Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10](Br)=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH3:17])[N:3]=1.[CH3:18][O-:19].[Na+]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([O:19][CH3:18])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH3:17])[N:3]=1
Reactant: C[O-]
Reactant: CSc1nc(N)nc(-c2ccc(Br)o2)c1C#N
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2nc(N)nc(SC)c2C#N)o1
Temperature: 50 °C
Yield: 87.6 %

Procedure:
To a stirred solution of 493 mg (1.58 mmol) 2-amino-4-(5-bromo-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile in 10 ml DME was added 2.1 ml (11,3 mmol) sodium methylate solution (5.4M in methanol) and the mixture heated at 50° C. for 1 h. The reaction mixture was then poured into 100 ml ice-water and the resulting precipitate collected by filtration and washed with water. Chromatography (ethyl acetate/hexane 1/1) afforded 363 mg (87%) 2-amino-4-(5-methoxy-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 262 (M+, 100).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:14])[C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:14][C:7]1[C:8]([O:12][CH3:13])=[C:9]([NH:11][S:23]([CH3:22])(=[O:25])=[O:24])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: COc1c(N)cc(C(C)(C)C)cc1N
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To an oven dried 250 mL round bottom flask containing 5.0 g (25.73 mmol) 5-tert-butyl-2-methoxy-benzene-1,3-diamine, 150 mL DCM was added. The reaction mixture was cooled to 0° C. after which triethylamine (5.0 mL, 36.0 mmol) was added followed by the drop wise addition of methylsulfonyl chloride (1.99 mL, 25.7 mmol). The reaction was allowed to stir at 0° C. for 30 min. then warmed to room temperature stirring for an additional 2 h. The reaction mixture was poured over saturated solution of sodium bicarbonate (100 mL) and the layers separated. The aqueous layer was washed twice more with 50 mL dichloromethane and the combined organic layers were dried over magnesium sulfate and concentrated under vacuum to afford a crude oil that was purified by flash chromatography (silica gel, 1:1 EtOAc:Hex) to yield 6.1 g of the desired product (87%). Calculated mass=272. Observed mass=273
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([F:17])[CH:10]=1)=[O:5])[CH3:2].B(Br)(Br)Br.CO>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:17])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1c1ccc(OC)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C1CC1c1ccc(O)c(F)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
After 2-(3-fluoro-4-methoxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (0.494 g, 2.07 mmol) obtained in Step B was dissolved in anhydrous DCM (7 mL), BBr3 1 M DCM solution (3 mL, 3.11 mmol) was added thereto at −78° C., and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was added with MeOH, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain the title compound (0.424 g, 91%).
Reaction SMILES: [C:1]1([C:7]2O[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[CH3:29][NH2:30]>CO.O>[C:1]1([C:7]2[N:30]([CH3:29])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O
Reactant: CN
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2)n(C)c(-c2ccccc2)cc1=O

