Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Si:19]([O:26][CH2:27][CH:28]([CH2:33][N:34]1[C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=2)=[C:41]2[C:36]([N:37]([CH3:53])[C:38](=[O:52])[N:39]([CH3:51])[C:40]2=[O:50])=[CH:35]1)[CH2:29][C:30](O)=[O:31])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C.Cl.[CH3:64][NH:65][O:66][CH3:67]>CN(C=O)C.C(OCC)(=O)C>[Si:19]([O:26][CH2:27][CH:28]([CH2:33][N:34]1[C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=2)=[C:41]2[C:36]([N:37]([CH3:53])[C:38](=[O:52])[N:39]([CH3:51])[C:40]2=[O:50])=[CH:35]1)[CH2:29][C:30]([N:65]([O:66][CH3:67])[CH3:64])=[O:31])([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:20])[CH3:21]
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(CO[Si](C)(C)C(C)(C)C)CC(=O)O)cc2n(C)c1=O
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)CC(CO[Si](C)(C)C(C)(C)C)Cn1cc2c(c1-c1cccc(F)c1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
T3P® (2.62 mL, 4.5 mmol) was added to a suspension of 4-((tert-butyldimethylsilyl)oxy)-3-((5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)methyl)butanoic acid (1.13 g, 2.2 mmol), DIPEA (2.16 mL, 12.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (263 mg, 2.7 mmol) in DMF (8 mL) at 0° C. The mixture was stirred at room temperature for 30 minutes. The reaction was diluted with ethyl acetate (40 mL) and was washed with water (1×20 mL), 1M HCl(aq) (1×20 mL) and saturated NaHCO3(aq) (1×20 mL). The organic phase was dried over magnesium sulfate and the solvent was removed under vacuum. Purification by chromatography on silica, eluting with 0-3% MeOH/DCM, afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]([O:15][C:16](=[O:37])[CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14]>ClCCl>[CH2:13]([O:15][C:16](=[O:37])[CH:17]=[C:10]1[CH2:11][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:9]1)[CH3:14]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CC(c2cccc(Br)c2)C1
Solvent: ClCCl
Product: CCOC(=O)C=C1CC(c2cccc(Br)c2)C1
Yield: 89 %

Procedure:
A solution of 3-(3-bromophenyl)cyclobutanone (2.03 g 9.02 mmol) and triphenylphosphoranylidene acetic acid ethyl ester (15.72 gms 45.12 mmol) dichloromethane was irradiated in a CEM Discover™ microwave instrument for 30 minutes at 120° C. Pressure reached a maximum of 180 PSI. Standard work-up procedures followed by purification by column chromatography (isocratic; 10% diethyl ether in hexanes) afforded [3-(3-bromophenyl)cyclobutylidene]acetic acid ethyl ester as an oil, 2.37 g (89% yield), 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.1 Hz, 3 H) 2.89-3.00 (m, 1 H) 3.03-3.11 (m, 1 H) 3.16-3.27 (m, 1 H) 3.46-3.57 (m, 1 H) 3.63 (q, J=8.0 Hz, 1 H) 4.08 (q, J=7.0 Hz, 2 H) 5.71 (q, J=2.9 Hz, 1 H) 7.25-7.35 (m, 2 H) 7.39-7.43 (m, 1 H) 7.48-7.52 (m, 1 H); MS (APPI) m/z 295 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:36]3[O:35][CH2:34][CH2:33][NH:32][C:31]=3[CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].N1C=CC=CC=1.O>ClCCl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:36]3[O:35][CH2:34][CH2:33][N:32]([S:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)(=[O:12])=[O:11])[C:31]=3[CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2OCCN3)CC1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2OCCN3S(=O)(=O)c2cccc([N+](=O)[O-])c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
3-Nitro benzenesulfonyl chloride (122.9 mg, 0.55 mmol) was added in small portions under nitrogen to an ice-cold solution of 4-(3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester (161 mg, 0.504 mmol) and pyridine (88 mg, 1.11 mmol) in dichlormethane (2 mL). After 0.5 hour at ambient temperature, water was added. The organic phase was separated, washed with saturated aqueous solution of sodium bicarbonate (20 mL), dried (Na2SO4) and concentrated to give 4-[4-(3-nitro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl]-piperazine-1-carboxylic acid tert-butyl ester as an oil (260 mg). MS: MH+=505.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([N:52]3[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(Br)cc2)C1
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)CC1
Temperature: 90 °C
Yield: 63.2 %

