Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([CH2:16][O:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[C:29](=[O:30])[N:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=5)=[CH:34][C:33]=4[F:46])[C:27]([CH2:47][CH2:48][CH3:49])=[N:26][C:25]=3[CH3:50])=[CH:20][CH:19]=2)[CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([CH2:16][O:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[C:29](=[O:30])[N:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[NH:3][C:4](=[O:7])[O:5][N:45]=5)=[CH:34][C:33]=4[F:46])[C:27]([CH2:47][CH2:48][CH3:49])=[N:26][C:25]=3[CH3:50])=[CH:20][CH:19]=2)[CH2:15][CH2:14]1
Reactant: CCCc1nc(C)c(-c2ccc(OCC3CC3)nc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)c(-c2ccc(OCC3CC3)nc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.71 g), sodium hydrogen carbonate (1.01 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.53 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.29 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.41 g, 60%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][C:14]1[CH:19]=[C:18]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]([F:32])=[CH:25][C:26]=3F)[N:21]=2)[CH:17]=[C:16]([CH3:33])[N:15]=1.O>CN(C=O)C.C(O)(=O)C>[CH3:13][C:14]1[CH:19]=[C:18]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]([F:32])=[CH:25][C:26]=3[O:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:21]=2)[CH:17]=[C:16]([CH3:33])[N:15]=1
Reactant: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)n1
Reactant: OCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc(-c2nc3cc(F)cc(OCCOc4ccccc4)c3c(=O)[nH]2)cc(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-phenoxyethanol (4.81 g, 34.8 mmol) in DMF (20 mL) was added sodium hydride (60% suspension in mineral oil, 0.70 g, 17.4 mmol) in portions and the reaction mixture was stirred at room temperature for 1 hour. To this mixture was added 2-(2,6-dimethylpyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (0.50 g, 1.74 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water (1 mL) was added, neutralized to pH approximately 6-7 with acetic acid, concentrated, dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (eluted with 50% ethyl acetate in hexanes, then 5% methanol in DCM) to give 2-(2,6-dimethylpyridin-4-yl)-7-fluoro-5-(2-phenoxyethoxy)-3H-quinazolin-4-one as a light yellow solid. Yield: 0.59 g (83%).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][N:29]([CH2:31][C:32]#[CH:33])[CH3:30]>>[CH3:28][N:29]([CH3:30])[CH2:31][C:32]#[C:33][C:13]1[CH:12]=[C:11]2[C:16]([C:7](=[N:6][OH:5])[CH:8]=[C:9]([C:18]3[N:19]=[CH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:10]2)=[CH:15][CH:14]=1
Reactant: C#CCN(C)C
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Product: CN(C)CC#Cc1ccc2c(=NO)cc(-c3cc4ccccc4cn3)oc2c1

Procedure:
7-(3-dimethylamino-prop-1-ynyl)-2-isoquinolin-3-yl-chromen-4-one oxime was prepared in 20% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and N,N-dimethylamino-2-propyne. The title compound was purified by preparative HPLC (gradient 70-55% Water/acetonitrile+0.05% trifluoroacetic acid) and isolated as an orange solid and as a 85/15 mixture of Z/E oxime isomers.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.P(O)(O)O.C(N(CC)CC)C.[OH-].[Na+]>O>[CH2:1]([NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: OP(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Product: c1ccc(CNCc2ccccc2)cc1
Yield: 98 %

Procedure:
The imine from benzaldehyde and benzylamine (19.5 g; 0.1 mole) was heated with phosphorous acid (8.2 g; 0.1 mole) and triethylamine (10.1 g; 0.1 mole) for 2 hours at reflux (125°-130°). After cooling to 90° the reaction mixture was diluted with water (50 ml), basified (NaOH) and extracted with chloroform. The extract was concentrated by evaporation of the chloroform and triethylamine to yield dibenzylamine 19.3 g (98% yield).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:7]=1[CH2:8][C:9]1[C:10]([CH3:25])=[N:11][N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[NH:14][C:13]=12.C(=O)(O)[O-].[Na+]>CO.O>[Cl:5][C:6]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:7]=1[CH2:8][C:9]1[C:10]([CH3:25])=[N:11][N:12]2[C:17]([OH:18])=[CH:16][C:15]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[N:14][C:13]=12
Reactant: Cc1nn2c(=O)cc(-c3ccncc3)[nH]c2c1Cc1cccc(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1nn2c(O)cc(-c3ccncc3)nc2c1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of 3-(2,3-dichlorobenzyl)-2-methyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one acetate (100 mg, 0.225 mmol), sodium bicarbonate (0.5 g) in methanol/water (20 mL/10 mL) was stirred at room temperature overnight. Then the mixture was concentrated. The residue was purified by silica gel column to give the titled product (75 mg, 87%); LC/MS: MS (ES+) m/e 385 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.15 (s, 3H), 4.14 (s, 2H), 6.11 (s, 1H), 6.97-7.00 (m, 1H), 7.25 (t, J=8.1 Hz, 1H), 7.48-7.50 (m, 1H), 7.82-7.82 (m, 2H), 8.71-8.74 (m, 2H), 12.20 (s, 1H).
Reaction SMILES: Cl[O-:2].[K+].[OH-].[K+].[Cl:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([C:14](=[O:16])C)=[C:9]([F:17])[CH:8]=1>[Cl-]>[Cl:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([C:14]([OH:16])=[O:2])=[C:9]([F:17])[CH:8]=1
Reactant: CC(=O)c1cc(F)c(Cl)cc1F
Reactant: [O-]Cl
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc(F)c(Cl)cc1F
Temperature: 40 °C

