Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[F:8][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][C:34]=1[O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:43]([Si:48]1([CH3:62])[CH2:53][CH2:52][CH:51]([CH:54]2[CH2:59][CH2:58][CH:57]([CH:60]=O)[CH2:56][CH2:55]2)[CH2:50][CH2:49]1)[CH2:44][CH2:45][CH2:46][CH3:47].O>C1COCC1.C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:60][CH:57]2[CH2:56][CH2:55][CH:54]([CH:51]3[CH2:52][CH2:53][Si:48]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])([CH3:62])[CH2:49][CH2:50]3)[CH2:59][CH2:58]2)[CH:32]=[CH:33][C:34]=1[O:35][Si:36]([C:39]([CH3:40])([CH3:41])[CH3:42])([CH3:37])[CH3:38]
Reactant: CCCCC[Si]1(C)CCC(C2CCC(C=O)CC2)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCC[Si]1(C)CCC(C2CCC(C=Cc3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.0 g of potassium t-butoxide was added to a mixture of 60 g of 3-fluoro-4-(t-butyldimethylsiloxy)benzyltriphenylphosphonium bromide and 200 ml of THF to prepare an orange-colored ylide solution. A solution, in 50 ml of THF, of 33 g of 4-(4-n-pentyl-4-methyl-4-silacyclohexyl)cyclohexane carbaldehyde was added to the ylide solution. The reaction mixture was agitated at room temperature for 2 hours, followed by pouring into iced water and extraction with ethyl acetate. After ordinary washing, drying and concentration, n-hexane was added to the resultant residue. The resulting crystals of triphenylphosphine oxide was removed by filtration and the filtrate was concentrated. The resultant reside was purified through silica gel chromatography to obtain 4-(4-(2-(3-fluoro-4-(t-butyldimethylsiloxy)phenyl)ethenyl)cyclohexyl)-1-pentyl-1-methyl-1-silacyclohexane. This product was dissolved in 200 ml of ethyl acetate and hydrogenated in the presence of a catalyst composed of 200 mg of platinum oxide at a pressure of 0.1 MPa. After theoretical consumption of hydrogen, the catalyst was removed by filtration and the resultant filtrate was concentrated. 100 ml of a THF solution of 1 mol/liter of tetrabutylammonium fluoride was added to the concentrate, followed by agitation at room temperature for 3 hours. The reaction mixture was poured into 10% hydrochloric acid. After ordinary washing, drying and concentration, the resultant residue was purified through silica gel chromatography. The purified product was reacted with 24 g of sodium hydride in 1,3-dimethyl-2-imidazolidinone to obtain a sodium salt. After ordinary washing, drying and concentration, the sodium salt was purified through silica gel chromatography, followed by recrystallization to obtain 15.0 g of the intended trans isomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[Br:13]Br>>[Br:13][C:8]1[CH:7]=[C:6]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: BrBr
Product: COc1ccc(CC(=O)O)cc1Br
Yield: 98.9 %

Procedure:
Proceeding as in Reference 14, but substituting 4-methoxyphenylacetic acid (16.6 g, 0.1 mol) and bromine (16.0 g, 0.1 mol), gave 3-bromo-4-methoxyphenylacetic acid (24.24 g, 98%) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1cccc(CBr)c1F
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3cccc(F)c3F)c2c1

Procedure:
The titled compound (14 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2,3-difluorobenzyl bromide according to the method of the process (7) of Example 4.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:19])=O>>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:19])[C:5]=2[S:4][CH:3]=1
Reactant: O=c1[nH]cnc2c(Br)csc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ncnc2c(Br)csc12
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 7-bromo-3H-thieno[3,2-d]pyrimid-4-one (126, 0.94 g, 4.1 mmol) in phosphorus oxychloride (4 mL) under N2 was heated at reflux for 1 hour. The resulting solution was allowed to cool to room temperature and then poured into a saturated aqueous solution of sodium bicarbonate to neutralize. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with water followed by saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to yield 7-bromo-4-chlorothieno[3,2-d]pyrimidine (0.83 g, 82% yield) as a yellow solid.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](Cl)(=[O:15])[C:12](Cl)=[O:13]>O1CCCC1>[C:1]1([N:7]2[C:12](=[O:13])[C:11](=[O:15])[NH:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)Nc1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(=O)N(c2ccccc2)C1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
272.3 g of N-phenylurea are dissolved in 1.5 liters of tetrahydrofuran. The solution is heated to 50°C and slowly treated with 171 ml of oxalyl chloride, in the course of which the reaction temperature should not exceed 65°C. Stirring is continued for 1 hour at room temperature and then for 4 hours under reflux. The reaction mixture is evaporated and the residue is recrystallised from isopropanol to give 1-phenyl-2,4,5-trioxo-imidazolidine (m.p. 214°-216°C).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>>[Cl:26][CH2:27][C:28]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:24][CH:25]=1)=[O:29]
Reactant: NCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Reactant: O=C(Cl)CCl
Product: O=C(CCl)NCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 62.1 %