Procedure:
To a suspension of 3-(4-bromophenyl)-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 8.8 mmol), palladium acetate (80 mg, 0.36 mmol), 2-(di-t-butyl phosphino)biphenyl (210 mg, 0.70 mmol), and sodium t-butoxide (1.2 g, 125 mmol) in toluene (30 mL) was added N-methylpiperazine (1.3 g, 13.0 mmol) at room temperature. After heating at 90° C. for 5 h, the resulting suspension was passed through a Celite column. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting 5-25% of ethyl acetate in hexane to afford 3-(4-(4-methylpiperazin-1-yl)-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 5.56 mmol, 63%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:82])[C@H:71]([CH2:73][CH2:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[NH2:72].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:72][C@@H:71]([CH2:73][CH2:74][C:75]([O:77][C:78]([CH3:79])([CH3:81])[CH3:80])=[O:76])[C:70]([O:69][CH3:68])=[O:82])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (500 mg, 1.1 mmol), HATU (500 mg, 1.32 mmol) and N,N-diisopropylethylamine (426 mg, 3.3 mmol) in anhydrous DMF (8 ml) was stirred at room temperature for 10 minutes, followed by addition of L-Glutamic acid 5-tert-butyl 1-methyl ester hydrochloride (334 mg, 1.32 mmol). The mixture was stirred for another 10 minutes and poured into 200 ml of water. 2M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% MeOH/CHCl3 to give (S)-5-tert-butyl 1-methyl 2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate as off-white solid. Yield: 380 mg, 52%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(CC)CC>C1COCC1.CN(C=O)C>[C:20]([NH:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Oc2ccc(CCNC(=O)c3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine amine starting material of Example 34 (100 mg, 0.39 mmol), benzoyl chloride (50 μL, 0.43 mmol) and Et3N (120 μL, 0.86 mmol) in THF (4 mL) and DMF (0.5 mL). Stir the mixture at room temperature for 3 hours. Eliminate the solvent and purify by flash chromatography on silica gel (eluent: EtOAc/hexane 75/25) to give the title compound. (90 mg, 65%). Electrospray MS M+1 ion=362, 1H-NMR (methanol-d4, 400 MHz): 8.62 (d, 1H, J=2.8 Hz), 8.24 (dd, 1H, J=2.8 and 9.0 Hz), 7.79-7.76 (m, 2H), 7.55-7.42 (m, 5H), 7.09-7.06 (m, 2H), 6.96 (d, 1H, J=9.0 Hz), 3.62 (t, 2H, J=7.3 Hz), 2.95 (t, 2H, J=7.3 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Br[C:31]1C=CC(C(=C2CCOCC2)C2C=CC(O)=CC=2)=CC=1.C(OC(C)(C)C)(=O)C(C)=C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:31])/[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1
Reactant: Oc1ccc(C(=C2CCOCC2)c2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: C=C(C)C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C/C(=C\c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1)C(=O)OC(C)(C)C
Yield: 59 %

