Cc1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CSC
Product: CC(C)(Cc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Reaction time: 12 h
Yield: 85.1 %

Procedure:
A solution of 59.2 g (0.47 mol) of dimethyl sulphate and 32 g (0.517 mol) of dimethyl sulphide in 270 ml of acetonitrile is stirred at room temperature for 5 days. A solution of 81.5 g (0.2655 mol) of 4-chlorophenyl 4-chlorophenyl-tert.-butyl ketone in 80 ml of acetonitrile is then added dropwise at 20° to 25° C. in the course of about 2 hours. 28.7 g (0.53 mol) of sodium methylate are added at the same temperature. The entire reaction mixture is subsequently stirred for 12 hours and is then concentrated in vacuo. The residue is stirred overnight with a mixture of 200 ml of ethyl acetate and 150 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 72.6 g (85.2% of theory) of crude 2-(4-chlorophenyl)-2-(4-chlorophenyl-tert.-butyl)-oxirane are obtained and are further reacted directly. ##STR156##
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].O1[CH2:15][CH2:14]OCC1>>[C:2]1([C:2]2[CH:7]=[CH:6][C:14]([CH3:15])=[CH:4][CH:3]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: C1COCCO1
Agent: [Cs+]
Agent: [F-]
Product: Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 102 mg (0.15 mmol) of {[(t-Bu)2P(OH)]PdCl2}2 (from Experiment 7), 1.13 g (10.0 mmol) of chlorobenzene, 2.04 g (15.0 mmol) of MeC6H4B(OH)2 and 4.56 g (30.0 mmol) of CsF in 30.0 mL of 1,4-dioxane. The resulting mixture was refluxed for 15 h until the starting material was completely consumed as judged by TLC. The reaction was cooled to room temperature, transferred to a separatory funnel, and diluted with 300 mL of hexane. The layers were separated, and organic layer was washed with H2O (2×100 mL), brine (100 mL), and dried over mgSO4, filtered, and the hexane and dioxane removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 1.58 g (94% yield) of 4-phenyltoluene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH2:13])[CH:5]=1.CCN(CC)CC.[Cl:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH:13][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][Cl:22])[CH:5]=1
Reactant: CCOc1cc(N)cc(C(=O)OC)c1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(NC(=O)CCCCl)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 113.9 %

Procedure:
3-Amino-5-ethoxy-benzoic acid methyl ester (D49) (4.0 g, 20.5 mmol, 1 equiv) was suspended in CH2Cl2 (40 ml) and treated at room temperature with NEt3 (2.32 g, 23 mmol, 1.1 equiv). The resulting solution was cooled to 0° C. and 4-chlorobutyryl chloride (3.1 g, 22 mmol, 1.1 equiv) was added dropwise. The resulting mixture was stirred at 0° C. for 3 h then allowed to warm to room temperature. The solution was washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo to give of 3-(4-chloro-butanoylamino)-5-ethoxy-benzoic acid methyl ester (D51) (7.0 g, 115%) as a brown oil.