Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:22][C:23]1[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([O:31]C)=[O:30])=[C:25]([CH3:35])[CH:24]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([N:5]([CH2:22][C:23]1[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:35])[CH:24]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of methyl {4-[(butyl{6-[4-(trifluoromethyl)phenyl]pyridin-2-yl}amino)methyl]-2-methylphenoxy}acetate (40 mg, 0.082 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL), was added 2M NaOH aq. (2 mL). After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue acidified with 2M HCl, before extraction into ethyl acetate (2×15 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a white solid (35 mg).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7]1)=[O:5].[CH2:22]([Mg]Br)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[C:24]1([CH2:23][CH2:22][C:4]([C@@H:6]2[CH2:7][CH2:8][C@H:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:10][CH2:11]2)=[O:5])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](CNC(=O)OC(C)(C)C)CC1
Reactant: Br[Mg]CCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](C(=O)CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of tert-butyl [(cis-4-{[methoxy(methyl)amino]carbonyl}cyclohexyl)methyl]carbamate (4.51 g, 15.0 mmol) in dry tetrahydrofuran (15 ml) under nitrogen cooled in an ice-bath was added dropwise via syringe over five minutes a 1M solution of phenethyl magnesium bromide in tetrahydrofuran (60 ml, 60 mmol, 4 equivalents). The mixture was stirred 18 hours while warming from ice-bath temperature to ambient temperature. The reaction was quenched by addition of saturated ammonium chloride solution (60 ml). The mixture was diluted with ethyl acetate (240 ml) and the layers were separated. The organic layer was washed with water (60 ml), and brine (60 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give crude product (6.30 g) as a yellow oil. The crude product was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (16:84 increasing to 25:75) to give tert-butyl {[cis-4-(3-phenylpropanoyl)cyclohexyl]methyl}carbamate (3.50 g, 68%) as a white solid: 1H NMR (CDCl3) 7.27 (2H, m), 7.18 (3H, m), 4.55 (1H, br s), 2.99 (2H, t, J 6.5 Hz), 2.88 (2H, t, J 7.5 Hz), 2.75 (2H, t, J 7.5 Hz), 2.44 (1H, m), 1.88 (2H, m), 1.53 (4H, m), 1.43 (9H, s), 1.26 (3H, t, J 7 Hz): MS: 346.3 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH:25]=[C:24](B(O)O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH:23]=[C:24]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:6][N:7]=2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC=C(B(O)O)CC1
Reactant: Brc1ccc(-c2ncccn2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3ncccn3)cn2)CC1

Procedure:
Refluxed mixture of 2-(6-Bromo-pyridin-3-yl)-pyrimidine (1Q) (200 mg, 0.85 mmol), N-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid, pinacol ester (290 mg, 0.93 mmol); Cesium Carbonate (500 mg, 1.538 mmol); PdCl2dppf (30 mg) in dioxane/H2O (10 ml v/v 4/1) for 4 hours. Cooled reaction, then evaporated solvent. Extracted with EtOAc (200 ml) washed with H2O (50 ml), dried over MgSO4, filtered and solvent evaporated yielding a solid which chromatographed on silica gel eluting with 30% v/v acetone/hexanes yielding 2Q as a white solid (110 mg, 38%) ESMS (MH, 339).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[OH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>[Cu].CCOC(C)=O>[O:10]=[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1I
Reactant: Oc1ccccn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccccc1-n1ccccc1=O
Temperature: 200 °C

Procedure:
2-Iodoanisole (1.30 mL, 0.01 mol), 2-hydroxypyridine (0.95 g, 0.01 mol), anhydrous K2CO3 (2.76 g, 0.02 mol) and copper powder (0.0636 g, 0.001 mol) were combined and heated at 200° C. for 2 hr. The reaction mixture was cooled, EtOAc added, and filtered. The filtrate was washed with H2O, aqueous saturated NaHCO3 solution, brine, and dried (Na2SO4). Filtration and concentration gave the title compound after chromatography (silica gel, 2% CH3OH, CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:3]=1.[NH2:14][C:15]1[C:16](=[O:25])[C:17](=[O:24])[C:18]=1OCCCC.O>N1C=CC=CC=1>[NH2:14][C:15]1[C:16](=[O:25])[C:17](=[O:24])[C:18]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:3]=1
Reactant: Nc1cccc(-c2ccncc2)n1
Reactant: CCCCOc1c(N)c(=O)c1=O
Solvent: O
Solvent: c1ccncc1
Product: Nc1c(Nc2cccc(-c3ccncc3)n2)c(=O)c1=O
Reaction time: 1 h
Yield: 13.8 %