Procedure:
1-[1-(4-Aminomethylphenethyl)piperidin-4-yl]indoline (0.1 g) and chloroacetyl chloride (0.026 ml) were treated as in Example 36 to give the title compound (0.074 g) as a pale yellow oil (yield: 62.1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[C:9]2=[O:28])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C>ClCCl>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:9]2=[O:28])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)C2=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(CCN2CCNCC2)CCC1(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
The product from Example 63B (2.00 g, 4.12 mmol) was dissolved in dichloromethane (40 mL) and treated with trifluoroacetic acid (7.40 g, 64.9 mmol) at 0° C. The reaction was allowed to come to room temperature and stirred for 1 hour. The reaction was neutralized with triethylamine and concentrated. The residue was taken into ethyl acetate, and then it was washed with water and brine, dried with MgSO4, filtered and concentrated to give the title compound. MS (DCI) m/z 386.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:15]([OH:17])=O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[I:50][C:51]1[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][CH:52]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:25])([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[C:15](=[O:17])[NH:55][C:54]2[CH:56]=[CH:57][C:51]([I:50])=[CH:52][CH:53]=2)=[CH:9][CH:8]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(C(=O)O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: Nc1ccc(I)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(NC(C(=O)Nc2ccc(I)cc2)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
(4-{[(4-tert-Butyl-phenyl)-carboxy-methyl]-amino}-benzoic acid tert-butyl ester (760 mg, 2.0 mmol), was taken up in 5 mL of DMF followed by addition of HOBt (765 mg, 5.0 mmol) and EDCI (958 mg, 5.0 mmol). The reaction was stirred at RT for 30 min, 4-iodoaniline (657 mg, 3 mmol) was added followed by Hunig's base (640 mg, 5 mmol) and allowed to stir an additional 16 h at RT. Ethyl acetate (20 mL) and 20 mL water were added and separated. The aqueous layer was then back extracted with another 10 mL of EtOAc, the organic layer were combined and washed with water (3×20 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give a brown solid. The solids were triturated with methanol to give a white solid (818 mg, 70%). 1H NMR (CDCl3): δ 1.32 (9H, s), 1.58 (9H, s), 4.89 (2H, d), 5.02 (1H, d), 6.62 (2H, d, J=8.4 Hz), 7.22-7.95 (10H, m), 8.81 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18]O)=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.O=S(Cl)[Cl:23]>>[Cl:23][CH2:18][C:17]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:20]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc2cc(CO)c(-c3ccccc3F)nc12
Product: Cc1cccc2cc(CCl)c(-c3ccccc3F)nc12
Yield: 88.8 %

Procedure:
Prepared according to Procedure C using (2-(2-fluorophenyl)-8-methylquinolin-3-yl)methanol (0.700 g, 2.62 mmol) in SOCl2 (2 mL, 27.4 mmol, 10.5 eq). 3-(chloromethyl)-2-(2-fluorophenyl)-8-methyl-quinoline (0.665 g, 89%) was obtained after purification as a brown foam. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.61 (1 H, s), 7.92 (1 H, d, J=7.9 Hz), 7.71 (1 H, d, J=6.7 Hz), 7.53-7.66 (3H, m), 7.40 (2 H, t, J=7.9 Hz), 4.81 (2 H, s), 2.69 (3 H, s) Mass Spectrum (ESI) m/e=286.1 and 288.1 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:21]=[CH:20][C:19]([N:22]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][C:10]=1[C:11]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:33]=[N+:34]([O-:57])[CH:35]=[C:36]([Cl:56])[C:37]=1[CH2:38][C@@H:39]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:50])[F:49])=[C:43]([O:51][CH2:52][CH:53]2[CH2:55][CH2:54]2)[CH:42]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([O:8][C:9]1[CH:21]=[CH:20][C:19]([N:22]([CH2:27][CH:28]2[CH2:29][CH2:30]2)[S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][C:10]=1[C:11]([O:13][CH2:14][C:15]([O:17][C@H:39]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:49])[F:50])=[C:43]([O:51][CH2:52][CH:53]2[CH2:54][CH2:55]2)[CH:42]=1)[CH2:38][C:37]1[C:36]([Cl:56])=[CH:35][N+:34]([O-:57])=[CH:33][C:32]=1[Cl:31])=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)OCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)OCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A mixture of 2-(2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)-methylsulfonamido)benzoyloxy)acetic acid (0.215 g, 0.485 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (204 g, 0.485 mmol), EDC (0.279 g, 1.454 mmol), and DMAP (0.059 g, 0.485 mmol) in DCM (25 mL) was stirred at RT overnight. The mixture was diluted with DCM and washed with 1N HCl and 5% NaHCO3. The organic phase was dried over sodium sulfate and the solvent was removed. The crude was purified by chromatography on silica gel cartridge (DCM:MeOH=99:1) affording (S)-4-(2-(2-(2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)methylsulfonamido)-benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.326 g, 0.385 mmol, 80% yield, MS/ESI+ 845.1 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6]([OH:23])=[C:7]([C:16]([NH:18][CH2:19][C:20]([O-:22])=[O:21])=[O:17])[C:8](=[O:15])[C:9]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6]([OH:23])=[C:7]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[C:8](=[O:15])[C:9]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)C(C(=O)NCC(=O)[O-])=C(O)c2ccc(Cl)c(F)c21
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(Cl)c(F)c21
Yield: 100.7 %