Procedure:
3.5 gms of 2,6-diphenyl-3-ethoxycarbonyl-4-pyrone was dissolved in 33 mls of methanol. 2 mls of glacial acetic acid was added. 13.3 mls of 40% aqueous methylamine was then added very slowly at room temperature. After 6 hours the reaction mixture was diluted with 200 mls of water and extracted with methylene chloride. Evaporation yielded 3.5 gms of ethyl 2,6-diphenyl-1-methyl-4-oxonicotinate which was recrystallized from methylene chloride/ether. mp=177°-9°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].C([Li])CCC.C1(O[C:32]#[N:33])C=CC=CC=1.O>O1CCCC1.CCCCCC>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:32]#[N:33])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1
Reactant: N#COc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCC[C@H]1CC[C@H](c2ccc(C#CC#N)cc2)CC1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.2 g of 1-ethynyl-4-(trans-4-pentylcyclohexyl)benzene (prepared according to Example 3) in 50 ml of absolute tetrahydrofuran was placed at -40° C. in a sulphonation flask under argon gasification and treated with 4.72 ml of a 1.2N solution of butyl lithium in hexane. After completion of the addition, the mixture was stirred at -40° C. for a further 15 minutes, subsequently treated at -78° C. with 1.07 ml of phenyl cyanate and stirred at -78° C. for a further 45 minutes. The mixture was then poured into 50 ml of water and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed with 50 ml of water and 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the crystalline residue on silica gel with 3% ethyl acetate/petroleum ether gave 1.20 g (91%) of p-(trans-4-pentylcyclohexyl)phenylpropiolonitrile as colourless crystals (purity 99.6%). A single crystallization from 50 ml of methanol yielded 687 mg of the product with m.p. (C-N) 49.7° C. and cl.p. (N-I) 128.9° C.
Reaction SMILES: [C:1]([C:6]1[CH:47]=[C:46]([C:48]([CH2:51][CH3:52])([CH3:50])[CH3:49])[CH:45]=[CH:44][C:7]=1[O:8][CH:9]([CH2:42][CH3:43])[C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:39]=[CH:40][CH:41]=1)[C:16]([NH:18][C:19]1[CH:23]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)[C:22](=[O:29])[N:21]([C:30]2[C:35]([Cl:36])=[CH:34][C:33]([Cl:37])=[CH:32][C:31]=2[Cl:38])[N:20]=1)=[O:17])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:60](OCl)(=[O:64])[CH2:61][CH2:62][CH3:63].C(OCC)(=O)C>O1CCCC1>[C:1]([C:6]1[CH:47]=[C:46]([C:48]([CH2:51][CH3:52])([CH3:49])[CH3:50])[CH:45]=[CH:44][C:7]=1[O:8][CH:9]([CH2:42][CH3:43])[C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:39]=[CH:40][CH:41]=1)[C:16]([NH:18][C:19]1[C:23]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[C:22]([O:29][C:60](=[O:64])[CH2:61][CH2:62][CH3:63])[N:21]([C:30]2[C:31]([Cl:38])=[CH:32][C:33]([Cl:37])=[CH:34][C:35]=2[Cl:36])[N:20]=1)=[O:17])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2n2cccn2)c1
Reactant: CCCC(=O)OCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Oc1c(-n2cccn2)c(NC(=O)c2cccc(NC(=O)C(CC)Oc3ccc(C(C)(C)CC)cc3C(C)(C)CC)c2)nn1-c1c(Cl)cc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
30.6 g of 3-{3-[2-(2,4-di-tert-amylphenoxy)butyramido]benzamido}-1-(2,4,6-trichlorophenyl)-4-(1-pyrazolyl)-5-oxo-2-pyrazoline (prepared by the method described in German Patent Application (OLS) No. 2,536,191) was dissolved in 100 ml of tetrahydrofuran and 5 g of triethylamine was added. To the solution, a solution containing 3.5 g of butanoyloxy chloride dissolved in 10 ml of tetrahydrofuran was dropwise added. After the addition of the solution, the mixture was stirred for 1 hour. 500 ml of ethyl acetate was added to the reaction mixture and washed several times with water. The oil layer was dried with anhydrous sodium sulfate and concentrated. Upon crystallization of the residue from acetonitrile, 24 g of Coupler (5) was obtained. The melting point of the coupler was 63° to 68° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]([N+:13]([O-])=O)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[H][H].C(OCC)(=O)C.C(O)C.N>C(O)C.ClCCl.[Pd]>[NH2:13][C:12]1[C:3]([NH:2][CH3:1])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: CNc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ncc(C(=O)OC)cc1N

Procedure:
To a solution of 3.1 g (15 mmol) of methyl 6-methylamino-5-nitronicotinate in 100 mL of ethanol/dichloromethane (3:1) was added 1 g of palladium on charcoal (10%) and the resulting suspension was hydrogenated at room temperature under 5 bar of hydrogen pressure for 1.5 hours. The catalyst was then filtered off and the solvent was distilled off in vacuo. The crude oily product obtained was further reacted directly. Yield: 2.4 g (92% of theory); Rf value: 0.44 (silica gel; ethyl acetate/ethanol/ammonia=90:10:1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.[CH2:13](Br)[CH:14]=[CH2:15].C([O-])([O-])=O.[K+].[K+].[CH3:23][C:24]([CH3:26])=O>>[CH2:13]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:26][CH:24]=[CH2:23])[CH:8]=2)[CH:3]=1)[CH:14]=[CH2:15]
Reactant: CC(C)=O
Reactant: C=CCBr
Reactant: Oc1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc2cc(OCC=C)ccc2c1
Temperature: 25 °C

