Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(#N)C>[CH:16]1([NH:19][CH:6]2[CH2:7][CH2:8][C:3]([CH2:2][OH:1])([C:10]3[N:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[CH2:4][CH2:5]2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: O=C1CCC(CO)(c2ncccn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Product: OCC1(c2ncccn2)CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 4-(hydroxymethyl)-4-(pyrimidin-2-yl)cyclohexanone (238 mg, 1.15 μmol), cyclopropylamine (106 μl, 1.50 mmol), and acetic acid (87 μl, 1.50 mmol) in acetonitrile (6 mL) was treated at 0° C. with NaBH(OAc)3 (367 mg, 1.73 mmol). After being stirred at 25° C. for 20 h, the reaction was then basified (1 M aqueous NaOH, pH˜12), extracted (5×10% MeOH/DCM), and washed (1× brine). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide (4-(cyclopropylamino)-1-(pyrimidin-2-yl)cyclohexyl)methanol (281 mg, 1.14 mmol, quantitatively) as a pale yellow film.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: C1=COCCC1
Reactant: OCCCCCCCCCBr
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: BrCCCCCCCCCOC1CCCCO1
Yield: 89 %

Procedure:
A solution of 9-bromo-1-nonanol (2.00 g, 8.96 mmol), 3,4-dihydro-2H-pyran (792 mg, 9.41 mmol), and pyridinium toluene-4-sulfonate (1.08 g, 4.30 mmol) in dichloromethane (34 mL) was stirred at room temperature for 16 h, then washed with 2 M aq. sodium carbonate solution and brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced 2-(9-bromo-nonyloxy)-tetrahydro-pyran (2.45 g, 89%). Colorless oil, m/e=324.1 ([M+NH4]).
Reaction SMILES: C([C@H]1COC(C2C=CC=C(C3OC[C@H](C(C)C)N=3)N=2)=N1)(C)C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:65]2[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][CH:66]=2)([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[O:32][CH2:33][C@H:34]2[O:38][C@@H:37]([N:39]3[C:56]4[N:55]=[CH:54][N:53]=[C:43]([NH:44][C:45](=[O:52])[C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[C:42]=4[N:41]=[CH:40]3)[C@H:36]([OH:57])[C@@H:35]2[OH:58])=[CH:27][CH:26]=1.[C:73]1([N:79]=[C:80]=[O:81])[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1.C([O-])([O-])=O.[K+].[K+].COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)OC[C@H]2O[C@@H](N3C4N=CN=C(NC(=O)C5C=CC=CC=5)C=4N=C3)[C@H](OC(=O)NC3C=CC=CC=3)[C@@H]2O)=CC=1>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].C1COCC1>[CH3:72][O:71][C:68]1[CH:67]=[CH:66][C:65]([C:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[O:32][CH2:33][C@H:34]2[O:38][C@@H:37]([N:39]3[C:56]4[N:55]=[CH:54][N:53]=[C:43]([NH:44][C:45](=[O:52])[C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[C:42]=4[N:41]=[CH:40]3)[C@H:36]([OH:57])[C@@H:35]2[O:58][C:80](=[O:81])[NH:79][C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)=[CH:70][CH:69]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: [Cu+2]
Agent: CC(C)[C@H]1COC(c2cccc(C3=N[C@@H](C(C)C)CO3)n2)=N1
Agent: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)[C@H](OC(=O)Nc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)[C@H](O)[C@@H]2OC(=O)Nc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
