Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[Br:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(O)(=O)/C=C/C(O)=O>C1C=CC=CC=1.CCOCC.CO.CC(C)=O.C(O)C>[Br:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][CH:17]=1)[O:8][C@@H:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cccc(Br)c1
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)/C=C/C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CC(C)=O
Solvent: CCO
Product: CN1CC[C@@H](Oc2cccc(Br)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4.78 g of cis-1-methyl-3-phenyl-4-piperidinol, 4.76 g of m-bromophenol, 7.21 g of triphenylphosphine and 125 ml of anhydrous benzene is added, dropwise at 5°-10° C. under nitrogen over a 45-minute period, a solution of 4.79 g of diethyl azodicarboxylate in benzene (100 ml). After the addition is complete the mixture is stirred overnight at room temperature, filtered and concentrated in vacuo. The residue is triturated overnight in a stoppered flask with hexane (250 ml). The hexane is decanted and the gummy solid triturated with 2:1/petroleum ether:ether solution to give a well-formed solid. The solid is washed with 2:1/petroleum ether:ether. The filtrates are combined and concentrated in vacuo to give a residue which is dissolved in ether (250 ml). The ether solution is extracted with 2 N hydrochloric acid (1×100 ml, 1×50 ml). The acid extracts are washed with ether (50 ml) and extracted with dichloromethane (1×100 ml, 1×50 ml). The dichloromethane extracts are washed with 10% aqueous sodium hydroxide solution (100 ml), water (100 ml), saturated sodium chloride solution (100 ml), dried overnight over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford an orange gum. Chromatography of the gum on 230 g of silica gel, using 25% methanol/acetone solution as solvent, gives a yellow gum. The latter is dissolved in ether (75 ml) and treated dropwise with a solution of 1.33 g of fumaric acid in a mixture of 30 ml of absolute ethanol and 105 ml of ether. After stirring overnight the mixture is filtered and the solid washed with ether and dried to afford a salt. Recrystallization from isopropanol (35 ml) affords product as a colorless, crystalline solid, mp 158.5°-160.5° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.Cl[C:14]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:14]2[CH:21]=[CH:20][C:19]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:18][C:15]=2[C:16]#[N:17])[CH:7]=1
Reactant: N#Cc1cc(S(=O)(=O)c2ccccc2)ccc1Cl
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Product: N#Cc1cc(S(=O)(=O)c2ccccc2)ccc1Oc1cc(Cl)cc(CC(=O)O)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 18 step (iv) and the product from step (i).
Reaction SMILES: [C:1]([CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([O:17]C)[CH:10]=[CH:11][C:12]=2[O:15]C)[CH2:7][S:6]1)([O:3][CH3:4])=[O:2]>CC#N.O>[C:1]([CH:5]1[CH2:14][C:13]2[C:12](=[O:15])[CH:11]=[CH:10][C:9](=[O:17])[C:8]=2[CH2:7][S:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1Cc2c(OC)ccc(OC)c2CS1
Solvent: O
Solvent: CC#N
Product: COC(=O)C1CC2=C(CS1)C(=O)C=CC2=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a stirred solution of isothiochroman from step 1 above (253 mg, 0.94 mmol) in 3 ml of CH3CN was added dropwise a solution of ceric ammonium nitrate (1.550 g, 283 mmol) in 3 ml of H2O. The reaction mixture was stirred at 0° C. for 10 minutes and then at room temperature for 10 minutes, followed by extraction with CH2Cl2 (10 ml×3). The combined organic layers were washed with brine and water, dried over MgSO4, and then concentrated to a yellow residue (213 mg, 0.89 mmol) in 95% yield, which was found to be pure by H1NMR. 1H NMR (300 MHz, CDCl3) d:2.90 (m, 2H, HCHa,eCHC=O), 3.56 (m, 2H, HCHae--S), 3.73 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.75 (m, 1H, HC--S), 6.75 (m, 2H, ArH). 13C NMR (75.44 MHz, CDCl3) δ:22.2, 26.0, 37.4, 52.8, 136.2, 137.0, 140.0, 140.5, 172.0 (CO ester), 185.8, 187.0 (CO quinones). IR: (neat) 2956, 1736, 1658, 1607, 1442, 1409 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.CC([O-])(C)C.[K+].Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:3]=1
Reactant: Clc1ccccn1
Reactant: Oc1cncc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cncc(Oc2ccccn2)c1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 5-chloro-pyridin-3-ol (1000 mg, 7.72 mmol), potassium tert-butylate (866 mg, 7.72 mmol) and 2-chloro-pyridine (730 g, 7.72 mmol) in DMF (6 mL) was stirred at 130° C. for 3 h. The solvent was removed in vacuo and the residue was partitioned between DCM (50 mL) and 2 N NaOH solution (50 mL). After extraction of the aqueous layer with DCM (6×50 mL) the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with mixtures of hexane and EA) to give the title compound. MS (m/z): 207.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[CH2:15]([N:6]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
To a stirred solution of 4-bromoaniline (500 mg, 2.92 mmol, 1.0 eq) and K2CO3 (1.21 g, 8.76 mmol, 3.0 eq) in CH3CN (10 mL) was added benzyl bromide (1.24 g, 7.30 mmol, 2.5 eq) and the mixture stirred for 16 h at 80° C. and cooled to RT. K2CO3 was filtered out, the filtrate concentrated, the resulting crude product was purified by CC using EtOAc/PE (1:19) to get N,N-dibenzyl-4-bromoaniline (900 mg, 87%; TLC system: EtOAc/PE (3:7), Rf: 0.7).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-])=[O:2].[Cl-].[NH4+]>[Zn]>[CH3:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:1][OH:2]
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: Cc1ccccc1NO