Procedure:
A stirred solution of 2-amino-6-(4-pyridyl)pyridine (0.34 g) and 3-amino-4-n-butoxy-3-cyclobutene-1,2-dione (0.34 g) in pyridine (2 ml) is heated under reflux for 8 hours. The cool mixture is treated with water (15 ml) and the mixture stirred for 1 hour. The solid is filtered, washed with water, ethanol and ether, charcoaled and recrystallised from dimethylformamide to give 73 mg of the title compound, mp >340° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:33]([NH2:36])([CH3:35])[CH3:34]>C1COCC1>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][NH:36][CH:33]([CH3:35])[CH3:34])[CH:17]=3)[NH:12][N:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NCCOc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.378 g, 0.800 mmol) and isopropylamine (1.0 mL, 12 mmol) in THF (8 mL) was stirred at 70° C. for 6 hours in a sealed tube. Additional isopropyl amine (1.0 mL, 12 mmol) was added, and the reaction mixture was stirred at 80° C. for 6 hours in a sealed tube. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 10% methanol in chloroform. After drying in vacuo at 80° C. for 30 minutes, [2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl]-isopropyl-amine as a pale yellow solid was obtained (0.110 g, 38.2%). This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 74° C. for 13.5 hours to yield the hydrochloride as an off-white solid (0.117 g): MP: 275-7° C. (dec); Mass Spectrum (+EI, [M+H]+) m/z 360. 1HNMR (500 MHz, DMSO-d6): δ14.22 (br, 1H), 8.75 (br, 2H), 7.96-7.98 (m, 2H), 7.56-7.68 (m, 4H), 7.41 (d, 1H, J=2.08 Hz), 7.19 (dd, 1H, J=9.15 Hz and 2.32 Hz), 4.30-4.33 (m, 2H), 3.34-3.40 (m, 3H), 1.25 ppm (d, 6H, J=6.59 Hz). Elemental Analysis for C18H21N3O3S.1.00 mol HCl.0.10 mol H2O: Calcd: C, 54.36; H, 5.36; N, 10.57; Found: C, 54.02; H, 5.42; N, 10.22.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[OH:11])([O-])=O>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[OH:11]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1O
Solvent: CCO
Product: Nc1ccc(Cl)cc1O
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 2-nitro-5-chloro-phenol (2.2 g, 14.0 mmol) in ethanol (40 mL) was added PtS2-C (5%, 200 mg) and hydrogenated at 45 psi for 4 hours. The mixture was filtered through celite and washed with ethyl acetate (100 mL). The solvent was evaporated and purified by chromatography ((ethyl acetate-hexanes: 2-3) to afford 1.89 g (95%) of a light brown solid. Recrystallization afforded an analytical sample: mp 149-151° C.
Reaction SMILES: [C:1]([C:9]1[CH:28]=[CH:27][C:12]([CH2:13][O:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:30][NH2:31]>CO>[N:30](=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:28]=[CH:27][C:12]([CH2:13][O:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[CH:11][CH:10]=1)[NH2:31]
Reactant: O=C(NCCOCc1ccc(C(=O)c2ccccc2)cc1)Nc1ccccc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NN=C(c1ccccc1)c1ccc(COCCNC(=O)Nc2ccccc2)cc1
Yield: 94.8 %

Procedure:
A solution of (XI) (0.7 g, 1.9 mmol) in methanol (10 ml) was treated with hydrazine hydrate (1.9 g, 38 mmol). The resulting solution was heated to a gentle reflux for 16 h., cooled and concentrated in vacuo. The residue was partitioned between DCM and water and the organic layer was collected, washed with water and dried over MgSO4. Concentration in vacuo yielded (XII) (0.7 g, 99%) as a thick cloudy white oil; δH (CDCl3, 200 MHz) 3.47 (m, 2H, N(H)CH2CH2), 3.61 (m, 2H, OCH2CH2), 4.43, 4.52 (s, 2H, ArCH2O), 5.49 (s, 2H, NNH2), 6.55 (m, 1H, CH2NHC(O)), 6.99 (m, 1H, 4″-H), 7.22 (m, 7H, 3-, 3′-, 3″-, 4′-, 5-, 5′-, 5″-H), 7.46 (m, 6H, 2-, 2′-, 2″-, 6-, 6′-, 6″-H), 7.80 (m, 1H, ArNHC(O)) ppm; υmax 3435 (N—Hstr), 1734 ((R(H)N)2C═Ostr) cm−1; m/z 389 [M+H]+ (15%), 447 [M+MeCN+NH4]+ (100%); found 389.1973, C23H25N4O2 requires 389.1978.
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1.C(OC(=O)C)(=O)C.[CH2:25]([OH:27])[CH3:26]>O>[C:25]([C:15]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[C:3]([CH2:2][NH2:1])[C:16]=31)[C:9]1[C:8]2=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:27])[CH3:26]
Reactant: NCC12CC(c3ccccc31)c1ccccc12
Reactant: CCO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C12CC(c3ccccc31)c1cccc(CN)c12