Procedure:
A 3.6 liter aqueous solution containing 500 g (5.5 mole) of potassium hypochlorite and 115 g potassium hydroxide, was taken in a 5 liter, 3-necked round-bottomed flask equipped with a Trubore stirrer, a thermometer, an addition funnel and a water condenser. 228.5 g (1.2 mole) of 4'-chloro-2',5'-difluoroacetophenone was dissolved in 550 ml of chloride and the solution was slowly added to the flask via the addition funnel. The temperature was not allowed to exceed 40° C. After the addition was complete, the heterogeneous mixture was stirred vigorously at reflux (40° C.) for 18 hours.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.[OH:12]N1C(=O)C2=CC=CC=C2C1=O.O=O>C(O)(=O)C>[OH:12][C:7]12[CH2:9][CH:3]3[CH2:4][CH:5]([CH2:10][CH:1]([C:2]3=[O:11])[CH2:8]1)[CH2:6]2
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: O=O
Solvent: CC(=O)O
Product: O=C1C2CC3CC1CC(O)(C3)C2
Yield: 37 %

Procedure:
A mixture of 0.1 mol of 2-adamantanone, 10 mmol of N-hydroxyphthalimide, 0.33 mmol of acetylacetonatovanadium V(AA)3, 0.17 mmol of acetylacetonatomanganese Mn(AA)2, and 250 ml of acetic acid was stirred at 80° C. in an oxygen atmosphere (1 atm) for 6 hours. The resulting reaction mixture was concentrated and was then extracted with ethyl acetate. A portion of an organic layer was concentrated and was then cooled for crystallization to yield 5-hydroxy-2-adamantanone (yield: 37%). The conversion rate from 2-adamantanone was 64%.
Reaction SMILES: [C:1]12([N:11]3[C:15]4[CH:16]=[C:17]([O:20][CH2:21][CH3:22])[CH:18]=[CH:19][C:14]=4[N:13]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=4[O:33][CH3:34])(=[O:25])=[O:24])[C:12]3=[O:35])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:36]([N:38]([CH2:41][CH3:42])[C:39]#[N:40])[CH3:37].CCOC(C)=O.[ClH:49]>CCO>[OH2:20].[ClH:49].[C:1]12([N:11]3[C:15]4[CH:16]=[C:17]([O:20][CH2:21][CH3:22])[CH:18]=[CH:19][C:14]=4[N:13]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:39]([N:38]([CH2:41][CH3:42])[CH2:36][CH3:37])=[NH:40])=[CH:28][C:27]=4[O:33][CH3:34])(=[O:24])=[O:25])[C:12]3=[O:35])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CCOc1ccc2c(c1)n(C13CC4CC(CC(C4)C1)C3)c(=O)n2S(=O)(=O)c1ccc(N)cc1OC
Reactant: CCN(C#N)CC
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)n(C13CC4CC(CC(C4)C1)C3)c(=O)n2S(=O)(=O)c1ccc(NC(=N)N(CC)CC)cc1OC
Product: O
Reaction time: 5 h