The THF solution (75 ml) containing 2,6-bis[(4S)-isopropyl-2-oxazoline-2-yl]pyridine (0.15 mmol, 45.2 mg) and copper chloride (II) (0.15 mmol, 25.6 mg) was stirred for a day at room temperature. After the reaction mixture was cooled to −15° C., the THF solution (15 ml) of 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-N6-benzoyladenosine (1.5 mmol, 1.0 g) and the THF solution (15 ml) of phenyl isocyanate (1.5 mmol, 178.7 mg) and K2CO3 (1.5 mmol, 207.3 mg) were added thereto. After the mixture was continuously stirred for 42 hours at −15° C., the mixture was analyzed with high-performance liquid chromatography. As a result, it was found that 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-N6-benzoyl-2′-O-phenylcarbamoyladenosine and 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-N6-benzoyl-3′-O-phenylcarbamoyladenosine were produced at the ratio of 93:7, and the transformation ratio of the reaction was 99%.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][C:5]1[N:10]=[C:9]2[CH2:11][O:12][C:13](=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=4)[NH:16][C:15]3=[O:24])[C:8]2=[CH:7][CH:6]=1.S(=O)(=O)(O)O>C1COCC1>[F:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:24])[C:14]2=[C:13]1[C:8]2[C:9](=[N:10][C:5]([CH2:4][CH:3]=[O:2])=[CH:6][CH:7]=2)[CH2:11][O:12]1
Reactant: COC(Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21)OC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=CCc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 60 °C
Yield: 54.4 %

Procedure:
A solution of 3-[2-(2,2-dimethoxy-ethyl)-7H-furo[3,4-b]pyridin-5-ylidene]-5-fluoro-1,3-dihydro-indol-2-one (52 mg, 0.16 mmol) in THF (5 mL) is treated with 0.63 mL of an aqueous 2.5 M sulfuric acid solution (0.63 mL). The reaction mixture is heated to 60° C. for 1 h, cooled to room temperature and poured into 100 mL ice water with stirring. The brown solid which precipitated is collected by filtration, washed with water, and dried under vacuum to give the title compound as brown solid (27 mg, 54%).
Reaction SMILES: [C@@H:1]1([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][C:17]([C:18]4[N:19](S(N(C)C)(=O)=O)[CH:20]=[CH:21][N:22]=4)=[C:12]3[CH:11]=[CH:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1>C(O)(=O)C>[C@@H:1]1([N:9]2[C:13]3=[N:14][CH:15]=[CH:16][C:17]([C:18]4[NH:19][CH:20]=[CH:21][N:22]=4)=[C:12]3[CH:11]=[CH:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: CN(C)S(=O)(=O)n1ccnc1-c1ccnc2c1ccn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: CC(=O)O
Product: OC[C@H]1O[C@@H](n2ccc3c(-c4ncc[nH]4)ccnc32)C[C@@H]1O
Temperature: 60 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
N-Dimethylaminosulfonyl-2-(tributylstannyl)imidazole (930 mg, 2.0 mmol) was added to a solution of 1-[2-deoxy-3,5-di-O-(toluoyl)-β-D-ribofuranosyl]-4-iodo-pyrrolo[2,3-b]pyridine (596 mg, 1.0 mmol), lithium chloride (42 mg, 1.0 mmol), and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) in dioxane (10 mL), followed by stirring at 120° C. for 4 hr. The reaction solution was concentrated and was then purified with a silica gel column, and methanolic ammonia (30 mL) was added thereto. The resulting mixture was stirred at room temperature for 24 hr. The reaction solution was concentrated and purified with a silica gel column and then with HPLC to yield 218 mg (54%, second stage yield) of 1-(2-deoxy-β-D-ribofuranosyl)-4-(N-dimethylaminosulfonyl-2-imidazolyl)-pyrrolo[2,3-b]pyridine. 1-(2-Deoxy-β-D-ribofuranosyl)-4-(N-dimethylaminosulfonyl-2-imidazolyl)-pyrrolo[2,3-b]pyridine (200 mg, 0.49 mmol) was dissolved in 80% acetic acid, followed by stirring at 60° C. for 3 hr. The reaction solution was concentrated, and aqueous ammonia was added thereto for further concentration. Subsequently, 1-(2-deoxy-β-D-ribofuranosyl)-4-(2-imidazolyl)-pyrrolo[2,3-b]pyridine (dDia: 109 mg, 74%) was obtained through purification by HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[O:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:30]>O1CCOCC1>[ClH:30].