Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1>C(O)C>[CH:11]([C:12]1[CH:13]=[N:1][C:2]2[C:7]([CH:17]=1)=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:3]=2)=[O:10]
Reactant: Nc1cccc(NC(=O)OCc2ccccc2)c1
Solvent: CCO
Product: O=Cc1cnc2cc(NC(=O)OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 197.9 %

Procedure:
A slurry of benzyl 3-aminophenylcarbamate (8.0 g, 0.033 mol) and 2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propane bis(tetrafluoroborate) (31 g, 0.087 mol) in ethanol (400 mL) was heated at reflux for 24 h. The solution was concentrated under vacuum and the residue was dissolved in THF (200 mL) and 1N HCl (200 mL). The reation mixture was stirred at rt overnight, then poured into a saturated solution of sodium bicarbonate (200 mL), and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under vacuum to afford the desired product (10.0 g, 99%) as a yellow solid. LC-MS: 2.84 min, 307.1 (M+1).
Reaction SMILES: [CH2:1]([C:5]1([CH3:47])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20](=[O:35])[NH:21][CH2:22][C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=4[O:30][CH2:31][CH2:32][CH:33]=[CH2:34])[N:19]=[C:15]3[CH:14]=[C:13]([CH3:36])[C:12]=2[C@H:37]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:38]([O:40]C)=[O:39])[CH2:7][CH2:6]1)[CH2:2]C=C.C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(CCCCCOC2C=CC=CC=2CNC3=O)CC1)C(O)=O)(C)(C)C>>[C:43]([O:42][C@@H:37]([C:12]1[C:13]([CH3:36])=[CH:14][C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:47])([CH2:1][CH2:2][CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:24]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=2[CH2:22][NH:21][C:20]3=[O:35])[CH2:6][CH2:7]1)[C:38]([OH:40])=[O:39])([CH3:45])([CH3:46])[CH3:44]
Reactant: C=CCCOc1ccc(F)cc1CNC(=O)c1cn2c(N3CCC(C)(CCC=C)CC3)c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc2n1
Agent: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CCCCCOc2ccccc2CNC3=O)CC1
Product: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CCCCCCOc2ccc(F)cc2CNC3=O)CC1
Yield: 12 %

Procedure:
Prepared from methyl(2S)-2-{5-[4-(but-3-en-1-yl)-4-methylpiperidin-1-yl]-2-({[2-(but-3-en-1-yloxy)-5-fluorophenyl]methyl}carbamoyl)-7-methylimidazo[1,2-a]pyridin-6-yl}-2-(tert-butoxy)acetate in 12% yield using the same procedure as (2S)-2-(tert-butoxy)-2-{4,25-dimethyl-10-oxo-19-oxa-1,7,11,30-tetraazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.90-8.81 (m, 1H), 8.21 (s, 1H), 7.27 (dd, J=8.9, 3.1 Hz, 1H), 7.22 (s, 1H), 7.10-7.03 (m, 1H), 6.95 (dd, J=9.0, 4.4 Hz, 1H), 5.91 (s, 1H), 4.30 (t, J=5.0 Hz, 2H), 4.05-3.95 (m, 2H), 3.79-3.71 (m, 2H), 3.01 (d, J=11.0 Hz, 1H), 2.62 (d, J=11.0 Hz, 1H), 2.37 (s, 3H), 1.82-1.33 (m, 14H), 1.17 (s, 9H), 0.96 (s, 3H); LCMS (ESI, M+1): 609.3.
Reaction SMILES: ClC1C=C(Cl)C(OC)=CC=1N[C:12]1[C:21]2[C:16](=[CH:17][C:18](F)=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[C:23]#[N:24]>C(O)CC>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[C:13]([C:23]#[N:24])[CH:14]=1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(F)ccc23)c(Cl)cc1Cl
Solvent: CCCO
Product: N#Cc1cnc2ccccc2c1