Procedure:
A solution of 1,1-dimethylethyl N-((6N-((7-chloro-8-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.148 g, 0.372 mmol) in TFA (5.00 mL, 64.9 mmol) was stirred at 25° C. for 15 minutes. The solution was concentrated, azeotroped using DCM (2×100 mL), and dried in vacuo to give the title compound (0.128 g). MS m/e=342.4 (M+H)+. Calculated for C15H13ClFNO5 341.05.
Reaction SMILES: [C:1]1([NH:7][C:8](=[S:10])[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3]C=1.[CH:11]1(NC)CCCC1>O1CCOCC1>[CH:1]1([NH:7][C:8](=[S:10])[NH:9][CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(=S)Nc1ccccc1
Reactant: CNC1CCCC1
Solvent: C1COCCO1
Product: CNC(=S)NC1CCCC1

Procedure:
14.5 g of N-[4-(β-<2-methoxy-5-methyl-benzamido>-ethyl)-benzenesulfonyl]-N'-phenyl-thiourea were dissolved in 50 ml of dioxane. After addition of 6 g of cyclopentyl-methylamine, the whole was heated for 2 hours to the boiling temperature under reflux. After having removed the dioxane by distillation, the residue was dissolved in 1% aqueous ammonia. The solution was filtered through charcoal and acidified with dilute hydrochloric acid. The N-[4-(β-<2-methoxy-5-methyl-benzamido>-ethyl)-benzenesulfonyl]-N'-cyclopentyl-methyl-thiourea so obtained was found to melt, after recrystallization from methanol, at 152° - 154° C.
Reaction SMILES: [C@@H:1]1([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C>[Si:24]([C@@:3]1([OH:4])[C@@H:5]([CH2:6][O:7][Si:24]([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25])[O:8][C@@H:1]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:2]1)([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@]1(O)[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2′-deoxyguanosine dG (0.89 g, 3.30 mmol), imidiazole (2.0 g, 29.32 mmol), and TBSCl (2.34 g, 15.55 mmol) were added to anhydrous DMF (8 mL) at 0° C. under a N2 atmosphere. The reaction mixture was gradually warmed to room temperature and stirred overnight. The mixture was then concentrated in vacuo, treated with a mixture of CHCl3 (8 mL) and MeOH (8 mL), concentrated in vacuo, and purified by silica gel chromatography to yield 3′,5′-O-bis-tert-butyldimethylsilyl-2′-deoxyguanosine dG.01 (1.57 g, 96%) as a white powder.
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][C:20](=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH:9]=1>C(OCC)(=O)C>[CH3:36][Si:33]([CH3:34])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:38])([CH3:37])[CH3:1])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: CCOC(=O)C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a 50 mL roundbottom flask was charged ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)-methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate (800 mg, 1.43 mmol) and ethyl acetate (15 mL). The flask was flushed with argon, and 5% palladium on carbon (100 mg) was added. The flask was sealed and degassed under vacuum. Hydrogen gas was then added via balloon. The reaction was stirred under a hydrogen atmosphere for 18 hours. The reaction was then filtered through celite to yield ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (761 mg, 1.35 mmol, 95% yield) as pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][CH:16]([N:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C:15]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1.[OH-].[K+].I[CH2:36][CH2:37][CH3:38]>CS(C)=O.C(OCC)C.O>[F:32][C:2]([F:1])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][CH:16]([N:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:36][CH2:37][CH3:38])=[CH:26][CH:25]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)N(C)C1CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(O)cc1
Reactant: CCCI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2N(C)C(=O)OC)cc1
Temperature: 50 °C