Procedure:
Following the procedure described for compound 47, from 4-[(4-bromophenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenol (46) (0.101 g, 0.293 mmole), tert-butyl methacrylate (0.095 mL, 0.585 mmole), P(o-tolyl)3 (0.0092 g, 0.0302 mmole), Et3N (0.125 mL, 0.897 mmole), Pd(OAc)2 (0.0038 g, 0.0169 mmole) and DMF (1.5 mL) yielded compound 59 (0.070 g, 59%) as a white solid. 1H NMR (CDCl3): δ 7.55 (s, 1H), 7.31 (d, J=8.1 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H), 6.98 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 4.91 (s, 1H), 3.73 (m, 4H), 2.41 (m, 4H), 1.58 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24](Cl)[N:25]=1)[C:19]([O:21][CH3:22])=[O:20].O.[Na+].[Cl-]>CN1C(=O)CCC1.CCOC(C)=O>[C:10]([O:9][C:8]([NH:7][CH:4]1[CH2:3][CH2:2][N:1]([C:24]2[CH:23]=[C:18]([CH:17]=[C:16]([Cl:15])[N:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:6][CH2:5]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)c1
Temperature: 150 °C

Procedure:
tert-Butyl piperidin-4-ylcarbamate (972 mg, 4.85 mmol), was dissolved in anhydrous NMP (5 ml). Methyl 2,6-dichloroisonicotinate (Intermediate 24, 1 g, 4.85 mmol) was added followed by TEA (675 μl, 4.85 mmol). The mixture was heated under microwave conditions at 150° C. for 10 minutes. Water (50 ml) and EtOAc (100 ml) were added, the aqueous phase was treated with solid NaCl and extracted with EtOAc (4×100 ml). The EtOAc layer was dried, concentrated in vacuo and purified by flash chromatography eluting with hexane:EtOAc (4:1) to give the title product as an off-white solid. (1.4 g).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][C:11]([SiH2:14][O:15][CH:16]1[CH2:21][C:20]2([CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[O:19][CH:18]([CH2:27]/[CH:28]=[C:29](\[CH3:35])/[C:30](OCC)=[O:31])[CH2:17]1)([CH3:13])[CH3:12].CO.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[CH3:13][C:11]([SiH2:14][O:15][CH:16]1[CH2:21][C:20]2([CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[O:19][CH:18]([CH2:27][CH2:28]/[C:29](/[CH3:35])=[CH:30]/[OH:31])[CH2:17]1)([CH3:10])[CH3:12]
Reactant: CCOC(=O)/C(C)=C/CC1CC(O[SiH2]C(C)(C)C)CC2(CCCCO2)O1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: C/C(=C\O)CCC1CC(O[SiH2]C(C)(C)C)CC2(CCCCO2)O1

Procedure:
A solution of 1M DIBAL (155 ml; 155 mmoles) is added dropwise to a solution of ethyl 4-[4-[(1,1-dimethylethyl)silyl]oxy-1,7-dioxaspiro[5.5]undec-2-yl]-2-methyl-2E-butenoate, (29.0 g; 70.3 mmoles) in methylene chloride (350 ml) with stirring under nitrogen at -78°. Upon completion of the addition, the reaction mixture is allowed to warm to 2° and stirred for two hours. The reaction mixture is cooled to 0° and treated dropwise (slight foaming) with methanol (45 ml). After 15 minutes the reaction mixture is partitioned between methylene chloride (500 ml) and a mixture of 6.67N sulfuric acid (150 ml) and crushed ice (300 g). The mixture is intermittently shaken over a ten minute period. The layers are separated and the aqueous phase extracted with methylene chloride (500 ml). The combined organic phases are dried over anhydrous sodium sulfate, filtered through celite, and concentrated in vacuo to give an oil. Chromatography (15-40% ethyl acetate/hexane) yields the title compound, 4-[4-[(1,1-dimethylethyl)silyl]oxy-1,7-dioxaspiro[5.5]undec-2-yl]-2-methyl-2E-butenol; (21.8 g; 83.8%) as an oil.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@H:36](O)[C@@H:35]([CH2:47][O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[C@@H]1[C@@H](OCC2C=CC=CC=2)[C@@H](OC(F)(F)F)[C@@H](C(=S(=O)=O)OCC2C=CC=CC=2)O[C@@H]1OC)C1C=CC=CC=1.OS(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@@H:36]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])[C@@H:35]([CH2:47][O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CO[C@H]1O[C@H](C(OCc2ccccc2)=S(=O)=O)[C@H](OC(F)(F)F)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OS(=O)(=O)C(F)(F)F)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of dry pyridine (0.46 mL) in methylene chloride (17.5 mL) cooled to -15° C. was added trifluoromethane sulfonic anhydride (0.87 mL). The mixture was stirred during 15 min at -10° C., then methyl 2,3,6-tri-O-benzyl-α-D-galactopyranoside (1.2 g, 2.58 mmol) in methylene chloride (5 mL) was added (N. Morishima, S. Koto, M. Oshima, A. Sugimoto and S. Zen, Bull. Chem. Soc. Jpn, 56, 2849 (1983)). The mixture was washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil which was the expected triflate methyl 2,3,6-tri-O-benzyl-4-O-trifluoromethyl-sulfonyl-α-D -galactopyranoside (1.43 g, 93%).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[C:5](=[S:9])[O:6]CC)[CH2:2][CH3:3].S(OCC)(O[CH2:17][CH3:18])(=O)=O>CO>[CH2:10]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:9])[S:6][CH2:17][CH3:18])[CH2:11][CH3:12]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCCN(CCC)C(=S)OCC
Solvent: CO
Product: CCCN(CCC)C(=O)SCC
Temperature: 160 °C
Yield: 91 %