Procedure:
Following the procedure used to prepare Example 15, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-3-quinolinecarbonitrile (200 mg, 0.55 mmol) and 3-(4-methyl)piperazin-1-yl)propanol provided 71 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[3-(4-methyl)piperazin-1-yl)propoxy]-3-quinolinecarbonitrile, mp 154-155° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[OH:11].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16].C1N2CCN(CC2)C1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[O:11][C:15](=[S:16])[N:14]([CH3:18])[CH3:13]
Reactant: COC(=O)c1ccc(Br)cc1O
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a mixture of 4-bromo-2-hydroxy-benzoic acid methyl ester (Mori, N. et al, Bull Chem. Soc. Jpn. 1969, 42(2), 488-491) (29.3 g, 127 mmol) and dimethylthiocarbamoyl chloride (17.2 g, 140 mmol) in DMF at room temperature was added DABCO (21.3 g, 190 mmol). The resulting mixture, after being stirred at room temperature overnight, was diluted with water (1.25 L) and acidified to a pH of around 4 using 1 N HCl. The precipitate was collected, rinsed with water and dried in vacuo to provide 4-bromo-2-dimethylthiocarbamoyloxy-benzoic acid methyl ester as an off-white solid (36.8 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=7.84 (d, J=8.2 Hz, 1H), 7.43 (dd, J=8.6, 2.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 3.83 (s, 3H), 3.45 (s, 3H), 3.38 (s, 3H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][N:17]=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:15]=2[CH:30]=1)=[O:9])(=O)C.C[O-].[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C.C(Cl)Cl>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:16]1[C:15]2[CH:30]=[C:11]([NH:10][C:8]([NH:7][CH2:6][CH2:5][OH:4])=[O:9])[CH:12]=[CH:13][C:14]=2[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][N:17]=1
Reactant: CC(=O)OCCNC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)NCCO)ccc21

Procedure:
20 mg (0.048 mM) of 2-[3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]ureido]ethyl acetate are dissolved in 2 ml of absolute methanol and stirred at 30°-40° C. for 1 hour with 13 mg of sodium methylate. The mixture is then buffered with a few drops of glacial acetic acid, diluted with methylene chloride, treated with 10% sodium bicarbonate solution and extracted several times with methylene chloride. The organic phases are combined, dried over sodium sulphate, filtered and concentrated. The residue is crystallised from acetone/ether. There is obtained 1-[5-(o-fluorophenyl)-2,3dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea which, according to the IR spectrum, is identical with a sample of this substance prepared in another manner (see Example 7).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([O:13][Si](C)(C)C)=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[F:20]OC(F)(F)F>C(Cl)(Cl)(Cl)F>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([F:20])[C:4]([OH:13])=[O:3])=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)OC(=Cc1ccc(Cl)cc1)O[Si](C)(C)C
Reactant: FOC(F)(F)F
Solvent: FC(Cl)(Cl)Cl
Product: O=C(O)C(F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.4 %