Procedure:
Into a 1,000 ml two-necked flask equipped with a refluxing condenser, 20.0 g of 2,6-dihydroxynaphthalene (Sigma-Aldrich), 27.0 ml of allyl bromide (Sigma-Aldrich), 103.61 g of K2CO3, and 500 ml of acetone were charged and mixed at room temperature. Then, the reaction temperature was set to 80° C., and the homogeneous mixture thus obtained was refluxed overnight. After finishing the reaction, the reaction mixture was cooled to room temperature and filtered using Celite. The solvent was evaporated to obtain a coarse product. A target product was extracted from the coarse product using ethyl acetate, washed three times using water, and dried using MgSO4. MgSO4 was filtered off, and solvents were removed by using an evaporator to obtain an intermediate product (11), 2,6-bis(allyloxy)naphthalene. The reaction scheme in the 1st step is as follows.
Reaction SMILES: CO[C:3](OC)([N:5]([CH3:7])C)[CH3:4].[C:10]([NH:13][NH2:14])(=O)[CH3:11].N[C@H:16]1[CH2:21]C[CH2:19][C@@H:18]([NH:22][S:23]([C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:29]([CH:35]([CH3:37])[CH3:36])=[CH:28][C:27]=2[CH:38]([CH3:40])[CH3:39])(=[O:25])=[O:24])[CH2:17]1>C(#N)C>[CH3:11][C:10]1[N:5]([C@@H:7]2[CH2:21][CH2:16][CH2:17][C@H:18]([NH:22][S:23]([C:26]3[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:29]([CH:35]([CH3:37])[CH3:36])=[CH:28][C:27]=3[CH:38]([CH3:39])[CH3:40])(=[O:25])=[O:24])[CH2:19]2)[C:3]([CH3:4])=[N:14][N:13]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)NN
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N[C@@H]2CCC[C@H](N)C2)c(C(C)C)c1
Solvent: CC#N
Product: Cc1nnc(C)n1[C@@H]1CCC[C@H](NS(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)C1
Temperature: 100 °C

