Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:19]1[CH:24]=[C:23](C)[CH:22]=[C:21](CCCCCCCCC)[C:20]=1O)[C:2]1C=C(C)C=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCCC)[C:3]=1O.[OH:36]C1C(CCCCCCCCC)=CC(C)=CC=1CC1C(O)=C(CC2C=C(C)C=C(CCCCCCCCC)C=2O)C=C(C)C=1>>[CH2:1]([C:19]1[CH:24]=[CH:23][C:22]([OH:36])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCc1cc(C)cc(Cc2cc(C)cc(CCCCCCCCC)c2O)c1O
Reactant: CCCCCCCCCc1cc(C)cc(Cc2cc(C)cc(Cc3cc(C)cc(CCCCCCCCC)c3O)c2O)c1O
Product: CCCCCCCCCc1ccc(O)cc1

Procedure:
A lubricating oil composition comprising, as essential components, (A) 100 parts by weight of a base oil having a kinematic viscosity at 40° C. of 5 to 500 cSt, a pour point of -30° C. or lower, a cloud point of -20° C. or lower and a viscosity index of 70 or more, and (B) 0.01 to 5 parts by weight of at least one alkyl group-substituted phenol compound having a melting point of 20° C. or lower selected from the group consisting of 2,2'-methylenebis(4-methyl-6-nonylphenol); 2,6-bis(2-hydroxy-3-nonyl-5-methylbenzyl)p-cresol; and p-nonylphenol in which the nonyl group is formed by removing a hydrogen from propylene trimer.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH3:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[F:34][CH:2]([F:1])[C:3]([NH:5][C@H:9]([CH2:10][F:11])[C@H:8]([OH:7])[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[N:20][C:21]([CH:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH3:25])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)=[O:4]
Reactant: CC(c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1)N1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
To a stirred solution of 2,2-Difluoro-1-((4S,5R)-4-fluoromethyl -2,2-dimethyl-5-{4-[6-(1-morpholin-4-yl-ethyl)-pyridin-3-yl]-phenyl}-oxazolidin-3-yl)-ethanone (0.101 g, 0.309 mmol) in CH2Cl2 (5 mL) is added trifluoroacetic acid (1 mL) at 0° C. Reaction mixture is allowed to stir at room temperature for 4 hours. The solvent evaporated in vacuo and the crude material is diluted with saturated bicarbonate solution and extract with 10% MeOH:DCM. Combined organic layer dried over sodium sulphate, concentrated and purified by combiflash using 5% methanol:CH2Cl2 as eluent to afford desired compound (0.076 g): 1H NMR (400 MHz, CDCl3) δ: 1.33 (d, J=2.52 Hz, 3H), 2.32-2.35 (m, 2H), 2.49-2.50 (m, 2H), 3.55-3.57 (m, 4H), 3.59-3.60 (m, 1H), 4.29-4.30 (m, 1H), 4.32 (m, 0.5H), 4.40-4.44 (m, 0.5H), 4.54-4.55 (m, 0.5H), 4.64-4.66 (m, 0.5H), 4.88 (bs, 1H), 5.92 (d, J=3.96 Hz, 1H), 6.20 (t, J=53.72 Hz, 1H), 7.45 (d, J=8.24 Hz, 2H), 7.49 (d, J=8.24, 1H), 7.69 (d, J=8.28 Hz, 2H), 8.03-8.06 (dd, J1=8.2 Hz, J2=2.4 Hz, 1H), 8.80 (d, J=2.04 Hz, 1H), 8.86 (d, J=8.56 Hz, 1H). LC-Ms (m/z): 438.1[M+H].
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (120 mg, 0.36 mmol) in DCM (6 ml), were sequentially added triethylamine (79 μl, 1.08 mmol) and methanesulfonyl chloride (33.4 μl, 0.43 mmol). The reaction was stirred at RT for 3 hours, and then the volatiles were evaporated. The crude was taken up with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude was triturated with Et2O to obtain (R)-quinuclidin-3-yl 2-(methylsulfonamido)-2-phenylacetate (38.9 mg; 32% yield).
Reaction SMILES: [CH2:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH2:4][CH2:3][NH:2]1>C(Cl)Cl.O=[Mn]=O>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH2:4][CH2:3][N:2]=1
Reactant: N#Cc1cccc2c1CCNC2
Agent: O=[Mn]=O
Solvent: ClCCl
Product: N#Cc1cccc2c1CCN=C2
Yield: 93.8 %