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C3CCN(C(=O)OC(C)(C)C)CC3)on2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)Oc2cc(C3CCNCC3)on2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(3-{[(4-methylphenyl)sulfonyl]oxy}isoxazol-5-yl)piperidine-1-carboxylate (719 mg, 1.76 mmol) was dissolved in anhydrous 4N HCl in dioxane (15 mL) and the resulting solution was stirred at rt for 1 h. The reaction mixture was concentrated to afford 5-piperidin-4-ylisoxazol-3-yl 4-methylbenzenesulfonate hydrochloride, which did not require further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37]O)[CH2:32][CH2:31]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:37][CH2:36][N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: CN1CCN(CCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1CCN(CCOc2ccc(Br)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.8 %

Procedure:
A flask was charged with 4-bromo-3-fluorophenol (5.00 g, 26 mmol) and triphenylphosphine (10.30 g, 39 mmol). Methylene chloride (120 mL) was added followed by 2-(4-methylpiperazin-1-yl)ethanol (4.61 g, 32 mmol) and the solution was stirred on an ice water bath to cool. After 5 minutes, diisopropyl azodicarboxylate (7.6 ml, 39.1 mmol) was added over 6 to 8 minutes. The reaction was left stirring on the cold bath to slowly warm to room temperature overnight. The reaction was concentrated and the residue purified by flash chromatography (25% to 100% EtOAc in hexanes) to provide the product as a colorless oil (2.62 g, 33%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1ccc(Cc2ncc[nH]2)cc1
Product: COc1ccc(COc2ccc(Cc3ncc[nH]3)cc2)cc1

Procedure:
This substance is prepared analogously to Example 1 from 4-(1-imidazolylmethyl)-phenol and 4-methoxybenzyl chloride.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[NH:15][C:16]([C:18]2[N:19]=[C:20]([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])[S:21][C:22]=2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:17])[CH2:4][CH2:3]1.FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[F:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[C:20]1[S:21][C:22]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:18]([C:16](=[O:17])[NH:15][C:10]2[CH:11]=[N:12][N:13]([CH3:14])[C:9]=2[N:5]2[CH2:6][CH2:7][CH2:8][C@@H:2]([NH:1][CH2:45][C:46]([F:49])([F:48])[F:47])[CH2:3][CH2:4]2)[N:19]=1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](N)CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
(R)-tert-butyl 4-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate (112 mg, 0.204 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (95 mg, 0.409 mmol) were dissolved in methylene chloride/DMF (1.5 mL/1.5 mL). N,N-diisopropylethylamine (132 mg, 1.02 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove DMF, redissolved in ethyl acetate and washed with brine. The aqueous layer was extracted with ethyl acetate 3×. Combined organic layers were concentrated and purified by flash chromatography eluted with 0 to 100% ethyl acetate in heptane to give (R)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(4-(2,2,2-trifluoroethylamino)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (96 mg, 75%), which was deprotected by 4N HCl in dioxane and purified on reversed phase HPLC to give 197. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 7.59-7.43 (m, 4H), 7.25 (t, J=8.7 Hz, 2H), 3.64 (s, 3H), 3.24-3.01 (m, 6H), 2.81 (s, 1H), 2.14 (d, J=6.1 Hz, 1H), 1.96-1.74 (m, 3H), 1.65-1.48 (m, 3H). MS (ESI) m/z: 530.2 [M+H+].
