Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2cccs2)c2ccccc12
Temperature: 100 °C
Yield: 73 %

Procedure:
A mixture of 28.6 g (100 mmol) of 1,4-dibromonaphthalene, 15.35 g (120 mmol) of thiophen-2-ylboronic acid, 2.31 g (2 mmol) of tetrakis(triphenyl phosphine)palladium, 75 ml of 2M Na2CO3, 150 ml of EtOH and 300 ml toluene was degassed and placed under nitrogen, and then heated at 100° C. for 4 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica(hexane-dichloromethane) to give product (21.1 g, 73 mmol, 73%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:5][CH:4]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>CN(C)C=O.O>[CH:22]([N:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][C:6]3[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:16][CH:15]=2)[CH:11]=[N:12]1)([CH3:24])[CH3:23]
Reactant: CC(C)I
Reactant: COc1ccc(Oc2ccc3[nH]ncc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccc3c(cnn3C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(4-methoxy-phenoxy)-1H-indazole (0.20 grams, 0.83 mmol) in 1 mL of dimethylformamide was added sodium hydride (0.040 grams of a 60% dispersion in mineral oil, 1.0 mmol). After shaking at room temperature for 10 minutes, the mixture was treated with 2-iodopropane (0.090 mL, 0.15 grams, 0.9 mmol). The mixture was heated to 50° C. for 6 hours. After cooling to room temperature, the mixture was diluted with water and was extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-30% ethyl acetate in hexanes, affording 1-isopropyl-5-(4-methoxy-phenoxy)-1H-indazole (90 miligrams) MS: 283.4 [M+H]+ and 2-isopropyl-5-(4-methoxy-phenoxy)-2H-indazole MS: 283.4 [M+H]+ (75 miligrams) as colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4](Cl)[N:3]=1.[NH2:27][C@@H:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:29][OH:30].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4]([NH:27][C@H:28]([CH2:29][OH:30])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:3]=1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
The title compound is prepared by combining acetic acid [(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl-carbamoyl]-methyl ester (1 equivalent) and (S)-2-amino-3-phenyl-propan-1-ol 1 equivalent) in dichloromethane with triethylamine (1.1 equivalents) and stirring overnight. The reaction is diluted with dichloromethane, and washed consecutively with 0.1M hydrochloric acid, water and brine, before drying over magnesium sulfate. Filtration and removal of the volatile components under reduced pressure, affords the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Reactant: COc1ccccc1B(O)O
Agent: O=Cc1cccc(B(O)O)c1
Product: COc1ccccc1C1=NCC(=O)N(C)c2ccc(-c3ccccc3)cc21
Yield: 58 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 2-methoxyphenyl boronic acid. The title compound (87 mg) was obtained as a beige solid, (yield=58%).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:19]([O-:24])([N+]([O-])=O)=[O:20].[OH-].[Na+].Cl>ClCCl.C(O)(=O)C>[N+:19]([C:8]1[O:9][C:10]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([O-:24])=[O:20]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)c1ccc2c(-c3ccccc3)coc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)c1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1
Reaction time: 70 h

Procedure:
A solution of 2 g of 3-phenyl-6-benzofurancarboxylic acid in 100 ml of dichloromethane and 20 drops of acetic acid is treated with 3.0 g of dinitrogen tetroxide. The mixture is stirred for about 70 hours then evaporated to provide a residue. The residue is treated with cold 5% sodium hydroxide solution until solution occurs. The solution is acidified with 6N hydrochloric acid and the yellow solid is collected and recrystallized from ethanol to provide 2-nitro-3-phenyl-6-benzofurancarboxylic acid, m.p. 244°-247° C.
Reaction SMILES: Br[C:2]1[N:3]([CH2:12][C:13]#[C:14][CH3:15])[C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].O>CN(C)C=O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:3]([CH2:12][C:13]#[C:14][CH3:15])[C:4]3[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=3[N:11]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC#CCn1c(Br)nc2cn[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cn[nH]c(=O)c21
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 2.11 g of 2-bromo-3-(2-butyn-1-yl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one, 1.64 g potassium carbonate and 1.91 g 1-tert.-butyloxycarbonyl-piperazine in 20 ml N,N-dimethylformamide is stirred for six hours at 80° C. After cooling to ambient temperature the reaction mixture is combined with water and the precipitate formed is suction filtered. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol (95:5 to 90:10).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[NH:25][C:26]([NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:27]([F:32])[C:28](=[N:30][NH2:31])[N:29]=1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:23][C:24]1[N:29]=[C:28]([NH:30][NH:31][C:8](=[O:10])[C@H:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[C:27]([F:32])=[C:26]([NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:25]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: NN=c1nc(Cl)[nH]c(NC2CCOCC2)c1F
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NC2CCOCC2)c1F)OCc1ccccc1
Reaction time: 8 h
Yield: 81.2 %