Procedure:
1,2,3,4-tetrahydroisoquinoline-5-carbonitrile (0.338 g, 2.137 mmol) was oxidized with MnO2 (2.79 g, 32.0 mmol) in DCM (30 mL) over night. Filtered through Celite® and concentrated to yield 0.313 g (94%) of desired product as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.36 (1H, t, J=2.3 Hz), 7.67 (1H, dd, J=7.7, 1.4 Hz), 7.47-7.54 (1H, m), 7.43 (1H, d, J=7.8 Hz), 3.88 (2H, td, J=7.8, 2.3 Hz), 2.95-3.04 (2H, m) ppm. MS (ESI) m/z: 157 (M+H)+
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[C:30](Cl)(=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33]>>[CH3:33][CH:32]([CH3:34])[CH2:31][C:30]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)=[O:35]
Reactant: CC(C)CC(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Product: CC(C)CC(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
3-Methyl-1-((R)-3-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-pyrrolidin-1-yl)-butan-1-one was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and isovaleryl chloride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH:13]=[CH2:14])=[C:6]([CH:10]=1)[CH:7]=[N:8][OH:9].Cl[O-].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH:13]=[CH2:14])=[C:6]([CH:10]=1)[C:7]#[N+:8][O-:9]
Reactant: C=CCOc1ccc(Br)cc1C=NO
Agent: [Na+]
Agent: [O-]Cl
Product: C=CCOc1ccc(Br)cc1C#[N+][O-]

Procedure:
The oxidation of 5-bromo-2-allyloxybenzaldoxime using sodium hypochlorite solution to give 5-bromo-2-allyloxybenzonitrile oxide and the subsequent 1,3-dipolar cycloaddition were carried out in a static micromixer (Technical University of Ilmenau, Faculty of Machine Construction, Dr. Norbert Schwesinger, Postfach 100565, D-98684 Ilmenau) having a physical size of 40 mm×25 mm×1 mm with a total of 11 mixing stages each with a volume of 0.125 μl. The total pressure loss was about 1000 Pa.
Reaction SMILES: [NH2:1][C:2](=[S:15])[CH:3]([N:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6]1)[CH3:4].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=O>>[F:27][C:26]([F:28])([F:29])[C:22]1[CH:21]=[C:20]([C:18]2[N:1]=[C:2]([CH:3]([N:5]3[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6]3)[CH3:4])[S:15][CH:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cnn(C(C)C(N)=S)c1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1cnn(C(C)c2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Yield: 90.5 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (227 mg, 1.00 mmol) obtained in Example 14b and 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (267 mg, 1.00 mmol), the title compound (358 mg, 90%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:9]1[C:10]([F:33])=[C:11]([CH:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:25]=3)[NH:20][CH:19]=2)[OH:17])[C:12]([F:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:34]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[C:10]([F:33])=[C:11]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:25]=3)[NH:20][CH:19]=2)=[O:17])[C:12]([F:15])=[CH:13][CH:14]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: OC(c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=C(c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (3-dibenzylamino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (54, 0.90 g, 1.7 mmol) in methylene chloride (20 mL) under an atmosphere of nitrogen was added Dess-Martin periodane (0.97 g, 2.3 mmol). The reaction was stirred at room temperature for 15 minutes. The reaction was poured into a solution of sodium bicarbonate and sodium thiosulfate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% methanol in methylene chloride to provide the compound (55, 0.70 g, 78%). MS (ESI) [M+H+]+=531.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:12]#[N:13])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].[BH4-].[Na+].[H][H]>CO>[CH3:1][O:2][C:3]([C:5]1([CH2:12][NH2:13])[C:7]2([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C#N)CC12CCCC2
Reactant: [H][H]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(CN)CC12CCCC2
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a solution of 1-cyano-spiro[2.4]heptane-1-carboxylic acid methyl ester (3.45 g, 19.3 mmol) in methanol (240 mL) was added CoCl2-6H2O (9.16 g, 38.5 mmol) to give a deep purple colored solution. Sodium borohydride (7.30 g, 193 mmol) was added portionwise over 10 minutes with caution to control the evolution of hydrogen and the exothermic reaction that ensued to give a black solution. The reaction mixture was stirred for 30 minutes under nitrogen after the addition was completed. The reaction was quenched carefully by the addition of 0.5N HCl (1.3 L). The solution was made alkaline (pH˜9) by the addition of concentrated ammonium hydroxide. The mixture was extracted with ethyl acetate (4×400 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to afford 3.07 g (87%) of 1-aminomethyl-spiro[2.4]heptane-1-carboxylic acid methyl ester as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 0.74 (br d, 1H), 1.4-1.7 (m, 10H), 1.9 (m, 1H), 2.58 (d, J=13.8 Hz, 1H), 3.16 (d, J=13.8 Hz, 1H), 3.48 (s, 3H); MS (APCI) m/z 184 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:24]([C:26]([O:28]CC)=[O:27])[S:25][C:17]3=4)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[OH-].[Na+].CCO>O>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[C:24]([C:26]([OH:28])=[O:27])[S:25][C:17]3=4)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(OCCN3CCOCC3)cc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1sc2c(ccc(=O)n2-c2ccc(OCCN3CCOCC3)cc2)c1-c1ccccc1
Yield: 44.2 %

