Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[Li]CCCC.[C:26](=[O:28])=[O:27]>O1CCCC1>[CH2:15]([C:3]1[C:2]([C:26]([OH:28])=[O:27])=[CH:14][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:5]=2[CH:4]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCc1cc2c(cc1Br)CCCCC2(C)C
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCc1cc2c(cc1C(=O)O)CCCCC2(C)C
Reaction time: 0.67 h

Procedure:
This 3.21 g of 2-bromo-3-hexyl-5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene were placed in 30 ml of abs. tetrahydrofuran under Ar and treated at -78° with 6.75 ml of 1.55M nBuLi (hexane) (1.1 eq.). The metal/halogen exchange was followed by gas chromatography (GC). After 40 min., a large excess of CO2 gas was introduced and the cooling bath was removed. After 10 min., the mixture was poured on to ice/NH4Cl solution, extracted with diethyl ether, washed with H2O, dried over Na2SO4 and the solvent was removed in a vacuum. Flash chromatography on SiO2 (hexane/ethyl acetate=8/2) yielded 2.26 g of 3-hexyl-5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid as white crystals of m.p. 74-75°.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=1[C:12]([F:13])([F:14])[F:15])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(Br)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
2-(4-Bromo-2-(trifluoromethyl)phenoxy)ethanol (17.54 mmol, 5 g) and triethylamine (35.1 mmol, 4.88 ml, 3.55 g) were combined and stirred in DCM (100 ml) at 0° C. methanesulfonyl chloride (26.3 mmol, 2.036 ml, 3.01 g) was added and the reaction allowed to warm to room temperature over 1 hour. The reaction mixture was washed with water, dried over sodium sulfate and concentrated in vacuo to afford 2-(4-bromo-2-(trifluoromethyl)phenoxy)ethyl methanesulfonate. (5.64 g)
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[P:12]([O:21]C(C)C)([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15]>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][P:12](=[O:21])([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CC(C)OP(=O)(Cc1ccc([N+](=O)[O-])cc1)OC(C)C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
A mixture of 4-nitrobenzylbromide (15.0 g) and triisopropyl phosphite (15.9 g) was stirred for 3 hr while heating under reflux. The reaction mixture was subjected to silica gel column chromatography, and diisopropyl 4-nitrobenzylphosphonate (19.5 g) was obtained as an oil from a fraction eluted with ethyl acetate-chloroform (1:1, volume ratio). A mixture of this oil, 5% palladium-carbon (2.3 g) and ethanol (130 ml) was stirred at room temperature for 6 hr under a hydrogen atmosphere. The catalyst was filtered off and the filtrate (ethanol solution) was concentrated to give diisopropyl 4-aminobenzylphosphonate (17.2 g, yield 98%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:6]([C:12]1[CH:26]=[CH:25][C:15]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:13]=1)=[N:7]2.[NH2:33][NH2:34]>O1CCOCC1>[NH:33]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:6]([C:12]1[CH:26]=[CH:25][C:15]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:13]=1)=[N:7]2)[NH2:34]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Reactant: NN
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccnc(NN)c3cc2-c2ccccc2)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of 16-1 (6.8 g, 15.2 mMol) in anhydrous 1,4-dioxane (20 mL) was added hydrazine (10.8 mL, 343 mMol). The solution was heated to 100° C. in a microwave reactor for 5 minutes. The solvent was removed in vacuo and the crude residue was taken up in ethyl acetate and washed with aqueous NaHCO3 solution followed by brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo to yield 16-2 as an orange solid. LC/MS (M+1) calculated: 442.5; observed: 442.2
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH:12]1[N:16]=[C:15]([NH2:17])[S:14][CH:13]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:9]([NH:17][C:15]2[S:14][CH:13]=[CH:12][N:16]=2)=[O:11])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Reactant: Nc1nccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Nc1nccs1)c1nc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution (400 ml) of 14.1 g (73.0 mmol) of 3,6-dichloro-2-pyridinecarboxylic acid in chloroform were successively added 9.00 g (89.9 mmol) of aminothiazole, 12.1 g (89.7 mmol) of N-hydroxybenzotriazole hydrate and 19.0 g (99.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride followed by stirring at room temperature for 24 hours. After the reaction solution was concentrated, ethyl acetate was added to the residue followed by washing with 0.2N aqueous solution of hydrochloric acid, water and saturated aqueous solution of sodium hydrogen carbonate. After drying and concentrating, the resulting residue was crystallized from a mixed solvent of hexane and ethyl acetate (5:1) to give 12.8 g (yield: 64%) of 3,6-dichloro-N-(thiazole-2-yl)-2-pyridine carboxamide as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:45])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][OH:37])=[CH:34][N:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-ethoxy-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M35) (876 mg, 1.35 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (360 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].[C:11]([O:15][C:16]([N:18]1[CH:22]2[CH2:23][CH2:24][CH:19]1[CH:20]([CH2:25]OS(C)(=O)=O)[CH2:21]2)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[CH3:1][C:2]1[C:7]([O:8][CH2:25][CH:20]2[CH2:21][CH:22]3[N:18]([C:16]([O:15][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:17])[CH:19]2[CH2:24][CH2:23]3)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(COS(C)(=O)=O)C2
Reactant: Cc1ncccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1OCC1CC2CCC1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To 2-methylpyridin-3-ol in DMF was added KOH. The solution was stirred for 30 min at rt, then the title compound from step A was added and the reaction was heated at 80° C. After 5 h, H2O was added and the mixture extracted with EtOAc. The combined organic layers were dried (MgSO4). Purification via silica gel chromatography (0-7% MeOH in DCM) gave the title compound (201 mg, 90%). MS (ESI) mass calcd. for C18H26N2O3, 318.2; m/z found 319.0 [M+1]+.
Reaction SMILES: [C:1]1([CH:7]([CH3:20])[CH2:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[C:17]3[CH3:19])=[N:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[CH3:19][C:17]1[N:18]2[C:11]([CH:9]([CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:20])[OH:10])=[CH:12][N:13]=[C:14]2[S:15][CH:16]=1
Reactant: Cc1csc2ncc(C(=O)CC(C)c3ccccc3)n12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1csc2ncc(C(O)CC(C)c3ccccc3)n12
Yield: 88.7 %