Procedure:
A mixture of N,N-dimethylacetamide dimethylacetal (21.0 mg, 0.158 mmol) and acetic hydrazide (10.7 mg, 0.145 mmol) in acetonitrile (2.0 mL) was heated to 50° C. for 30 min, at which point, compound 7c (50.0 mg, 0.131 mmol) was added, and the resulting mixture was heated to 100° C. overnight. After cooling to rt, the reaction mixture was partitioned between EtOAc and water. The layers were separated, and the aq. layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by preparative thin layer chromatography on silica gel (10% MeOH/DCM as eluent) to afford the title compound, 7d. m/z (ES) 461 (MH)+; IC50=9.8 nM
Reaction SMILES: [SH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.C(N(CC)CC)C.[CH3:20][C:21]1([CH3:24])[CH2:23][S:22]1>CO>[SH:22][C:21]([CH3:24])([CH3:23])[CH2:20][S:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1
Reactant: CC1(C)CS1
Reactant: OCc1cc(CO)cc(CS)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(S)CSCc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
(5-(mercaptomethyl)-1,3-phenylene)dimethanol (0.163 g, 0.885 mmol) was dissolved in methanol (3 mL) in a small vial and a stir bar was added. To this solution was added triethylamine (0.016 mL, 0.118 mmol) followed by 2,2-dimethylthiirane (0.058 mL, 0.590 mmol) and the resulting mixture was capped and stirred overnight (16 hrs) at room temperature. The reaction was then concentrated, redissolved in dichloromethane, loaded onto a silica ptlc plate (1000 micron) and the plate was developed using 10% methanol in dichloromethane. The band corresponding to the product was scraped, filtered with neat ethyl acetate, and concentrated to give (5-((2-mercapto-2-methylpropylthio)methyl)-1,3-phenylene)dimethanol (0.095 g, 0.349 mmol, 59.1% yield). 1H NMR (400 Hz, CDCl3): δ 7.26 (s, 3H), 4.69 (s, 4H), 3.82 (s, 2H), 2.74 (s, 2H), 2.17 (s, 1H), 2.12 (br s, 2H), 1.43 (s, 6H); 13C NMR (400 Hz, CDCl3): δ 141.6, 138.9, 126.7, 124.3, 65.0, 49.0, 45.4, 38.4, 31.5; MS (m/z), expected: 272.4. found 295.0 (M+Na). See FIG. 30.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18](O)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[ClH:33].O>C(O)CCC>[ClH:33].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15](=[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(Br)cc1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: Brc1ccc(C=CCCN2CCC(=C(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A mixture of 10 g (0.02 mole) of α-(p-bromophenyl)-4-(α-hydroxy-α-phenylbenzyl)-1-piperidinebutanol, 150 ml of conentrated HCl, 150 ml of water and 50 ml of n-butanol was heated for 2 hours at reflux. The solvent was removed under vacuum, and the remaining residue was recrystallized from ethyl acetate to give the desired product, M.P. 215°-217° C. Alternatively, the title compound may be prepared by a similar acid dehydration reaction of α-(p-bromophenyl)-4-(diphenylmethylene)-1-(piperidinebutanol hydrochloride, M.P. 215°-217° C.
Reaction SMILES: [Br:1][CH:2]1[CH2:10][CH:9]([CH3:11])[CH2:8][C:7]2[C:6](=[NH:12])[NH:5][C:4](=N)[C:3]1=2.Cl.[CH3:15][CH:16]1[CH2:21][N:20]([C:22]2[S:23][CH2:24][C:25](=[NH:27])[N:26]=2)[CH2:19][CH2:18][O:17]1.N=C1C2CCCCC=2C(=N)N1.Cl.N=C1NC(=N)CS1>>[NH:12]=[C:6]1[C:7]2[CH2:8][CH:9]([CH3:11])[CH2:10][CH:2]([Br:1])[C:3]=2[C:4](=[C:24]2[S:23][C:22]([N:20]3[CH2:19][CH2:18][O:17][CH:16]([CH3:15])[CH2:21]3)=[N:26][C:25]2=[NH:27])[NH:5]1
Reactant: CC1CC2=C(C(=N)NC2=N)C(Br)C1
Reactant: CC1CN(C2=NC(=N)CS2)CCO1
Agent: Cl
Agent: N=C1CSC(=N)N1
Agent: N=C1NC(=N)C2=C1CCCC2
Product: CC1CC2=C(C(=C3SC(N4CCOC(C)C4)=NC3=N)NC2=N)C(Br)C1

Procedure:
Proceeding in a manner similar to that described above in Example 10, part A, but substituting equivalent amounts of 4-bromo-6-methyl-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(2-methylmorpholino)-4-imino-2-thiazoline hydrochloride for 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazolidine hydrochloride respectively, there is obtained as the product 1-imino-4-bromo-6-methyl-4,5,6,7-tetrahydro-3-[2-(2-methylmorpholino)-4-imino-2-thiazolin-5-ylidene]isoindoline.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)OCC1.[H-].[Na+].[CH3:15]I.O>O1CCCC1>[CH3:15][O:12][CH2:11][CH:8]1[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To (1,4-Dioxa-spiro[4.5]dec-8-yl)-methanol (10 g) in tetrahydrofuran (300 mL) in an ice bath was added sodium hydride (3.6 g of 60% in mineral oil) and the mixture stirred for 30 min. Methyl iodide 7.8 mL in THF (20 mL) was added dropwise and the reaction was allowed to warm slowly to room temperature overnight. Water (20 mL) was added and the reaction mixture partially concentrated, then partitioned between water (100 mL) and diethyl ether (300 mL). The organic phase was isolated, dried and concentrated in vacuo. The crude was then taken up in tetrahydrofuran (250 mL) and 40 mL of 3N aqueous HCl was added. The reaction was stirred for 2 h at room temperature, partially concentrated and then the crude product was extracted with diethyl ether, dried, concentrated and purified by flash chromatography (eluant 4 hexane: 1 ethyl acetate) to give 4-methoxymethyl-cyclohexanone 4.9 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:27])[N:9]([CH3:26])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:24]O)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:27])[N:9]([CH3:26])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH2:24][C@@H:19]([C:20]([O:22][CH3:23])=[O:21])[N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1COC(c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)=N1
Yield: 51 %