Procedure:
A solution of 29.92 g (0.095 mol) of the aforesaid β,β-bis(trimethylsiloxy)p-chlorostyrene in 300 ml of CFCl3 was cooled to -70° C. and 9.88 g (0.095 mol) of trifluoromethyl hypofluorite were passed into the solution over a period of 2 hours. The mixture was allowed to warm to room temperature and evaporated to dryness under reduced pressure. The resultant white solid residue was stirred with 10 ml of water for approximately 10 minutes. The solids were recrystallized from 1 l of hexane to give 9.38 g (53% yield) of p-chlorophenylfluoroacetic acid as shiny white crystals, mp 66°-68° C.; 1H NMR (CDCl3) δ5.75 (d, J≅47 Hz, 1H), δ7.35 ppm (s, 4H), δ10.95 (s, 1H); 19F NMR (CDCl3) δ-182.60 (d, J≅47 Hz).
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[S:34]([N:12]1[C:13]2[C:9](=[C:8]3[CH:2]([CH3:1])[N:3]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:4][CH2:5][O:6][C:7]3=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)(=[O:35])=[O:36]
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C)cc1S(=O)(=O)n1ccc2c3c(ccc21)OCCN(C(=O)OC(C)(C)C)C3C
Reaction time: 8 h
Yield: 17.3 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2-methoxy-5-methylbenzenesulfonyl chloride (25 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2-methoxy-5-methylphenyl)sulfonyl]-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (7 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (2 mg). MS m/z 387 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:17]2[CH2:16][S:15][C:14](=O)[C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].B(F)(F)F.CCOCC>O1CCCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:17]2[CH2:16][S:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c1CSC2=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cccc2c1CSC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
A suspension of 8.0 g of 1,3-dihydro-N-(1,1-dimethylethyl)-1-oxobenzo[c]thiophene-4-sulfonamide in a mixture of 15 ml of tetrahydrofuran, 25 ml of boron trifluoride etherate was cooled to 10° under N2, and 56 ml of a 1M solution of borane tetrahydrofuran complex was added dropwise at approximately 10°. The reaction mixture was allowed to warm to ambient temperature as a gas was evolved. When ambient temperature was reached, a slow exotherm to 31° occurred. When the exotherm subsided, the reaction mixture was heated to reflux for two hours, then cooled and allowed to stand overnight. The supernatant was decanted fom some brown solid, and concentrated in vacuo. The resulting yellow oil was cooled to approximately 5°, acidified with 5% hydrochloric acid (gas evolution), and diluted with 150 ml water. The aqueous mixture was extracted with ethyl acetate. The organic solution was washed twice with water, dried over magnesium sulfate, then filtered and the filtrate concentrated in vacuo. The resulting yellow oil was purified by chromatography, using methylene chloride as eluent, to give 3.6 g of 1,3-dihydro-N-(1,1-dimethylethyl)benzo[c]thiophene-4-sulfonamide, m.p. 128.5°-132°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][OH:32])[C:6]=2[CH:33]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][O:32][C:34](=[O:36])[CH3:35])[C:6]=2[CH:33]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(CCO)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-5-(2-hydroxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) in pyridine (6 ml) is added acetic anhydride (0.09 ml), and the mixture is stirred at 80° C. for 2 hours. The reaction solution is poured into water, and extracted with ethyl acetate. The extract is washed successively with diluted hydrochloric acid, water and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-(2-acetyloxyethyl)-1-[6-(2-chlorobenzoylamino )nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (230 mg) as white powder.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:13])[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)([CH3:3])[CH3:2].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[CH:16]=1.C(N(CC)CC)C.[NH4+].[OH-]>C(O)CCC.CO.C(Cl)Cl>[CH:1]([NH:4][C:5](=[O:13])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:15]2[CH:16]=[C:17]([NH:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)[N:18]=[CH:19][N:20]=2)[CH2:9][CH2:8]1)([CH3:3])[CH3:2]
Reactant: Clc1cc(Nc2nccs2)ncn1
Reactant: CC(C)NC(=O)CN1CCNCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)CN1CCN(c2cc(Nc3nccs3)ncn2)CC1
Temperature: 150 °C

Procedure:
N-isopropyl-2-piperazin-1-ylacetamide 13-1 (0.74 g, 4.0 mmol)) was suspended in n-butanol to which compound 52-2 (0.85 g, 4.0 mmol) and triethylamine (1.22 g, 12.0 mmol) were added and then heated at 150° C. for 6 hours. The reaction was cooled to room temperature and the precipitate was filtered off, washed with n-butanol and ethyl ether and dried to produce 52-3. Rf=0.45 (DCM:MeOH:NH4OH, 95:5:0.5). 1H-NMR (DMSO-d6): 11.16(s, 1H); 8.33(s, 1H); 7.54(d, 1H); 7.36(s, 1H); 7.05(s, 1H); 6.24(s, 1H); 3.90(m, 1H); 3.55(br s, 4H); 2.94(s, 2H); 2.49(br s, 4H); 1.08(d, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[O-:10][CH2:11][CH3:12].[Na+].OCCCl>C(O)C>[OH:10][CH2:11][CH2:12][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9]
Reactant: CC[O-]
Reactant: CSc1ccccc1O
Agent: OCCCl
Agent: [Na+]
Solvent: CCO
Product: CSc1ccccc1OCCO

Procedure:
o-Hydroxythioanisole (14.1 g., 0.1 mole) is dissolved in sodium ethoxide (6.8 g., 0.1 mole) in absolute ethanol (100 ml.) and stirred as β-hydroxyethyl chloride (8.1 g., 0.1 mole) is added. The reaction mixture is refluxed for 2 hours and cooled. The o-(β-hydroxyethoxy)-thioanisole is extracted.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>>[O:28]=[C:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][S:2]([C:5]3[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])=[CH:17][CH:18]=2)[CH2:23][CH2:24]1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(C(=O)O)cc3)cc2)CC1