Procedure:
A solution of 2-phenylpropyl-3-methylimidazo[2,1-b]thiazol-5-yl methanone (Formula B-3) (0.28 g) in ethanol (20 mL) was treated with NaBH4 (41.7 mg) and reacted for 48 hours. Solvent was evaporated and the residue was treated with water and the precipitated product was extracted into ethyl acetate. Drying and evaporation of the extract gave crude 3-Methyl-α-(2-phenylpropyl)imidazo[2,1-b]thiazole-5-methanol (Formula B-5) (0.25 g) which deposited pure 3-Methyl-α-(2-phenylpropyl)imidazo[2,1-b]thiazole-5-methanol (Formula B-5) (0.23 g), m.p. 135-136°, from isopropanol solution.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1COCC1.F[C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=1>CN(C=O)C>[C:43]([C:42]1[CH:45]=[CH:46][C:39]([O:1][C:2]2[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=2)[C:5]([NH:7][C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)=[O:6])=[CH:40][CH:41]=1)#[N:44]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: N#Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C#N)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a stirred solution of 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.164 mmol) in DMF (1 mL) was added a 1M solution of sodium hexamethyldisilazide in THF (0.164 mmol). The reaction was stirred at RT for 10 minutes before adding 4-fluorobenzonitrile (0.164 mmol) The reaction was stirred overnight at RT, then heated to 60° C. and stirred for a further 4 hours. The reaction was allowed to cool to RT, and treated with a further 0.2 equivalents of 4-fluorobenzonitrile and sodium hexamethyldisilazide, heated to 70° C. and stirred at this temperature for 3 hours. The reaction was cooled to RT, and treated with a further 0.2 equivalents of sodium hexamethyldisilazide, warmed to 70° C., and stirred at this temperature overnight. The solvent was removed in vacuo and the residual oil partitioned between ethyl acetate and water. The water layer was separated and re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to a residue which was chromatographed on silica, using 0-1% methanol in DCM as the eluent, to give the desired product (60% yield).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:6](=[O:7])[C:5]3[CH:16]=[CH:17][CH:2]=[CH:3][CH:4]=3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Oc1ccc(O)cc1)c1ccc(O)cc1
Product: O=C(Oc1ccc(OC(=O)c2ccc(OC(=O)c3ccccc3)cc2)cc1)c1ccccc1