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.220 g, 0.72 mmol), 2-chloro-5-fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-4(1H)-pyrimidinone hydrazone (0.199 g), NMM (0.42 mL, 3.80 mmol), HOAt (0.103 g, 0.76 mmol), EDC (0.146 g, 0.76 mmol) were dissolved in DMF (5 mL). Reaction left to stir overnight. Added ether, washed with water, back extracted aqueous layers with ether, dried (Na2SO4) and concentrated in vacuo to provide [(2R)-3-{2-[2-chloro-5-fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide as a dark brown solid (0.321 g). LCMS: (M+H)+=549.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1[CH:21]=[C:22]([NH:27]C(=O)OC(C)(C)C)[CH:23]=[CH:24][C:25]=1[OH:26]>CN(C)C=O>[F:19][C:20]1[CH:21]=[C:22]([NH2:27])[CH:23]=[CH:24][C:25]=1[O:26][C:2]1[CH:7]=[N:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Oc2ccc(N)cc2F)cn1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
10.9 g of 5-chloro-2-ethanesulfonyl-pyridine and 1.6 g of cesium carbonate were added to a dimethylformamide (150 ml) solution of 10.0 g of tert-butyl (3-fluoro-4-hydroxy-phenyl)-carbamate obtained in Example 196 (step 1), and the reaction liquid was stirred at 100° C. for 3 hours. The solvent was evaporated away under reduced pressure, diluted with chloroform, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/9) to obtain a crude product. The resulting crude product was dissolved in 4 N hydrochloric acid/dioxane, and stirred at room temperature for 1 hour. The solvent was evaporated away under reduced pressure, diluted with chloroform, washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/9) to obtain the entitled compound.
Reaction SMILES: [C:1]([O:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([C:17](Cl)=[O:18])([CH2:10]3)[CH2:8]1)[CH2:14]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[F:20][C:21]([F:28])([S:24]([O-:27])(=[O:26])=[O:25])[CH2:22][OH:23].[C:29]1([S+:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:20][C:21]([F:28])([S:24]([O-:27])(=[O:26])=[O:25])[CH2:22][O:23][C:17]([C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([CH2:14]3)[CH2:8]1)[CH2:10]2)=[O:18].[C:42]1([S+:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=S(=O)([O-])C(F)(F)CO
Reactant: C=C(C)C(=O)OC12CC3CC(C1)CC(C(=O)Cl)(C3)C2
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC12CC3CC(C1)CC(C(=O)OCC(F)(F)S(=O)(=O)[O-])(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To 3.3 g (11 mmol) of the 3-methacryloyloxyadamantane-carbonyl chloride were added 4.2 g (10 mmol) of triphenylsulfonium 1,1-difluoro-2-hydroxyethanesulfonate in Synthesis Example 1-13 and 20 g of methylene chloride. To the mixture under ice cooling, a solution containing 1.1 g (11 mmol) of triethylamine and 0.25 g (2 mmol) of N,N-dimethylaminopyridine in 5 g of methylene chloride was added at a temperature below 5° C., and the resulting mixture was stirred for 2 hours at room temperature. Thereafter, 11 g of 5% dilute hydrochloric acid was added to the reaction mixture. The organic layer was taken out and washed with water, from which methylene chloride was distilled off in vacuum. 30 g of methyl isobutyl ketone was added to the residue, from which the residual water was distilled off in vacuum together with methyl isobutyl ketone. Diethyl ether was added to the residue for recrystallization. The resulting crystals were recovered and dried, obtaining the target compound, triphenylsulfonium 1,1-difluoro-2-(3-methacryloyloxy-adamantane-1-carbonyloxy)-ethane-1-sulfonate. White crystals, 5.5 g (yield 82%). The compound has the following structure.
Reaction SMILES: [CH2:1]1[O:19][C:18]2[C:3](=[CH:4][C:5]3[C:11](=[O:12])[CH2:10][S:9][CH:8]([C:13]([O:15]C)=[O:14])[CH2:7][C:6]=3[CH:17]=2)[O:2]1.[OH-].[K+].O>CO>[CH2:1]1[O:19][C:18]2[C:3](=[CH:4][C:5]3[C:11](=[O:12])[CH2:10][S:9][CH:8]([C:13]([OH:15])=[O:14])[CH2:7][C:6]=3[CH:17]=2)[O:2]1
Reactant: COC(=O)C1Cc2cc3c(cc2C(=O)CS1)OCO3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CSC(C(=O)O)Cc2cc3c(cc21)OCO3
Temperature: 25 °C
Yield: 86.1 %