Procedure:
A mixture of 1.5 g of the compound obtained in EXAMPLE 40 step B), 1.5 g of N,N-diethylcyanamide, 20 ml of AcOEt and 3 ml of a 20% solution of HCl in EtOH is refluxed for 22 hours. 2 g of N,N-diethylcyanamide and 3 ml of a 20% solution of HCl in EtOH are then added and reflux is continued for 5 hours. After cooling, the reaction mixture is extracted with AcOEt, the organic phase is washed with water, with a 1N solution of NaHCO3 and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (94/6; v/v) as the eluent. The product obtained is dissolved in EtOH, 1 ml of concentrated HCl is added and the mixture is evaporated under vacuum to give 0.2 g of the hydrochloride of the expected product after crystallization from an EtOH/ether mixture (50/50; v/v). M.p.=186° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[As](=O)(O)(O)O.O[CH2:18][CH:19]([CH2:21]O)O.S(=O)(=O)(O)O>O.C(Cl)(Cl)Cl>[CH3:11][C:3]1[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[C:10]2[C:2]=1[N:1]=[CH:21][CH:19]=[CH:18]2
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[As](O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1c(C(=O)O)ccc2cccnc12
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A mixture of 3-amino-2-methylbenzoic acid (Intermediate M1) (6.06 g, 39.6 mmol) (commercially available from Aldrich) and arsenic acid (H5AS3O10) 7.43 g (commercially available from VWR/ALFA) in glycerol (5.8 mL, 79.2 mmol), and sulfuric acid (9 mL) was heated to 160° C. for 5 h. The mixture was cooled to rt, diluted with water and filtered through a bed of diatomaceous earth. The pH was adjusted to pH 6-7 with 2 M NaOH. The aqueous layer was exhaustively extracted with CHCl3:MeOH (3:1). The organic fractions were pooled and evaporated under vacuum to give a solid. This solid was titurated with CHCl3, and collected on a glass frit. The solid material was washed with hexanes and dried under high vacuum to give a pure solid, 8-methylquinoline-7-carboxylic acid (intermediate M2) 3.86 g (51%).
Reaction SMILES: CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29](OCC)=[O:30])=[CH:23][C:22]=1[NH:34][C:35](=[O:51])[CH2:36][CH:37]1[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:44][C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:20])([CH3:19])[CH3:18].Cl>O1CCCC1>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][OH:30])=[CH:23][C:22]=1[NH:34][C:35](=[O:51])[CH2:36][CH:37]1[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:44][C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CCc1ccc(C(C)(C)C)c(NC(=O)CC2c3ccccc3Oc3ccccc32)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(CCCO)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: -78 °C
Reaction time: 1.25 h
Yield: 66.7 %

Procedure:
5.96 ml (5.96 mmol) of a 1.0M hexane solution of diisobutylaluminum hydride were added dropwise, over a period of 10 minutes, to 14 ml of a tetrahydrofuran solution containing 702 mg (1.49 mmol) of N-[2-t-butyl-5-(2-ethoxycarbonylethyl)phenyl]-2-(9H-xanthen-9-yl)-acetamide (prepared as described in Preparation 17) which had previously been cooled at -78° C. The mixture was stirred for 75 minutes at this temperature and then for 45 minutes at room temperature. At the end of this time, the reaction solution was poured into a mixture of dilute aqueous hydrochloric acid and ice, and was then extracted with diethyl ether. The organic extract was washed with water, and then the solvent was removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 30 g of silica gel. Elution with a 5:4 by-volume mixture of methylene chloride and ethyl acetate afforded 427 mg (yield 67%) of the title compound as crystals, melting at 185°-186° C. (after recrystallization from a mixture of methylene chloride and diethyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[C:37]([NH:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:36]=2)[CH2:28][CH2:27]1)(OC(C)(C)C)=O>>[CH2:43]([N:42]1[C:37]2[CH:36]=[C:35]([O:34][CH2:33][CH2:32][N:29]3[CH2:28][CH2:27][NH:26][CH2:31][CH2:30]3)[CH:40]=[CH:39][C:38]=2[N:41]=[C:15]1[C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1)[CH2:44][CH2:45][CH3:46]
Reactant: O=Cc1ccc(OCCc2ccc(Cl)cc2)cc1
Reactant: CCCCNc1cc(OCCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Product: CCCCn1c(-c2ccc(OCCc3ccc(Cl)cc3)cc2)nc2ccc(OCCN3CCNCC3)cc21
Yield: 59.6 %

Procedure:
A mixture of 4-[2-(4-chloro-phenyl)-ethoxy]-benzaldehyde (0.08 g) and 1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine (0.10 g) was subjected to General Procedure K. Ethanol was removed in vacuo and the residue purified on silica gel with 1-2% MeOH/DCM. The BOC-group was removed employing General Procedure T1 to give 1-butyl-2-(4-[2-(4-chlorophenyl)ethoxy]-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole (0.081 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:22]([NH:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([C:17]2[CH:16]=[C:15]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:13]=[C:12]([CH3:14])[N:11]=3)[CH:20]=[CH:19][N:18]=2)[CH:35]=1)(=[O:29])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
3-{4-[4-(4-Chloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 4-(4-chloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-methyl-pyrimidine (example E.45) (0.32 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.47 g), which was subsequently deprotected.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1cnccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(Cc1cnccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36 %