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([S:15][CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH2:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O.C(NCC)C.[C:28](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[C:28]([NH:18][C@H:17]([C:19]([OH:21])=[O:20])[CH2:16][S:15][CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@@H](CSC1c2ccccc2Oc2ccccc21)C(=O)O
Solvent: CCNCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)[C@H](CSC1c2ccccc2Oc2ccccc21)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A sample of 1.0 g of S-(9H-Xanthen-9-yl)cysteine (3.3 mmole) from Example 4 was dissolved in 10 ml of chloroform. To the solution was added 1.5 ml of water and 1.5 ml of diethylamine. The mixture was cooled to 4° C. by an ice bath and 0.98 g of trityl chloride (3.5 mmole) was added in portions over a period of 30 min. After 2 h of stirring at room temperature. The reaction mixture was separated. The organic phase was washed twice with 4% diethylamine aqueous solution. The organic layer was dried over Na2SO4. The drying reagent was removed by filtration and the filtrate was condensed to dryness by rotary evaporation. The residue was refluxed in 10 ml of a 1:30 mixture of diethyl amine/ethyl alcohol. The resultant diethyl ammonium salt was partitioned between 10 ml of ethyl acetate and 7 ml of 5% aqueous KHSO4 and 7 ml of water. The ethyl acetate layer was separated and was dried over MgSO4 and was concentrated to get 1.4 g of product.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1nccc2c1c(-c1csc(C(=O)NC3CC3)c1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(NC1CC1)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-cyclopropylthiophene-2-carboxamide (68.4 mg) in acetonitrile (10 mL) were added sodium iodide (53.6 mg) and chloro(trimethyl)silane (0.181 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (56.8 mg).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:24]>C(O)(=O)C.O.[Cu]Br>[Br:24][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(N2CCC(c3ccccc3)CC2)cc1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-aminophenyl)-4-phenylpiperidine (2 g) in 47% hydrobromic acid (20 ml) and acetic acid (23 ml) was added dropwise sodium nitrite (0.55 g) in water (1 ml) under ice-cooling. The solution was then stirred for 30 minutes at 0° C. The reaction mixture was added dropwise copper(I) bromide (2.27 g) in 47% hydrobromic acid (2.3 ml) under ice-cooling. The reaction mixture was then stirred for 1.5 hours at ambient temperature. The reaction mixture was pulverized with water. The precipitate was collected by filtration. The powder was added 1N-sodium hydroxide (21 ml) and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica using dichloromethane/n-hexane (1:1) as the elution to give 1-(4-bromophenyl)-4-phenylpiperidine (1.23 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.FC(F)(F)C(O)=[O:33].[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([OH:16])[CH2:17][OH:33])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-7-oxiranylmethoxy-quinoline (compound 383) (30 mg) was dissolved in dichloromethane (1.5 ml) to prepare a solution. Trifluoroacetic acid (1 ml) was added to the solution at 0° C., and the mixture was then stirred at 0° C. for 2 hr. The reaction solution was made alkaline by the addition of a 1 N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (21 mg, yield 67%).
Reaction SMILES: NC(N)=O.[N:5]1([S:9]([C:12]2[C:13]([OH:20])=[C:14]([CH:16]=[CH:17][C:18]=2[Cl:19])[NH2:15])(=[O:11])=[O:10])[CH2:8][CH2:7][CH2:6]1.[Cl:21][C:22]1[C:27](Cl)=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>>[N:5]1([S:9]([C:12]2[C:13]([OH:20])=[C:14]([NH:15][C:30]([NH:29][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])=[O:31])[CH:16]=[CH:17][C:18]=2[Cl:19])(=[O:11])=[O:10])[CH2:8][CH2:7][CH2:6]1
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCC2)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Cl)Nc1ccc(Cl)c(S(=O)(=O)N2CCC2)c1O
Yield: 42.7 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 3-(azetidin-1-yl)sulfonyl-4-chloro-2-hydroxyaniline (235 mg, 0.9 mmol) and 2,3-dichlorophenylisocyanate (169 mg, 0.9 mmol) were coupled to form the desired urea (160 mg, 40%). LC-MS 450.0 (M+).