Procedure:
A solution of 9-aminomethyl-9,10-dihydro-9,10-methanoanthracene (235 mg) and acetic anhydride (217 mg) in ethanol (5.0 ml) was refluxed for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-acetyl-aminomethyl-9,10-dihydro-9,10-methanoanthracene. M.P. 184°-185.5° C.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][C:21]([NH:23][CH:24]1[C:31](=[O:32])[N:30]2[CH:25]1[S:26][CH2:27][C:28]([CH3:36])=[C:29]2[C:33]([OH:35])=[O:34])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(#N)C>[CH:7]([O:35][C:33]([C:29]1[N:30]2[CH:25]([S:26][CH2:27][C:28]=1[CH3:36])[CH:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:31]2=[O:32])=[O:34])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Temperature: 22 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
A solution of diphenyldiazomethane (116.5 g) in acetonitrile (800 cc) is added dropwise, in the course of 45 minutes, at a temperature of between 25° and 30° C., to a solution of 7-tert.-butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (188.6 g) in acetonitrile (2,100 cc). The reaction mixture is stirred for 16 hours at 22° C. and then concentrated to dryness under reduced pressure (20 mm Hg) at 40° C. The residue is redissolved in ethyl acetate (2 liters) and the solution is washed with 2 N hydrochloric acid (700 cc) and then with a saturated aqueous sodium bicarbonate solution (700 cc) and a saturated aqueous sodium chloride solution (700 cc). The solution is dried over sodium sulphate, treated with decolorising charcoal, filtered and then concentrated to dryness under reduced pressure (20 mm Hg) at 40° C. The residue is dissolved in boiling ethyl acetate (600 cc). Cyclohexane (1 liter) is added, and the mixture is heated under reflux and then allowed to cool. The crystals which have appeared are filtered off, washed with diethyl ether (3×250 cc) and then dried. 2-Benzhydryloxycarbonyl-7-tert.butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (191 g) is obtained in the form of white crystals (m.p.=179° C.). On concentrating the mother liquors to 500 cc, a second fraction of product (32.6 g, m.p.=178° C.) is obtained.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li][CH2:11]CCC.[C:15]([O:19][C:20]([NH:22][C@H:23]([C:29]([O:31][CH3:32])=[O:30])[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:21])([CH3:18])([CH3:17])[CH3:16].CI>C1COCC1>[C:15]([O:19][C:20]([NH:22][C@H:23]([C:29]([O:31][CH3:32])=[O:30])[CH:24]([CH3:11])[C:25]([O:27][CH3:28])=[O:26])=[O:21])([CH3:17])([CH3:18])[CH3:16]
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: [Li]CCCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of hexamethyldisilazane (88 mL, 0.421 mol), in THF (500 mL) at −30° C. was added BuLi (2.5M in hexanes, 169 mL, 0.423 mol) and the mixture stirred at this temperature for 15 minutes before cooling to −78° C. A solution of dimethyl N-(tert-butoxycarbonyl)-L-aspartate (Preparation 70, 50 g, 0.19 mol) in THF (200 mL) was added slowly over 15 minutes and the reaction stirred at −78° C. for 2 hours. MeI (14.3 mL, 0.23 mol) was added over 30 minutes and the reaction continued stirring at −78° C. for 18 hours. The reaction was quenched by pouring into an aqueous solution of KHSO4 (80 g in 600 mL, pH=3). THF was then removed in vacuo and the product extracted into EtOAc. The organic layer was collected, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% EtOAc in heptane to afford the title compound as a mixture of diastereomers in a ratio 7:3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].S(O[CH2:22][CH:23]1[CH2:28][CH2:27][CH:26]=[CH:25][O:24]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:22][CH:23]2[CH2:28][CH2:27][CH:26]=[CH:25][O:24]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(OCC2CCC=CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
A mixture of a solution of 247 mg of p-fluorophenol in 1 ml of dimethylformamide with 87 mg of 55% sodium hydride was stirred at room temperature for 30 minutes. 537 mg of 2-tosyloxymethyl-3,4-dihydro-2H-pyran were then added to the mixture, which was allowed to react at 90° C. for 3 hours. Thereafter, the mixture was treated and the product purified essentially as described in Example 34(a) to give 102 mg of 2-(4-fluorophenoxymethyl)-3,4-dihydro-2H-pyran as a colourless oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(Cl)(=O)C([Cl:13])=O>CN(C)C=O.C(OCC)C>[CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([Cl:13])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[Si](C)(C)CCC(=O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCC(=O)Cl
Reaction time: 16 h
Yield: 68.9 %