Procedure:
The title compound was prepared from 4-(chlorosulfonyl)benzoic acid and 1-(4-amino-phenyl)-piperidine-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a pale grey solid; 1H NMR (300 MHz, DMSO-d6) δ 2.36 (t, J=6.0 Hz, 4H), 3.49 (t, J=6.0 Hz, 4H), 6.87 (d, J=9.3 Hz, 2H), 6.91 (d, J=9.3 Hz, 2H), 7.77 (d, J=8.1 Hz, 2H), 8.04 (d, J=8.1 Hz, 2H), 9.97 (s, 1H), 13.10 (brs, 1H); MS (ES) m/z: 374.9 (MH+); HRMS Calcd. for C18H19N2O5S(MH+): 375.1009. Found: 375.1009.
Reaction SMILES: I[C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].[CH3:12]B1OB(C)OB(C)O1>C1COCC1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH3:12][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1scc(C)c1I
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1scc(C)c1C

Procedure:
A solution of methyl 3-iodo-4-methylthiophene-2-carboxylate (400 mg, 1.418 mmol), trimethylboroxine (793 μL, 5.67 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (92 mg, 0.142 mmol) in THF (2363 μL) was degassed by bubbling N2 through the solution. 1N aq. K2CO3 (2363 μL) was added and N2 was bubbled through the mixture for 30 s. The mixture was subjected to microwave irradiation in a sealed tube at 120° C. for 30 min. The reaction mixture was filtered through a plug of silica, eluted with EtOAc and the filtrate was washed with 1N aq. NaOH (2×), dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 10% EtOAc in hexanes over 1140 mL) to afford methyl 3,4-dimethylthiophene-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[Cl-].[Na+].Cl(O)(=O)(=O)=O.N[CH2:17][C:18]1[S:22][C:21]([Cl:23])=[N:20][CH:19]=1.[OH-].[Na+]>O>[CH3:1][O:2][C:3](=[N:4][N+:5]([O-:7])=[O:6])[NH:8][CH2:17][C:18]1[S:22][C:21]([Cl:23])=[N:20][CH:19]=1
Reactant: NCc1cnc(Cl)s1
Reactant: COC(=N)N[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
O-methyl-N-nitroisourea (1.2 g, 0.01 mol) was added to water (30 ml) dissolving sodium chloride (4.7 g). Then, 70% perchloric acid (1.52 g, 0.0106 mol, 1.06 equivalents) was added, and 5-(aminomethyl)-2-chlorothiazole (1.49 g, 0.01 mol, 1.00 equivalent) was added at 24° C. The mixture was adjusted to pH 7 with 30% aqueous sodium hydroxide solution. After 24 hours of stirring at room temperature, the resulting crystals were collected by filtration to provide 1.56 g (62.2% yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=C/N(C)C.O.CC[O:18]C(C)=O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[O:18]
Reactant: CCOC(C)=O
Reactant: CN(C)/C=C/c1nc2ccccc2o1
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1nc2ccccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To (E)-2-(benzo[d]oxazol-2-yl)-N,N-dimethylethenamine (1 g, 5.32 mmol) in THF (15 mL) at 0° C. was added water (15 mL) and NaIO4 (3.4 g, 16 mmol). The resulting mixture was stirred at 0° C. for 10 min, then at room temperature for 2 h. To the solution was added H2O and EtOAc and then the mixture was filtered. The clear solution was extracted with EtOAc and the organic phase was washed with aqueous NaHCO3 solution. The organic phase was concentrated and the residue was purified by column chromatography to give the title compound (120 mg). MS (ESI) m/z 148 (M+H+).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][C:18](F)(F)F)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:22])[CH:4]=1.[CH:25](=O)CC>>[F:1][C:2]([F:24])([F:23])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:25])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:22])[CH:4]=1
Reactant: O=c1cc(C(F)(F)F)c2cc3c(cc2[nH]1)CCCN3CC(F)(F)F
Reactant: CCC=O
Product: CCCN1CCCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc21

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 192 (Structure 33 of Scheme VI, where R1=H, n=1) and propionaldehyde. 1H NMR (400 MHz, CDCl3) 11.23 (br. s, 1H), 7.07 (s, 1H), 6.99 (s, 1H), 6.78 (s, 1H), 3.34 (t, 2H, J=5.6), 3.26 (t, 2H, J=7.4), 2.88 (t, 2H, J=6.3), 1.97 (m, 2H), 1.65 (m, 2H), 0.97 (t, 3H, J=7.4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]=[C:27]=[S:28]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:27]([NH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH3:19])=[S:28]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: Cc1ccccc1N=C=S
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccccc1C
Temperature: 80 °C
Reaction time: 96 h
Yield: 51.3 %