Procedure:
The 2-N(OZ)CO2CH3 -benzylbromide, methyl N-(2-bromomethylphenyl)-N-alkoxycarbamate, is prepared as described in both EP619301 and EP704430 in a 4 step sequence as shown in scheme B. As described in the aforementioned European patent applications o-nitrotoluene is reacted with ammonium chloride in the presence of zinc to provide N-2-methyl phenyl hydroxylamine (XI) as described in Organic Synthesis Collective Volume III, p.668. The hydroxylamine is acylated with methyl chloroformate to provide the methyl phenyl N-hydroxycarbamate (XII) which is alkylated, for example with dimethylsulfate (R is methyl), to provide (XIII) which is brominated under standard conditions such as N-bromosuccinimide in carbon tetrachloride in the presence of a catalyst such as benzoyl peroxide to afford the intermediate benzylbromide (XIV). ##STR9##
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[CH:11]=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[N:23]1[O:24][C:25]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)=[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=12>>[N:23]1[O:24][C:25]([NH:32][C:33]([N:15]2[CH2:14][CH2:13][C:12](=[CH:11][C:10]3[CH:18]=[CH:19][CH:20]=[C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([F:2])=[CH:22][CH:21]=4)[CH:9]=3)[CH2:17][CH2:16]2)=[O:34])=[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=12
Reactant: O=C(Nc1onc2ccccc12)Oc1ccccc1
Reactant: Fc1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Agent: Cl
Product: O=C(Nc1onc2ccccc12)N1CCC(=Cc2cccc(Oc3ccc(F)cc3)c2)CC1
Yield: 99.2 %

Procedure:
Following the procedure in Example 1, Step 6, 4-[3-(4-fluoro-phenoxy)-benzylidene]-piperidine hydrochloride (200 mg, 0.625 mmol) (Step 3) and phenyl benzo[c]isoxazol-3-ylcarbamate (175 mg, 0.688 mmol) were used to provide the title compound (275 mg). MS (APCI 10V) AP+ 444.2, 284.2, AP− 442.2; 1H NMR (400 MHz, CDCl3) δ ppm 2.46-2.52 (m, 2H) 2.57-2.63 (m, 2H) 3.56-3.62 (m, 2H) 3.66-3.72 (m, 2H) 6.39 (s, 1H) 6.78-6.87 (m, 2H) 6.91-6.96 (m, J=7.93, 1.25, 0.68, 0.57 Hz, 1H) 6.97-7.07 (m, 4H) 7.25-7.31 (m, 2H) 7.47 (dt, J=8.41, 0.77 Hz, 1H) 7.50-7.55 (m, 1H) 7.71 (s, 1H) 8.09 (d, J=7.90 Hz, 1H).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27](=O)[NH2:28])[CH:23]1[C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[N:31]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>C(COC)OC>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([C:27](=[S:2])[NH2:28])[CH:23]1[C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]2[CH:41]=[CH:40][N:39]=[CH:38]2)[N:31]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1cc(C2C(C(N)=O)CCN2C(=O)OC(C)(C)C)nc(-n2ccnc2)n1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C2C(C(N)=S)CCN2C(=O)OC(C)(C)C)nc(-n2ccnc2)n1
Temperature: 100 °C
Yield: 95.3 %