Procedure:
To 1.0 g (2.2 mmole) of N-(4-trifluoromethoxyphenyl)-3-(4-hydroxyphenyl)-4-(N-methyl-N-(methoxycarbonyl)amino)-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 297) dissolved in 7.5 ml of dimethylsulfoxide was added 0.35 g (2.8 mmole) of 45% aqueous potassium hydroxide and 1.02 g (6.0 mmole) of 1-iodopropane. The mixture was warmed to 50° C. for 30 minutes and diluted with diethyl ether and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and chromatographed over silica gel using hexane and diethyl ether to yield the title compound, a white solid, mp 153°-155° C.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.[ClH:10]>>[ClH:10].[Cl:10][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1
Reactant: OCCC1CCCCN1
Agent: Cl
Product: ClCCC1CCCCN1
Temperature: 25 °C
Yield: 46 %

Procedure:
A 27.2 g (0.2 mole) sample of 2-(2-hydroxyethyl)piperidine was treated with ethereal hydrogen chloride and the salt was dried briefly. The solid was dissolved in 125 mL of warm chloroform and then 33.5 mL (0.46) of thionyl chloride was added in portions to the solution. The mixture was refluxed for 2.5 hr. The reaction mixture was cooled to room temperature, and the solvent evaporated in vacuo to a brown solid. The solid was recrystallized from ethanol-ether to give 17 g (46% yield) of the title compound as solid, mp=160°-162° C.
Reaction SMILES: [CH:1]1([C:7]2[S:25][C:10]3[N:11]=[C:12]([CH3:24])[N:13]=[C:14]([CH2:15][NH:16][CH:17]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26]C#N.CI.CCN(C(C)C)C(C)C>O>[CH:1]1([C:7]2[S:25][C:10]3[N:11]=[C:12]([CH3:24])[N:13]=[C:14]([CH2:15][N:16]([CH3:26])[CH:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)[C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc(CNC2CCCCCC2)c2cc(C3CCCCC3)sc2n1
Reactant: CC#N
Solvent: CI
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(CN(C)C2CCCCCC2)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of N-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]cycloheptaneamine (132 mg) and CH3CN (3 mL) were added CH3I (100 μL) and DIPEA (200 μL), followed by stirring at room temperature for 15 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain N-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]-N-methylcycloheptaneamine (77 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].F[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3cc(C)ccc3[N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C

Procedure:
4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) and 2-Fluoro-4-methyl-1-nitro-benzene (756 mg, 4.87 mmol) are dissolved in 20 ml of dimethylformamide. After addition of potassium carbonate (1.3 g, 9.74 mmol) the mixture is stirred over night at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate and washed with water. The organic layers are dried over sodium sulfate and evaporated. The crude product is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:11]1[CH:12]=[C:13]([NH:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:15][CH:16]=1)=[O:10].N1C=CC=CC=1.[CH2:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:11]1[CH:12]=[C:13]([N:17]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:33]([CH2:31][CH3:32])(=[O:35])=[O:34])[CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccccc1S(=O)c1cccc(NCc2cccnc2)c1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(S(=O)c2ccccc2OC)c1
Temperature: 0 °C
Yield: 8.4 %

Procedure:
N-(3-(2-Methoxyphenylsulfinyl)phenyl)pyrid-3-ylmethylamine (159 mg, 0.44 mmol) was taken up in 1,2-dichloroethane (2.0 ml) and anhydrous pyridine (1.0 ml) and cooled under nitrogen to 0° C. Ethanesulfonyl chloride (103 mg, 0.80 mmol) is added dropwise via syringe and the reaction allowed to stir at 0° C. for thirty minutes. The ice bath is removed and the mixture stirred 88 hours at room temperature, as a matter of convenience. Solid potassium carbonate was added, the reaction stirred an additional hour, and then filtered and concentrated to a dark oil. Radial silica gel chromatography (2 mm Chromatotron® plate, eluting with 20/1 methylene chloride/methanol) afforded the title compound (16 mg, 8%). 1H NMR(400 MHz): 1.39(3H,t,J=7.3), 3.04(2H,q,J=7.3), 3.78(3H,s), 4.88(2H,s), 6.86(1H,d,J=7.8), 7.11-7.21(2H,m), 7.25-7.30(1H,m), 7.35(1H,t,J=7.8), 7.42(1H,dt,J=7.3, 2.0), 7.56-7.62(2H,m), 7.68(1H,m), 7.81(1H,dd,J=7.3, 1.5), 8.31(1H,br s), 8.46(1H,br s); MS(HRMS)m/z 431.1116([M+H]+calcd for C21H23N2O4S 431.1099).