Procedure:
A mixture of 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol), 2-methylphenyl isothiocyanate (0.55 mL, 4.11 mmol, and ethyl acetate 20 mL) was allowed to stand at room temperature. After 4 days, the reaction was heated to 80° C. for 3 hours then allowed to stand at room temperature for an additional 5 days. Filtration afforded the product (0.804 g); m.p. 172-174° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:20][C:21]([C@@H:23](/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]2([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])OCC[O:46]2)[C@@:24]([OH:36])([CH2:32][CH2:33][O:34][CH3:35])[C:25]([O:27]C(C)(C)C)=[O:26])=[O:22])[C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].O.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:20][C:21]([C@@H:23](/[CH:37]=[CH:38]/[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45](=[O:46])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C@@:24]([OH:36])([CH2:32][CH2:33][O:34][CH3:35])[C:25]([OH:27])=[O:26])=[O:22])[C:14](=[O:15])[NH:16][CH2:17][CH2:18][OH:19])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)NCCO)cc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC)C(=O)O)C(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
(2S,3S,E)-tert-Butyl 3-((S)-3-(4-(but-2-ynyloxy)phenyl)-1-(2-hydroxyethylamino)-1-oxopropan-2-ylcarbamoyl)-11-(2-heptyl-1,3-dioxolan-2-yl)-2-hydroxy-2-(2-methoxyethyl)undec-4-enoate (11.3 mg, 0.014 mmol) was dissolved in dichloromethane (0.5 mL), and water (50 μL) was added. Trifluoroacetic acid (1.5 mL) was further added. The reaction mixture was stirred at room temperature for 5 hours, and then concentrated. The resulting residue was dissolved in methanol (1.0 mL). To the solution was added an aqueous solution (50 μL) of 28% ammonia and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the resulting residue was then diluted in ethyl acetate, and washed with an aqueous solution of 0.5 M citric acid. The separated organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, then filtered, and concentrated. The resulting residue was purified by diol silica gel thin layer chromatography (dichloromethane/methanol) to obtain the target compound as colorless oil at a yield of 80%.
Reaction SMILES: CN(C)C1C(C)=CC=CC=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.[Cl:21][SiH:22]([Cl:24])[Cl:23]>>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][Si:22]([Cl:24])([Cl:23])[Cl:21])=[CH:15][CH:14]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: COc1ccc(CCl)cc1
Agent: Cc1ccccc1N(C)C
Product: COc1ccc(C[Si](Cl)(Cl)Cl)cc1
Reaction time: 15 h
Yield: 11.3 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.06 g (0.45 mmol) of N,N-dimethyltoluidine, 0.7 g (4.5 mmol) of 4-methoxybenzyl chloride, and 3.05 g (22.5 mmol) of trichlorosilane were reacted at 200+ C. for 15 hrs. The resulting mixture was distilled to give 0.13 g of (4-methoxybenzyl)trichlorosilane (yield; 11%).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[S:21][C:22]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:32]1[CH:41]=[CH:40][C:39]2[C:38]([CH3:43])([CH3:42])[CH2:37][CH2:36][C:35]([CH3:45])([CH3:44])[C:34]=2[CH:33]=1>>[CH3:42][C:38]1([CH3:43])[CH2:37][CH2:36][C:35]([CH3:45])([CH3:44])[C:34]2[CH:33]=[C:32](/[C:26](/[Si:27]([CH3:28])([CH3:29])[CH3:30])=[CH:25]/[C:22]3[S:21][C:20]([CH2:19][OH:18])=[CH:24][CH:23]=3)[CH:41]=[CH:40][C:39]1=2
Reactant: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)s1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Product: CC1(C)CCC(C)(C)c2cc(/C(=C/c3ccc(CO)s3)[Si](C)(C)C)ccc21

Procedure:
Following General Procedure A, 5-[(trimethylsilyl)ethynyl]thiophen-2-ylmethyl tert-butyldiphenylsilyl ether (Compound 13, 0.75 g, 1.8 mmol) and 2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (0.46 g, 1.62 mmol) were coupled to give the title compound.