Procedure:
Methyl 7,8-methylenedioxy-5-oxo-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxylate (16.5 g) was suspended in methanol (100 ml), to which 2N--KOH (100 ml) was added. After stirring for an hour at room temperature, the mixture was poured into water, acidified and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated to afford 7,8-methylenedioxy-5-oxo-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxylic acid (13.5 g, 86%). Recrystallization from ethyl acetate gave colorless prisms.
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].[I:23]I.O>CCCCCC.O1CCCC1>[CH2:6]([C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[C:17]([F:22])[C:18]([I:23])=[C:19]([F:21])[CH:20]=2)[CH2:13][CH2:14]1)[CH2:7][CH3:8]
Reactant: II
Reactant: CCC[C@H]1CC[C@H](c2cc(F)cc(F)c2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2cc(F)c(I)c(F)c2)CC1
Temperature: 25 °C

Procedure:
5.9 ml of a 1.6N butyllithium solution in hexane were added dropwise during 20 min. to a solution of 2.14 g of 1-(trans-4-propylcyclohexyl)-3,5-difluorobenzene in 20 ml of dry detrahydrofuran at -70° C. and the mixture was left to react at -70° C. for 1 hr. Then, a solution of 2.4 g of iodine in 10 ml of dry tetrahydrofuran was added dropwise at -60° C. within 10 min. and the mixture was gradually warmed to room temperature during a further 30 min. The yellow solution obtained was treated with 10 ml of water and then with 10 ml of a 10 percent aqueous sodium bicarbonate solution extracted with ether. The ether solution was washed with sat. sodium chloride solution and several times with water, dried over magnesium sulphate, filtered and concentrated. Chromatography of the residue over 150 g of silica gel with hexane gave 3.27 g of 1-(trans-4-propylcyclohexyl)-3,5-difluoro-4-iodobenzene as a colourless liquid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([N:36]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:37]1[NH:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[N:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:46]([N:36]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:37]1[N:41]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[N:38]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: c1ccc(CN(Cc2ccccc2)c2nc3ccccc3[nH]2)cc1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(N(Cc4ccccc4)Cc4ccccc4)nc4ccccc43)nc21