Procedure:
A mixture of the compound of Example 92 (230 mg, 0.46 mmol), sodium hydroxide (91 mg, 2.28 mmol) and EtOH (5 mL) was heated at reflux for 18 h. EtOH was removed in vacuo and the residue treated with 2M HCl(aq) (2 mL) to give a white solid. The reaction was diluted with water and then freeze dried. The resultant solid was extracted with isopropanol and the extracts concentrated in vacuo to give the title compound as a white solid (97 mg). δH (DMSO-d6) 7.62–7.37 (8H, m), 7.21–7.16 (2H, m), 6.50 (1H, J 9.6 Hz), 4.20 (2H, t, J 5.7 Hz), 3.62–3.59 (4H, m), 2.76 (2H, t, J 5.7 Hz), 2.54–2.51 (4H, m). LCMS (ES+) RT 2.35 minutes, 477 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=2)=[C:15]([C:26]([NH2:28])=[O:27])[CH:14]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38].O>CN(C=O)C>[CH3:40][O:39][C:37](=[O:38])[CH2:36][N:21]1[C:22](=[O:25])[CH:23]=[CH:24][C:19]([NH:18][C:16]2[S:17][C:13]([C:3]3[C:2]([F:1])=[CH:7][C:6]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:5][C:4]=3[F:12])=[CH:14][C:15]=2[C:26]([NH2:28])=[O:27])=[N:20]1
Reactant: COC(=O)CBr
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(=O)[nH]n3)s2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1=O
Temperature: 25 °C

Procedure:
5-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-[(6-oxo-1,6-dihydropyridazin-3-yl)amino]thiophene-3-carboxamide (Example 578 Step 3) (50 mg, 0.12 mmol), K2CO3 (18.70 mg, 0.14 mmol) and methyl bromoacetate (0.012 mL, 0.13 mmol) were stirred in DMF (1 mL) at 80° C. overnight. The reaction mixture was cooled to room temperature, water was added and the reaction mixture was extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (0-15% MeOH—CHCl3) gave the title compound as a yellow solid after triturating in DCM.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:81][O:82][C:83](=[O:93])[CH2:84][C:85]1[CH:90]=[CH:89][C:88](Cl)=[CH:87][C:86]=1[Cl:92]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:81][O:82][C:83](=[O:93])[CH2:84][C:85]1[CH:90]=[CH:89][C:88]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])=[CH:87][C:86]=1[Cl:92]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1ccc(Cl)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOCC
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(Cl)c2)c(C)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
Degassed toluene (0.13 mL) and water (0.013 mL) were added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 15.7 mg, 0.0259 mmol), palladium (II) acetate (0.8 mg, 0.004 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (3 mg, 0.007 mmol) and potassium phosphate (20.0 mg, 0.0942 mmol). After replacement with nitrogen, (2,4-dichloro-phenyl)acetic acid methyl ester (Example 41; 17 mg, 0.078 mmol) was added. After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 96 to 104° C. for 30 minutes. The reaction mixture was diluted with diethyl ether and filtered through cotton plug, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=50/1) to give the title compound (3 mg, 17%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:4][CH:3]=1.[CH2:30]([Mg]Br)[CH3:31].[Cl-].[NH4+]>[Cu]I>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:30][CH3:31])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(=O)CC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a mixture of ethyl (2E)-3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]prop-2-enoate (489 mg, 1.08 mmol) and copper (I) iodide (155 mg, 1.08 mmol) was added ethylmagnesium bromide (3.0 M in diethyl ether, 1.44 mL, 4.32 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr. Aqueous ammonium chloride was added to the reaction mixture at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound (308 mg, 0.641 mmol, 59%) as a colorless amorphous.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([O:22][CH3:23])=[C:13]([O:14]CC3C=CC=CC=3)[C:8]=2[CH2:7][C@@H:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:5]1>CO.[Pd].C(OCC)(=O)C>[ClH:1].[NH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([O:22][CH3:23])=[C:13]([OH:14])[C:8]=2[CH2:7][C@@H:6]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:5]1
Reactant: COc1ccc2c(c1OCc1ccccc1)C[C@@H](c1ccccc1)O[C@H]2CN
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1O)C[C@@H](c1ccccc1)O[C@H]2CN
Yield: 66.5 %