Procedure:
A suspension of 1B (1 g, 2.33 mmol) and platinium 5% wt on activated carbon (600 mg) in THF (30 mL) and MeOH (30 mL) was stirred at RT under H2 at 75 psi for 2 days. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel (40 g) column chromatography eluting with a gradient of methanol (0-6%) in EtOAc/hexane (1:1) to give the title compound as a white foam (360 mg, 36%). LC/MS (method A): retention time=2.77 min, (M+H)+=430.
Reaction SMILES: [CH:1]1[C:15](=[O:16])[N:14]=[C:13]2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3[O:12]2)[CH:2]=1.FC(F)(F)C(O)=[O:20]>CN(C)C=O>[C@@H:4]1([N:3]2[CH:2]=[CH:1][C:15](=[O:16])[NH:14][C:13]2=[O:12])[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]1[OH:20]
Reactant: O=C(O)C(F)(F)F
Reactant: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Solvent: CN(C)C=O
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Temperature: 80 °C

Procedure:
500 mg (2.23 mmol) of the above product 2 is taken as the starting material to immerse in 5 mL of dimethyl formamide. 70 mL of trifluoroacetic acid (0.05N) is added with continuously stirring at 80° C. The solution is concentrated under reduced pressure by removing the residual part of the solution after the completion of the reaction, and then purified by rapid column chromatography (MeOH/CHCl3=1:3). A white powder product (1-(β-D-arabinofuranosyl)-pyrimidin-2,4(3H)-dione) 3 is obtained. Its weight and yield are 510 mg and 95% respectively.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:2].[C:19]1([C:25]2[N:26]=[C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH2:1]([O:3][C:4]1[C:9]([NH:10][C:11]([N:33]2[CH2:34][CH2:35][N:30]([C:27]3[S:28][CH:29]=[C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:26]=3)[CH2:31][CH2:32]2)=[O:18])=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: CCOc1ncncc1NC(=O)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ncncc1NC(=O)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 43.1 %

Procedure:
A solution of 2,2,2-trichloroethyl (4-ethoxypyrimidin-5-yl)carbamate (315 mg, 1.00 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (245 mg, 1.00 mmol), diisopropylethylamine (0.174 ml, 1.00 mmol) and dimethylsulfoxide (5 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (177 mg, 43.2%) as a solid.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]=1[CH3:25])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([Li])[CH2:27]CC.IC>O1CCCC1>[C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N:16]([CH2:26][CH3:27])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]=1[CH3:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(Nc2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)cc1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCN(c1ccc(OC)cc1)c1cc2c(c(C(C)(C)C)c1C)OCC2(C)C
Yield: 92 %

Procedure:
Following general procedure L and using 7-t-butyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 53), (0.12 g, 0.35 mmol), 1.6M solution of n-butyllithium in hexanes (0.442 mL, 0.7 mmol) and iodomethane (0.281 mL, 3.5 mmol) in 2 mL of anhydrous tetrahydrofuran, the title compound (0.11 9 g, 92%) was obtained as a brown oil. 1H NMR (300 MHz, CDCl3): δ 6.76 (d, 2H, J=9.0 Hz), 6.72 (s, 1H), 6.41 (d, 2H, J=9.0 Hz), 4.14 (s, 2H), 3.73 (s, 3H), 2.60 (s, 3H), 1.52 (s, 9H), 1.26 (s, 6H), 1.20 (t, 3H, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[CH:12]([C:14]([CH2:16][CH3:17])=[O:15])=[CH2:13].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[F:1][C:2]([F:10])([F:11])[CH2:3][CH2:4][C:5]([CH2:13][CH2:12][C:14](=[O:15])[CH2:16][CH3:17])([C:8]#[N:9])[C:6]#[N:7]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: C=CC(=O)CC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)CCC(C#N)(C#N)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
3.2 g of 2-(3,3,3-trifluoropropyl)malononitrile and 1.7 g of ethyl vinyl ketone were dissolved in 30 ml of acetone, 3.3 g of potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.3 g of 2-(3,3,3-trifluoropropyl)-2-(3-oxopentyl)malononitrile.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.O>[CH3:31][S:32]([O:21][CH2:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]3[CH:10]=[CH:11][S:12][C:6]=23)[CH2:19][CH2:18]1)(=[O:34])=[O:33]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of {trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methanol (0.26 g, 0.84 mmol) and N,N-diisopropylethylamine (0.30 mL, 1.7 mmol) in methylene chloride (3 mL) was added methanesulfonyl chloride (0.085 mL, 1.1 mmol). The resulting mixture was stirred at room temperature for 2 h. After diluting with water, the mixture was extracted with dichloromethane. The organic layers were concentrated and purified on silica gel (eluting with 0 to 70% EtOAc in hexanes) to give the desired product (0.2 g, 61%). LCMS calculated for C15H20N3O5S2 (M+H)+: m/z=386.1. Found: 386.0.