Procedure:
2-(1-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.35 g) was reacted with N,N-dibenzyl-1H-benzo[d]imidazol-2-amine via General Procedure J for Buchwald coupling to give 255 mg of 2-(1-((2-(2-(dibenzylamino)-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol following flash chromatography.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=CC=CC=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(OC1C(C(O)=O)=NC(CC2(C3C=CC([Cl:72])=CC=3)CCCC2)=NC=1O)C1C=CC=CC=1.[Si](OCCN)(C(C)(C)C)(C)C>>[CH2:21]([O:20][C:19]1[C:14]([C:12]([NH:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[O:13])=[N:15][C:16]([CH2:29][C:30]2([C:35]3[CH:44]=[CH:39][C:38]([Cl:72])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:17][C:18]=1[OH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCNC(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCN
Product: CC(C)(C)[Si](C)(C)OCCNC(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
This compound was prepared by following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-amide (346) from 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (324) and 2-(tert-butyl-dimethylsilanyloxy)-ethylamine (8c).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:26]5[CH:31]=[CH:30][C:29]([S:32][CH:33]6[CH2:35][CH2:34]6)=[CH:28][CH:27]=5)[N:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[O:37]1CO1>ClCCl.CC(C)=O>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:26]5[CH:27]=[CH:28][C:29]([S:32]([CH:33]6[CH2:35][CH2:34]6)=[O:37])=[CH:30][CH:31]=5)[N:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CC(C)CNc1nc(-c2ccc(SC3CC3)cc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Reactant: C1OO1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)CNc1nc(-c2ccc(S(=O)C3CC3)cc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
A solution of 50 mg (100 μmol) N-cyclopropyl-4-{6-[4-(cyclopropylsulfanyl)phenyl]-8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide in 5.0 mL dichloromethane was cooled to −30° C. and 1.16 mL of a 0.15 molar dioxirane solution in acetone were added. After 15 minutes of stirring the mixture was warmed to 23° C., the solvent removed and the residue was purified by chromatography to give 33.3 mg (59%) of the title compound. 1H-NMR (CDCl3): δ=0.67 (2H), 0.86-1.05 (5H), 1.06 (3H), 1.07 (3H), 1.25 (1H), 2.09 (1H), 2.28 (1H), 2.95 (1H), 3.56 (2H), 6.36 (1H), 6.54 (1H), 7.60 (1H), 7.63 (2H), 7.70 (2H), 7.94 (2H), 7.96 (1H), 8.02 (2H) ppm.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][CH2:10][CH:11]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.C(N(C(C)C)CC)(C)C.C1([O:43][C:44](=O)[NH:45][C:46]2[S:47][C:48]3[N:49]=[CH:50][N:51]=[C:52]([O:55][CH3:56])[C:53]=3[N:54]=2)C=CC=CC=1>C(#N)C>[CH3:56][O:55][C:52]1[C:53]2[N:54]=[C:46]([NH:45][C:44]([N:25]3[CH2:26][CH2:27][N:22]([CH:11]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=4)[CH2:10][O:9][CH3:8])[CH2:23][CH2:24]3)=[O:43])[S:47][C:48]=2[N:49]=[CH:50][N:51]=1
Reactant: COCC(c1cccc(C(F)(F)F)c1)N1CCNCC1
Reactant: COc1ncnc2sc(NC(=O)Oc3ccccc3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCC(c1cccc(C(F)(F)F)c1)N1CCN(C(=O)Nc2nc3c(OC)ncnc3s2)CC1
Temperature: 70 °C
Yield: 40.8 %

Procedure:
A mixture of 1-[2-Methoxy-1-(3-trifluoromethyl-phenyl)-ethyl]-piperazine trifluoroacetate (160 mg, 0.40 mmol) and diisopropylethylamine (0.35 mL, 2.0 mmole) in acetonitrile (10 mL) was heated at 70° C. for ten minutes. After cooling to room temperature, (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-carbamic acid phenyl ester (120 mg, 0.40 mmol) was added to the above solution. The mixture was stirred at reflux for three hours. LCMS analysis indicated complete consumption of starting material. The reaction was concentrated and the crude was purified using reversed phase HPLC to give 4-[2-Methoxy-1-(3-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (81 mg, 41% yield) as a white powder. LRMS for C21H23F3N6O3S (M+H)+ at m/z=497. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:14][N:15](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:16].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:11]([N:15]([CH3:16])[CH3:14])=[O:13])=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1[nH]cc(C(=O)O)c1Cl
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1[nH]cc(C(=O)N(C)C)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of 4-chloro-5-[(methyloxy)carbonyl]-1H-pyrrole-3-carboxylic acid (0.075 g, 0.368 mmol) in DMF (1 ml) was added HATU (0.168 g, 0.442 mmol), DIPEA (0.097 ml, 0.553 mmol) and dimethyl amine (2M in THF) (0.276 ml, 0.553 mmol) and the reaction stirred at RT for 1 h. Purification was accomplished by HPLC to afford methyl 3-chloro-4-[(dimethylamino)carbonyl]-1H-pyrrole-2-carboxylate (0.042 g, 49% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.40 (br. s., 1H) 7.23 (d, 1H) 3.80 (s, 3H) 2.93 (s, 6H). MS: m/z 231.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]([CH2:21][CH2:22][NH2:23])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1.O>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:12][C:11]([CH2:21][CH2:22][NH:23][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1cc(OCC2CCCC2)c2c(N)c(C(N)=O)sc2c1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCc1cc(OCC2CCCC2)c2c(N)c(C(N)=O)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a stirred solution of 3-amino-6-(2-amino-ethyl)-4-cyclopentylmethoxy-benzo[b]thiophene-2-carboxylic acid amide (11) (HCl salt form, 0.100 g, 0.270 mmol) in pyridine (1 mL) at 0° C. was added methanesulfonyl chloride (0.08 mL, 1 mmol). It was allowed to warm to room temperature and stirred overnight. It was diluted with water, extracted with dichloromethane, washed with brine, dried with sodium sulfate, and concentrated. The residue was purified by preparatory thin layer chromatography to afford the title compound (0.021 g, 19%).