Procedure:
94.5 g. (0.5 moles) of O-ethyl N,N-dipropyl-thiocarbamate are introduced into a 250 ml. round-bottomed flask, and 4.7 g. of diethyl sulfate are added. The mixture is refluxed for 80 minutes on an oil bath heated to 160°C. The progress of the reaction is monitored by sampling the reaction mixture and recording the UV spectra of the samples in methanol. The absorption maximum at 250 nm, characteristic of the =S group of the starting substance, gradually decreases, and disappears when the isomerization is completed. Then the reaction mixture is cooled, and the small amount of oily substance separated at the bottom of the flask is removed. The upper phase is distilled in vacuo. The title compound boils at 122°-124°C/19 Hgmm. 86.0 g. (91 %) of S-ethyl N,N-di-propyl-thiocarbamate are obtained; nD 30 = 1.4750.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([NH2:13])=O)=[CH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[S:23])[NH2:13])=[CH:3]1
Reactant: Cn1cc(C(N)=O)c2ccccc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cn1cc(C(N)=S)c2ccccc21

Procedure:
1-Methylindole-3-carboxamide (0.6 g) was suspended in toluene (20 ml): Lawesson's Reagent (0.7 g) was added and the mixture was heated at reflux under nitrogen for 30 min until dissolution occurred. The solution was cooled and toluene was removed under reduced pressure. The orange residue was purified by column chromatography on alumina using CH2Cl2 as eluant. This afforded an orange crystalline material, (0.5 g). δH (360 MHz, DMSO-d6) 3.82 (3 H, s, NCH3), 7.18 and 7.23 (2 H, 2×dt, J=7.1, 1.1 Hz, H-5 and H-6), 7.49 (1 H. d, J=7.5 Hz, H-7), 8.08 (1 H, s, H-2), 8.59 (1 H, d, J=7.5 Hz, H-4), 8.76 (2 H, brs, NH2); m/z 190 (M+, 100%), 174 (20), 157 (80).
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].[CH:6]([O:9][B:10](OC(C)C)[O:11][CH:12]([CH3:14])[CH3:13])([CH3:8])[CH3:7]>>[CH:1]([B:10]([O:11][CH:12]([CH3:14])[CH3:13])[O:9][CH:6]([CH3:8])[CH3:7])([CH2:3][CH3:4])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: [Li]C(C)CC
Product: CCC(C)B(OC(C)C)OC(C)C
Temperature: 50 °C