Reaction SMILES: C[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:3]([O:5]C)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+].O1CCC[CH2:24]1>>[CH3:24][CH:3]([OH:5])[CH:2]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:7]
Reactant: C1CCOC1
Reactant: COC(=O)C(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CC(O)C(C)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Methyl 2-methyl-2-phenylpropanoate (10.8 g, 60.6 mmol, Eq: 1.00) in tetrahydrofuran (193 ml) was cooled to 0° C., lithium aluminium hydride was added (30.3 ml, 60.6 mmol, Eq: 1.00) via a syringe over 5 minutes. The mixture was stirred at 0° C. for 3 hours, and 2.3 ml water was added over 2 minutes. The mixture was stirred for 10 minutes, 2.3 ml 1N NaOH was added, the mixture was stirred for 5 minutes (a gel forms), 7 ml water was added, the mixture was stirred for 15 minutes, filtered through a pad of celite. The celite was washed with ether and the solvent was removed under vacuum to give methyl-2-phenyl-propan-1-ol (51) (9.0 g, 99%) as a clear oil.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7])[CH:2]=[CH2:3].[Cl:10][SiH:11]([Cl:13])[Cl:12]>CCCCCC>[C:5]([O:4][CH2:1][CH2:2][CH2:3][Si:11]([Cl:13])([Cl:12])[Cl:10])(=[O:9])[C:6]([CH3:8])=[CH2:7]
Reactant: C=CCOC(=O)C(=C)C
Reactant: Cl[SiH](Cl)Cl
Solvent: CCCCCC
Product: C=C(C)C(=O)OCCC[Si](Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
There was added dropwise over a period of 30 minutes, 50 grams of allylmethacrylate to a mixture refluxing at 32° C. of 80.6 grams of trichlorosilane and 0.397 grams of a [SG]--S--Pt catalyst sufficient to provide 100 ppm platinum/SiH. The mixture was stirred an additional 2 hours at reflux, cooled to ambient temperature and diluted with 100 ml of hexane and filtered. There was obtained 47.7 grams of a clear, colorless oil upon concentration of the filtrate on a rotary evaporator. Based on method of preparation, NMR and VPC analysis there was obtained a 98% yield of γ-methacryloxypropyltrichlorosilane.
Reaction SMILES: C(/[N:14]=[CH:15]/[C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23]2)=[CH:18][CH:17]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:33]1[C:38]([Cl:39])=[N:37][CH:36]=[CH:35][N:34]=1>C1COCC1>[Cl:39][C:38]1[C:33]([CH:15]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:23]3)=[CH:18][CH:17]=2)[NH2:14])=[N:34][CH:35]=[CH:36][N:37]=1
Reactant: Clc1nccnc1Cl
Reactant: C(=N/C(c1ccccc1)c1ccccc1)\c1ccc2ccc(-c3ccccc3)nc2c1
Solvent: C1CCOC1
Product: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
Benzhydryl-[1-(2-phenyl-quinolin-7-yl)-meth-(E)-ylidene]-amine (12.50 g, 31.4 mmol) was added to a 500 mL rbf fitted with a thermocouple. The flask was degassed and filled with nitrogen. THF (150 mL) was added and the solid dissolved. The mixture was cooled to −5° C. and 1.0 M of HMDS sodium salt in THF (39.2 mL) was added within 5 min. The temperature increased slightly to −3° C. The blue solution was stirred for 20 min at 0° C. and then 2,3-dichloropyrazine (5.61 g, 37.6 mmol) in THF (10 ml) was added within 3 min. The mixture was stirred for 30 min and then quenched with saturated NH4Cl/water (200 mL). EtOAc (200 mL) was added and the aqueous phase was removed. Toluene can also be used. The organic layer was washed with water (200 mL×2) and brine (200 mL). Concentrated HCl (10 mL) and water (200 mL) were added. The phases were separated and the organic layer was extracted with 0.1 M HCl (30 mL). The aqueous was washed with EtOAc (2×) and then saturated K2CO3 was used to adjust to pH 10. The aqueous solution was extracted with EtOAc (2×) and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to a brown oil which solidified upon standing to yield the title compound as a brown solid (9.94 g, 81% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.30 (br s, 2H), 5.79 (s, 1H), 7.43-7.56 (m, 3H), 7.62 (dd, J=8.46, 1.89 Hz, 1H), 7.81 (d, J=8.34 Hz, 1H), 7.86 (d, J=8.59 Hz, 1H), 8.07 (d, J=1.01 Hz, 1H), 8.10-8.16 (m, 2H), 8.19 (d, J=8.59 Hz, 1H), 8.31 (d, J=2.27 Hz, 1H), 8.60 (d, J=2.53 Hz, 1H). MS (ES+): m/z=347.01/349.03 (100/68) [MH+].