Procedure:
P2S5 (60 mg, 0.27 mmol) was added to a solution of 3-carbamoyl-2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (10 mg, 0.30 mmol) in dimethoxyethane (10 mL) at rt under an atmosphere of N2. The reaction mixture was heated to 100° C. for 2 h then cooled to rt. Water (20 mL) was added and the solution was extracted with DCM (3×30 mL). The combined organics were dried over Na2SO4, filtered and concentrated under vacuum to afford 100 mg (86%) of 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-3-thiocarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[I:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[CH3:8]
Reactant: CNc1ccccc1
Reactant: Cc1c(I)ccnc1F
Product: Cc1c(I)ccnc1N(C)c1ccccc1

Procedure:
2-Fluoro-4-iodo-3-methylpyridine (700 mg) in N-methylaniline (2.5 mL) was heated at 18° C. in a Biotage Initiator microwave reactor for 18 hours. The reaction mixture was loaded onto a silica gel cartridge, and was eluted with 0-100% dichloromethane in hexanes to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:16]([S:29]([CH3:32])(=O)=[O:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])[N:4]=1.C(O)(=O)C.OO>O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:16]([S:29]([CH3:32])=[O:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: COc1cc(OC)nc(OC(C(=O)O)C(c2ccccc2)(c2ccccc2)S(C)(=O)=O)n1
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OC)nc(OC(C(=O)O)C(c2ccccc2)(c2ccccc2)S(C)=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.2 g (2.9 mmol) of 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methylsulfonyl-3,3-diphenylpropionic acid were introduced into 15 ml of glacial acetic acid at 0° C. and 294 μl of 30% strength H2O2 were added dropwise. The mixture was stirred at room temperature overnight, poured into water, extracted with CH2Cl2 and washed with sodium thiosulfate solution and brine. After drying, 1 g of substance was isolated as a white foam.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](N)=[C:6]([F:11])[CH:5]=2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:21].[K+]>O>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([I:21])=[C:6]([F:11])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: [I-]
Reactant: Nc1ccc(C2CC2)cc1F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Fc1cc(C2CC2)ccc1I
Temperature: 0 °C
Yield: 70.6 %

Procedure:
4-Cyclopropyl-2-fluoro-phenylamine (400 mg, 2.65 mmol) was dissolved in water (5 ml) and cooled to 0° C. Concentrated sulfuric acid (1.6 ml) was added dropwise slowly, followed by a solution of sodium nitrite (0.18 ml, 2.65 mmol) in water (1 ml). The resulting mixture was added to a solution of potassium iodide (0.43 g, 5.30 mmol) in water (1 ml). The mixture was heated at 60° C. for 2 hours, then allowed to cool and extracted with dichloromethane (×2). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification of the resultant residue by flash chromatography (Si-PPC, pentane) afforded the title compound as a pale yellow oil (490 mg, 71%). 1H NMR (CDCl3) 0.60-0.77 (2H, m), 0.94-1.06 (2H, m), 1.81-1.90 (1H, m), 6.64 (1H, dd, J=8.17, 2.01 Hz), 6.74-6.96 (1H, m), 7.53-7.64 (1H, m).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:32]1([CH2:38][CH2:39][S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[OH:46][C:45]1[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)[O:16][C:42](=[O:43])[C:41]=1[S:40][CH2:39][CH2:38][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(Oc3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-phenoxyacetophenone (1.07 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 127°-128° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.77 (t, 2 H), 2.99 (t, 2 H), 6.72 (s, 1 H), 7.18 (m, 10H), 7.46 (t, 2 H), 7.82 (d, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[O:8][C:7]=2[CH:18]=1.[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)#[N:20]>Cl[Ti](Cl)(Cl)Cl.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:25]([C:24]3[CH:28]=[CH:29][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)=[O:26])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[O:8][C:7]=2[CH:18]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2cc(-c3ccc(C)cc3)oc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(C#N)cc3)c(-c3ccc(C)cc3)oc2c1
Reaction time: 4 h