Procedure:
A solution of 14.0 g (0.0356 mol) of methyl (S)-2-(7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepin-3-ylcarbonylamino)-3-hydroxy-propionate in 250 ml of tetrahydrofuran was treated while gassing with argon with 9.3 g (0.0392 mol) of methoxycarbonylsulphamoyl-triethylammonium hydroxide internal salt (Burgess reagent) according to the method described in Tert. Letters 1992, 33, 907. The mixture was boiled at reflux for 3 1/2 hrs. and completely freed from the solvents. The residue was partitioned between dichloromethane and water, extracted and chromatographed over silica gel with ethyl acetate/ethanol 19:1 as the eluent. There were obtained 6.80 g (51%) of methyl (S)-2-(7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[l,5-a][1,4]benzodiazepin-3-yl)-4,5-dihydrooxazole-4-carboxylate as white crystals; m.p. 216°-218°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH2:17]=O>ClCCl>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:13][CH2:12]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: C=O
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(Cc2c[nH]c3ccccc23)CC1
Reaction time: 1 h

Procedure:
In a three necked round bottom flask equipped with pressure equalizing funnel, indole (1.17 g, 0.01 mole) and dichloromethane (8 mL) were taken. 1-Methylpiperazine (1.01 g, 0.011 moles) and formaldehyde (9 mL, 0.012 mole) was added slowly at room temperature and the reaction mixture was stirred well for one hour. After the completion of reaction (TLC), the product was isolated by distillation under reduced pressure. The residue was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water, followed by brine, dried over anhydrous sodium sulfate. The organic layer was evaporated under vacuum. The residue could either be an oily liquid or solid mass. The oily mass was triturated with n-hexane to obtain a solid material. The solid obtained was identified by IR, NMR and mass spectral analyses.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:3]=1.[Cl:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C([O-])([O-])=O.[K+].[K+]>C(C#N)(C)=O>[Cl:21][C:22]1[N:26]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3)[N:3]=2)[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1
Reactant: COc1cc(Nc2ncnc(Cl)n2)cc(OC)c1OC
Reactant: Clc1nc2ccccc2[nH]1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2ncnc(-n3c(Cl)nc4ccccc43)n2)cc(OC)c1OC
Temperature: 65 °C

Procedure:
To a suspension of (4-chloro-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)amine (2.97 g, 10 mmol) and 2-chlorobenzimidazole (1.53 g, 10 mmol) in dry AcCN (100 mL) was added ground K2CO3 (1.68 g, 12 mmol). The resulting mixture was heated at 65° C. for 4 h, cooled to RT, concentrated in vacuo and purified by column chromatography (EtOAc/n-Hexanes) to provide [4-(2-chloro-benzimidazol-1-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine as a white powder. MS m/z 413=[M+H]+. Calc'd for C19H17ClN6O3: 412.11:
Reaction SMILES: [OH:1][CH:2]([C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:17])[CH:12]=2)[C:7]=1[OH:18])[C:3]([O-:5])=[O:4].N1[CH:23]=[CH:22]N=C1.[CH2:24]([Si:26](Cl)([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:25]>C(Cl)Cl>[CH2:24]([Si:26]([CH2:29][CH3:30])([CH2:27][CH3:28])[O:1][CH:2]([C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:17])[CH:12]=2)[C:7]=1[OH:18])[C:3]([O:5][CH2:22][CH3:23])=[O:4])[CH3:25]
Reactant: c1c[nH]cn1
Reactant: CC[Si](Cl)(CC)CC
Reactant: Cc1ccc2c(O)c(C(O)C(=O)[O-])c(C)cc2c1
Solvent: ClCCl
Product: CCOC(=O)C(O[Si](CC)(CC)CC)c1c(C)cc2cc(C)ccc2c1O
Temperature: 25 °C

Procedure:
A solution of 2-hydroxy-2-(1-hydroxy-3,6-dimethylnaphthalen-2-yl)acetate (4.55 g, 16.6 mmol) in DCM (165 mL) at 0° C. was subsequently treated with imidazole (1.53 g, 22.4 mmol) and triethylsilyl chloride (3.2 mL, 19.1 mmol). The cooling bath was removed and the reaction allowed to warm to room temperature over 1.5 hours. Water was added, and the resulting aqueous layer was extracted with DCM. The combined organics were washed with 1M HCl and brine. Following drying over anhydrous MgSO4, concentration in vacuo afforded the desired compound that was used without further purification.