Procedure:
Following the method of Example 1, reaction of sec-butyllithium (208 mL, 250 mmol) and triisopropoxyborane (47.0 mL, 250 mmol), with solvents removed at 0° C. and 15 mm Hg and oil bath temperature maintained at 50° C., yielded sec-butyldiisopropoxyborane, 42.0 g (206 mmol, 90%), bp 138°-140° C. (754 mm Hg); proton NMR (neat) δ4.35 (septet, J=18 Hz, 2H), 1.09 (d, J=18 Hz, 12H), 0.8 (bm, 9H); boron NMR (neat δ+79.5 ppm (s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1>ClCCl.CO>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21]([C:22]1[CH:27]=[CH:26][C:25]2[N:28]([CH3:29])[C:11]([CH2:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:30][C:24]=2[CH:23]=1)=[O:31]
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccn1
Yield: 22 %

Procedure:
Prepared analogously to Example 149a from 3-(4-cyanophenyl)-propionic acid and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide. Yield: 22% of theory, Rf value: 0.68 (silica gel; dichloromethane/methanol=19:1)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([NH:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH3:22])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.B1([C:29]2[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=2)OCCCO1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:17]([NH:16][N:15]1[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=[C:14]1[CH2:20][CH2:21][CH3:22])([CH3:19])[CH3:18]
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1NC(C)C
Reactant: c1cncc(B2OCCCO2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: CCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1NC(C)C
Temperature: 100 °C
Reaction time: 17 h
Yield: 51.8 %

Procedure:
A suspension of 7-bromo-N1-isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.00 g, 2.76 mmol) in 20 mL of 1-propanol was treated with pyridine-3-boronic acid 1,3-propane diol cyclic ester (0.540 g, 3.31 mmol). The head-space of the reaction flask was purged and back-filled with nitrogen (3×). The reaction mixture was then treated with triphenylphosphine (11 mg, 0.041 mmol), sodium carbonate (1.66 mL, 3.31 mmol, 2 M solution in water), water (2 mL) and palladium(II) acetate (3.1 mg, 0.014 mmol). Again the head-space of the reaction flask was purged and back-filled with nitrogen (3×). The reaction was heated to 100° C. After 17 h, the reaction was cooled to ambient temperature and concentrated under reduced pressure to yield a brown solid. The solid was dissolved and partitioned between 15 mL of water and 15 mL of chloroform and then separated. The aqueous portion was extracted with chloroform (2×15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a tan solid. The solid was purified by chromatography (SiO2, 95:5 CHCl3:MeOH) and recrystallized from acetonitrile to give 0.515 g of N1-isopropyl-2-propyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinoline-1,4-diamine as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][CH:45]=1)[CH2:12][C@H:13]1[C:17](=[CH2:18])[CH2:16][C@@H:15]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C@@H:14]1[CH2:27][CH2:28][C@@H:29]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.[OH:55]O.[OH-].[K+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][CH:45]=1)[CH2:12][C@@H:13]1[C@@H:14]([CH2:27][CH2:28][C@@H:29]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C@H:15]([O:19][Si:20]([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:21])[CH3:22])[CH2:16][C@@H:17]1[CH2:18][OH:55])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: C=C1C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CC[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H]1Cc1cccc(OCc2ccccc2)c1
Agent: B1C2CCCC1CCC2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCC[C@@H](CC[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](CO)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A degassed solution of ((1R,2R,3R)-3-(3-(benzyloxy)benzyl)-2-((S)-3-(tert-butyldimethylsilyloxy)octyl)-4-methylenecyclopentyloxy)(tert-butyl)dimethylsilane (0.75 g, 1.15 mmol) in 8 ml dry THF was cooled to 0° C. under nitrogen, and 9-borabicyclo[3,3,1]nonane (6.9 ml, 0.5M in THF) was dropwise added to the mixture. The colorless solution was stirred for overnight at 0° C. and treated with 30% hydrogen peroxide (3 ml) followed by 3N potassium hydroxide (3 ml). The resulting suspension was stirred for one hour at room temperature. The mixture was extracted with EtOAc, and the organic layer was washed with 20 ml brine, dried over MgSO4, and evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give the titled compound: 0.6 g (yield 78%)