Procedure:
One gram (4.2 mmol) of 6-Methoxy-2-(4methylphenyl)benzo[b]furan was dissolved 25 mL of dichloromethane and 830 mg (5.0 mmol) of 4-cyanobenzoyl chloride was added. The reaction was stirred and kept under a nitrogen atmosphere. 2.75 mL (25 mmol) of TiCl4 was slowly added to the reaction mixture. The reaction was allowed to proceed for four hours and quenched by the addition of 5 mL of methanol (MeOH). The solvents were removed by evaporation and the crude material was chromatographed on a silica gel column eluted with hexane-EtOAc (9:1). The desired fractions were determined by tlc and combined and evaporated to a solid. The resulting product was crystallized from diethyl ether (Et2O). This yielded 325 mg of the title compound as yellow powder.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)#[N:15].N1C=CC=CC=1>ClCCl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:22][C:19]2[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccc(S)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)Sc2ccc(C#N)cc2)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 4-acetoxybenzoyl chloride (3.33 g) in dry dichloromethane (20 ml) was added over 10 minutes to a cool (5° C.), stirred solution of 4-cyanothiophenol (2.06 g), pyridine (1.45 ml) and 4-N,N-dimethylaminopyridine (25 mg) in dry dichloromethane (30 ml). The stirred solution was allowed to reach room temperature overnight and the organic solution was washed successively with aqueous 2M hydrochloric acid, a saturated sodium bicarbonate solution and water. Evaporation of the extracts, which had been dried over magnesium sulphate, afforded the desired thioester (4.53 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:30](C([Sn])=C(CCCC)CCCC)[CH2:31]CC.[Cl-].[Li+].[F-].[K+]>CN(C=O)C.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>[Cl:1][C:2]1[C:3]([CH:30]=[CH2:31])=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(Cl)c1OS(=O)(=O)C(F)(F)F
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1c(C(=O)OC)cc(Cc2ccc(OC)cc2)c(C)c1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of methyl 3-chloro-5-(4-methoxybenzyl)-4-methyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (0.51 g) in DMF (10.0 mL) were added tributylvinyltin (0.54 g), trans-dichlorobis(triphenylphosphine)palladium(II) (0.04 g) and lithium chloride (0.36 g), and the mixture was stirred at 90° C. for 1 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.31 g).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:38][O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[C:46](Br)[CH:47]=1.[CH2:50]([C:52]([C:71]1[CH:76]=[CH:75][C:74](/[CH:77]=[CH:78]/[C:79]([C:85]([F:88])([F:87])[F:86])([OH:84])[C:80]([F:83])([F:82])[F:81])=[C:73]([CH3:89])[CH:72]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[C:57]([CH3:70])[CH:56]=1)[CH2:53][CH3:54])[CH3:51]>O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[C:46]([C:58]2[CH:59]=[CH:60][C:55]([C:52]([CH2:53][CH3:54])([C:71]3[CH:76]=[CH:75][C:74](/[CH:77]=[CH:78]/[C:79]([OH:84])([C:85]([F:87])([F:88])[F:86])[C:80]([F:83])([F:82])[F:81])=[C:73]([CH3:89])[CH:72]=3)[CH2:50][CH3:51])=[CH:56][C:57]=2[CH3:70])[CH:47]=1
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
A solution of palladium acetate (1.4 mg, 0.00623 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (5.3 mg, 0.0124 mmol) and potassium phosphate (27.6 mg, 0.1246 mmol) in water (0.020 mL) and toluene (0.100 mL) was stirred for three minutes. Then, a solution of (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 15.2 mg, 0.0659 mmol) and (E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-buten-2-ol (Example 26-(5); 26.9 mg, 0.0471 mmol) in toluene (0.12 mL) was added, and the mixture was stirred in a nitrogen atmosphere at 100° C. for one hour. After filtration through cotton plug, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/2) to give the title compound (5.0 mg, 17%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Na+].Br[C:13]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[CH2:23][CH:24]4[NH:28][CH:27]([C:16]=3[C:15]=2[C:14]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]4>>[CH3:1][C:2]1[CH:3]=[C:4]([S:8]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: Cc1cccc(S(=O)[O-])c1
Agent: [Na+]
Product: Cc1cccc(S(=O)(=O)c2ccc3c(c2C(=O)OC(C)(C)C)c2c(n3C)CC3CCC2N3)c1
Yield: 50 %

Procedure:
Intermediate 10 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude product was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(3-methylphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (130 mg, 50%) as light yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.19 (s, 1H), 7.72-7.78 (m, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.27-7.35 (m, 3H), 5.26 (br s, 1H), 4.72 (br s, 1H), 3.60 (s, 3H), 3.35 (br s, 1H), 2.49 (d, J=15.8 Hz, 1H), 2.38 (s, 3H), 2.13-2.36 (m, 3H), 1.89-2.01 (m, 1H), 1.38 (br s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:15][CH:16]=3)[NH:11][C:10]2=[O:26])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:29]I>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:15][CH:16]=3)[N:11]([CH3:29])[C:10]2=[O:26])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3NC2=O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the suspension of 3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (34.7 mg, 0.1 mmol) (from Example 24a supra) in tetrahydrofuran (5 mL) was added sodium hydride (60%, 10 mg, 0.25 mmol) (Aldrich) followed by methyl iodide (0.032 mL, 0.5 mmol) (Aldrich) in one portion. The reaction mixture was stirred at room temperature overnight and then heated under reflux for 5 hours. The reaction was then quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3×50 mL). The combined organic extracts were filtered to give 3-(4-methoxy-phenyl)-1-methyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-one as a white solid. (Yield 20.9 mg, 57.9%).