Procedure:
4-Benzoyloxyphenyl 4-benzoyloxybenzoate is prepared from 4-hydroxyphenyl 4-hydroxybenzoate and benzoyl chloride in accordance with the instructions from example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.C1(C)C=CC=CC=1.[CH2:17]([O:21][C:22]([C:24]1[N:25]=[C:26](Br)[C:27]2[C:32]([C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:23])[CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[CH2:17]([O:21][C:22]([C:24]1[N:25]=[C:26]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:27]2[C:32]([C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1OCc1ccccc1
Reactant: OB(O)c1ccccn1
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: Cc1ccccc1
Solvent: CCO
Product: CCCCOC(=O)c1nc(-c2ccccn2)c2ccccc2c1OCc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of Pyridin-2-ylboronic acid (323 mg, 2.5 mmol) in EtOH (2.5 ml) was added subsequently toluene (15 ml), 4-Benzyloxy-1-bromo-isoquinoline-3-carboxylic acid butyl ester (1.035 mg, 2.5 mmol, see example D-86a), Pd(PPh3)4 (292 mg, 0.25 mmol), and aq. 2 M Na2CO3 solution (2.5 ml, 5 mmol). The mixture was then refluxed with stirring under N2 protection for 24 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (15 ml) and the mixture was extracted with EtOAc (30 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using CH2Cl2 MeOH=98 2 as the eluent gave a dark oil that was further purified by flash column chromatography on silica gel using CH2Cl2 MeOH=99 1 as the eluent and subsequently by preparative TLC using CH2Cl2 MeOH=98 2 as the eluent (had to be repeated several times) to give the title compound as a yellow oil (19 mg); MS-(+)-ion M+1=413.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[N+:17]([C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1)([O-:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:16][O:15][C:13]([CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:23]1[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:14]
Reactant: COC(=O)C(CCCCCCO)C(=O)OC
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(CCCCCCOc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.6 %

Procedure:
Compound 16 (1.92 g, 8.3 mmol), 4-nitrophenol (1.39 g, 10.0 mmol) and triphenylphosphine (2.62 g, 10.0 mmol) were dissolved in dry THF (100 mL) and deaerated with argon. Diisopropyl azodicarboxylate (2.0 mL, 10.0 mmol) was added in ten portions under argon and the mixture was stirred for 3 days at r.t. The mixture was evaporated to dryness and purified on silica gel (CH2Cl2), yielding 2.6 g (89%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][C:4](=[S:8])[N:3]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C([O-])([O-])=O.[K+].[K+].O>[CH2:9]([N:3]1[C:4]([S:8][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5][CH2:6][CH2:7][N:2]1[CH3:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCNC(=S)N1Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN=C(SCc2ccccc2)N1Cc1ccccc1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
Seven grams of tetrahydro-1-methyl-2-(phenylmethyl)-1,2,4-triazine-3(2H)-thione was dissolved in 30 ml. of dimethyl formamide. Three grams of finely ground potassium carbonate (K2CO3) was added to the solution. Benzyl bromide (5.43 grams) was added in several additions at room temperature. The mixture was heated to 60°-65° C and held at that temperature for 2 hours. The mixture was chilled and diluted with additional K2CO3 (10 g.) and water (200 ml). The product was extracted with trichloromethane and washed with brine. The mixture was dried with magnesium sulfate. The mixture was diluted with ethyl ether and the insoluble particles filtered off. The filtrate was heated to 35° C to concentrate the solution. Upon chilling 2-benzyl-3-(benzylthio)-1,2,5,6-tetrahydro-1-methyl-1,2,4-triazine crystallized from the liquid reaction mass. This product was recrystallized from isopropanol-hexane. The product was found to have a melting point at 45° C. The structure was confirmed by IR, NMR and elemental analysis.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[N:12]=[C:13]([CH2:16][N:17]([CH3:27])C3C=CC(N(C)C)=CC=3)[S:14][CH:15]=2)[CH:8]=[C:7]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:6]=1[OH:32])([CH3:4])([CH3:3])[CH3:2].[N+:33]([C:36]1[CH:43]=[CH:42][C:39](C=O)=[CH:38][CH:37]=1)([O-:35])=[O:34].CO.[BH4-].[Na+]>O>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[N:12]=[C:13]([CH2:16][NH:17][CH2:27][C:39]3[CH:42]=[CH:43][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=3)[S:14][CH:15]=2)[CH:8]=[C:7]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:6]=1[OH:32])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)c1ccc(N(C)Cc2nc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cs2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(-c2csc(CNCc3ccc([N+](=O)[O-])cc3)n2)cc(C(C)(C)C)c1O
Yield: 55 %