Procedure:
A solution of 940 mg (2.28 mmol) of [1R,3S] 1-aminomethyl-5-benzyloxy-3,4-dihydro--6-methoxy-3-phenyl-1H-2-benzopyran hydrochloride, from Step 9, in 500 mL of methanol was treated with 500 mg of 10% palladium on carbon and the resultant mixture was shaken under a hydrogen atmosphere for 24 h. The reaction mixture was diluted with ethyl acetate and filtered through Celite filter aid. The filtrate was concentrated in vacuo to give an off-white solid which was crystallized from methanol/methylene chloride/ether to give 488 mg (66% yield) of the title compound, m.p. 234° C.; MS DCl-NH3M/Z: 286 (M+H)+. Analysis calculated for C17H20ClNO3 +0.25 CH2Cl2 : C, 60.40; H, 6.02; N, 4.08. Found: C, 60.07; H, 5.97; N, 4.03.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:27]([CH2:33][CH2:34][CH3:35])=[N:26][C:20]=3[C:21]([NH2:25])=[N:22][C:23]=2[CH:24]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:25][C:21]1[C:20]2[N:26]=[C:27]([CH2:33][CH2:34][CH3:35])[N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]=2[C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][NH:10][S:2]([CH3:1])(=[O:5])=[O:3])=[CH:24][C:23]=2[N:22]=1
Reactant: CCCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1CC(C)C
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(OCCCNS(C)(=O)=O)ccc3c2n1CC(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 26.2 %

Procedure:
Methanesulfonic anhydride (0.245 g, 1.41 mmol) was added in one portion to a suspension of 7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.41 mmol) in chloroform, and the reaction was stirred for 18 hours. Saturated aqueous sodium bicarbonate was added, and the reaction was stirred for 20 minutes. The aqueous layer was separated and extracted with chloroform. The combined organic fractions were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting off-white solid was dissolved in concentrated hydrochloric acid; the solution was then cooled to 0° C. and adjusted to pH 13 with the addition of 50% aqueous sodium hydroxide. The opaque solution was extracted with dichloromethane. The extract was washed sequentially with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was recrystallized from acetonitrile to yield 0.160 g of N-{3-[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]propyl}methanesulfonamide as a flocculent, white solid, mp 166.5-168.5° C.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=2[O:29][CH2:30][CH2:31][O:32]C2CCCCO2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.CO>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=2[O:29][CH2:30][CH2:31][OH:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc([N+](=O)[O-])c3OCCOC3CCCCO3)[nH]c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc([N+](=O)[O-])c3OCCO)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 134.9 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-{3-nitro-2-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-1H-indole-6-carboxylate (6.48 g, 18.6 mmol) in tetrahydrofuran (30 ml) and methanol (90 ml) was added 6N hydrochloric acid (15 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 4N aqueous sodium hydroxide solution (22.5 ml), saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1-2:1) to give methyl 3-cyclohexyl-2-[2-(2-hydroxyethoxy)-3-nitrophenyl]-1H-indole-6-carboxylate (11.00 g, yield 91%).
Reaction SMILES: CN[C@H](CC=CC1C(O)=NC(O)=NC=1)C.[CH3:16][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:18]([CH2:20][CH:21]=[CH2:22])[CH3:19].[CH3:30][O:31][CH:32]1[N:37](I)[C:36]([O:39][CH3:40])=[CH:35][CH:34]=[N:33]1>[Pd]>[CH3:16][N:17]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C@H:18]([CH2:20][CH:21]=[CH:22][C:35]1[C:36]([O:39][CH3:40])=[N:37][C:32]([O:31][CH3:30])=[N:33][CH:34]=1)[CH3:19]
Reactant: C=CC[C@H](C)N(C)C(=O)OC(C)(C)C
Reactant: COC1=CC=NC(OC)N1I
Agent: [Pd]
Agent: CN[C@@H](C)CC=Cc1cnc(O)nc1O
Product: COc1ncc(C=CC[C@H](C)N(C)C(=O)OC(C)(C)C)c(OC)n1

Procedure:
Scheme I shows the synthesis of (S)-N-methyl-5-(2,4-dihydroxy-5-pyrimidinyl)-4-penten-2-amine. In this synthesis, the previously described (S)-N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine is subjected to Heck-type coupling conditions by reaction with a 2,4-dimethoxy-3-iodopyrimidine in the presence of a palladium catalyst to form (S)-N-methyl-N-(tert-butoxycarbonyl)-5-(2,4-dimethoxy-5-pyrimidinyl)-4-penten-2-amine. The methoxy groups can be converted to hydroxy groups, concurrent with the cleavage of the amine protecting group, by reaction with trimethylsilyl iodide in methanol/dichloromethane to yield the desired N-methyl-5-(2,4-dihydroxy-5-pyrimidinyl)-4-penten-2-amine compound as a hydroiodide salt. Alternately, the tert-butoxycarbonyl protecting group can be selectively removed by trifluoroacetic acid, as described previously, to give the (S)-N-methyl-5-(2,4-dimethoxy-5-pyrimidinyl)-4-penten-2-amine. Cleavage of the methyl ethers using 48% HBr then provides (S)-N-methyl-5-(2,4-dihydroxy-5-pyrimidinyl)-4-penten-2-amine.