Procedure:
0.5 g (1.57 mmol) of the compound of Example 9, 0.237 g (1.57 mmol) of 4-nitrobenzaldehyde and 1 g of previously activated pulverulent 4 Å molecular sieve are added successively to a flask containing 30 ml of anhydrous MeOH, under an inert atmosphere. The reaction mixture is vigorously stirred for 18 hours before the addition, by portions, of 0.06 g (1.57 mmol) of NaBH4. Stirring is maintained for another 4 hours before the addition of 5 ml of water. After a quarter of hour, the sieve is filtered out and the reaction mixture is extracted with two times 100 ml of CH2Cl2. The organic phase is washed successively with 50 ml of water then with 50 ml of salt water, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is purified on a silica column (eluent: 50% ethyl acetate in heptane). A yellow oil is obtained with a yield of 55%.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8]([CH2:12][CH:13]=[CH2:14])[CH:7]=[N:6][C:5]=2[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1=[O:20].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CN([CH:34]=[O:35])C>C1COCC1>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[N:8]([CH2:12][CH:13]=[CH2:14])[C:7]([CH:34]=[O:35])=[N:6][C:5]=2[N:4]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]1=[O:20]
Reactant: C=CCn1cnc2c1c(=O)n(C)c(=O)n2CCCCC
Reactant: CN(C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCn1c(C=O)nc2c1c(=O)n(C)c(=O)n2CCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To 1-methyl-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.05 g, 3.6 mmol) in THF (15 ml) at −78° C. was added LiHMDS (4 ml, 1M in hexane, 4 mmol) over 10 min and the solution stirred for 0.5 h. DMF (0.5 ml) was added and the solution stirred at −78° C. for a further 0.5 h then allowed to warm to ambient temperature with the cooling bath over 2 h. The reaction was quenched with 2N hydrochloric acid (3 ml) and partioned between ethyl acetate and brine. The organics were isolated, dried and concentrated. The crude product was chomatographed over silica (gradient elution dichloromethane to 5:1 dichloromethane/ethyl acetate) to afford the title compound as a white solid (0.35 g, 30%). m/z 305[MH+]
Reaction SMILES: NC1C2C(OC)=CC=CC=2SC=1[C:7](OC)=[O:8].C=O.Cl[C:20]1[C:28]2[C:27]([N:29]([CH3:31])[CH3:30])=[C:26]([C:32]([O:34][CH3:35])=[O:33])[S:25][C:24]=2[CH:23]=[CH:22][CH:21]=1>>[CH3:30][N:29]([CH3:31])[C:27]1[C:28]2[C:20]([O:8][CH3:7])=[CH:21][CH:22]=[CH:23][C:24]=2[S:25][C:26]=1[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)c1sc2cccc(Cl)c2c1N(C)C
Reactant: COC(=O)c1sc2cccc(OC)c2c1N
Agent: C=O
Product: COC(=O)c1sc2cccc(OC)c2c1N(C)C

Procedure:
Alkylation of methyl 3-amino-4-methoxybenzo[b]thiophene-2-carboxylate (1.4 g, 5.9 mmol) [Beck J. R., supra] with paraformaldehyde as described for the preparation of methyl 4-chloro-3-(dimethylamino)benzo[b]thiophene-2-carboxylate provides methyl 3-(dimethylamino)-4-methoxybenzo[b]thiophene-2-carboxylate as a crude solid suitable for further synthesis; mp=69°-73° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:22]2[CH:31]=[CH:32][C:19]([O:18][CH2:17][C:15]3[N:14]([CH3:33])[C:13]4[CH:34]=[C:9]([O:8][C:7]5[CH:35]=[CH:36][C:4]([NH:3][S:43]([C:40]6[CH:41]=[CH:42][C:37]([CH3:47])=[CH:38][CH:39]=6)(=[O:45])=[O:44])=[CH:5][CH:6]=5)[CH:10]=[CH:11][C:12]=4[N:16]=3)=[CH:20][CH:21]=2)[S:28]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc4nc(COc5ccc(CC6SC(=O)NC6=O)cc5)n(C)c4c3)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 51.6 %

Procedure:
A mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), p-toluenesulfonyl chloride (153 mg), triethylamine (234 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate. and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=2:1→4:1 as the eluant and the product was recrystallized from a mixture of ethyl acetate and diisopropyl ether to afford the title compound (237 mg, mp 132.0-135.6° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[N:23]([CH2:26][C:27](O)=[O:28])=[N+:24]=[N-:25].C([O-])(O)=O.[Na+].C(Cl)CCl>CN(C=O)C>[N:23]([CH2:26][C:27](=[O:28])[NH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[N+:24]=[N-:25]
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCN
Reactant: [N-]=[N+]=NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNC(=O)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
To a 25 mL round bottomed flask equipped with a magnetic stir bar, rubber septum, and argon inlet containing tert-butyl 3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propylcarbamate (amine, 160 mg, 0.5 mmol), 2-azidoacetic acid (56 mg, 0.55 mmol, in 50% DCM solution), NaHCO3 (168 mg, 2 mmol), and 1 mL DMF was added EDC (115 mg, 0.6 mmol). The mixture was stirred at rt for 3 h and concentrated in vacuo. The crude product was purified by silica chromatography (gradient 5% to 90% EtOAc in hexane) to afford compound 141 as a clear oil (130 mg, 65%). MS (ESI) m/z 426 (M+Na+).