Procedure:
In a flask were place 13.4 g (0.0918 mole) of 4,4-dimethyl-4-silapentanoic acid, 100 mL of diethyl ether, and two drops of N,N-dimethylformamide. To this solution, which was cooled in an ice/water bath, was added 13.98 g (0.110 mole) of oxalyl chloride in diethyl ether in a dropwise manner. Upon completion of addition, the temperature was allowed to rise to ambient conditions, and the mixture was stirred for approximately 16 hours. At the conclusion of this period the solvent was evaporated from the reaction mixture under reduced pressure, leaving 10.42 g of 4,4-dimethyl-4-silapentanoic acid chloride as a residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8]1(=[O:19])=[O:18]>C(O)C>[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH:11]([OH:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8]1(=[O:19])=[O:18]
Reactant: O=C1CC(CCCCl)S(=O)(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=S1(=O)c2ccccc2C(O)CC1CCCCl
Yield: 90.9 %

Procedure:
200 mg (5.29 mmol) of sodium borohydride was added in portions to a solution of 620 mg (2.27 mmol) of the Compound 5 in 20 ml of ethanol while stirring under cooling with ice. After stirring for 17 hours at room temperature, the reaction mixture was concentrated under vacuum. A 0.1 M phosphate buffer solution (pH 6.0) was added to the residue and the mixture was extracted with chloroform (three times). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using a 1:1 ethyl acetate-hexane solution as an eluent to obtain 567 mg (yield: 91%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17](=O)[CH2:18][CH3:19])(C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[CH2:18]([C:17]1[NH:7][C:8]2[C:9]([CH:16]=1)=[CH:10][CH:11]=[C:12]([O:14][CH3:15])[CH:13]=2)[CH3:19]
Reactant: CCC(=O)Cc1ccc(OC)cc1NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2ccc(OC)cc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 166.9 %

Procedure:
To a solution of [5-methoxy-2-(2-oxo-butyl)-phenyl]-carbamic acid t-butyl ester 73b (1.36 g, 4.65 mmole) in 10 ml THF was added 4 ml TFA. The reaction mixture was stirred at room temperature for 5 h, quenched with 50 ml H2O and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (10-15% EtOAc in hexane) to give pale yellow solid (1.36 g, 73%). 1H NMR (CDCl3) δ7.75 (1H, bs), 7.49 (1H, d, J=8.6 Hz), 6.81 (1H, s), 6.73 (1H, d, J=8.6 Hz), 3.83 (3H, s), 2.75 (2H, q, J=7.5 Hz), 1.32 (3H, t, J=7.5 Hz). ESIMS (MH+): 272.10.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[C:14]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])[C:14]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCN(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A mixture of methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 114, 0.08 g), N,N-dimethylethanolamine (0.024 g) and triphenylphosphine (0.085 g) in dry THF (1 ml) was stirred and cooled to 0° C. A solution of di-isopropyl azodicarboxylate (0.065 g) in dry THF (1 ml) was added dropwise. The resultant mixture was stirred at 0° C. for 10 minutes then at room temperature overnight. Further triphenylphosphine (0.028 g) and di-isopropyl azodicarboxylate (0.022 g) was added and the mixture was stirred at room temperature for 1.5 hours then left to stand at room temperature overnight. The mixture was added to a SCX-2 column and eluted with acetonitrile followed by 2M ammonia in methanol. After evaporation of the basic eluent, the residue was repurified using an SCX-2 column, eluting with methanol followed by 2M ammonia in methanol to give methyl 6-(benzenesulphonylmethyl)-2-(2-dimethylaminoethoxy)-3-(furan-3-yl)benzoate (0.07 g) as a gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9].C(N(CC)CC)C.[C:25]1([C:31]2[N:32]([CH2:43][C:44](Cl)=[O:45])[C:33](=[O:42])[O:34][C:35]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[C:44](=[O:45])[C@H:43]([N:32]2[C:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:34][C:33]2=[O:42])[C@@H:7]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C(Cl)Cn1c(-c2ccccc2)c(-c2ccccc2)oc1=O
Reactant: COC(=O)C=NCc1ccc(OC)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1[C@@H](n2c(-c3ccccc3)c(-c3ccccc3)oc2=O)C(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 1 h

Procedure:
Methyl N-(2,4-dimethoxybenzyl)iminoacetate (1.43 g) is dissolved in 13 ml of dry methylene chloride and 1 ml of triethylamine and cooled in an ice bath. A solution of 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid chloride (2.0 g, 6.4 mmole) in 10 ml of methylene chloride is added over a 10 minute period. After one hour, the mixture is washed with water and 5% aqueous sodium bicarbonate then dried and evaporated to give a red oil which is chromatographed on silica gel to give methyl cis-1-(2,4-dimethoxybenzyl)-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-yl)-4-oxoazetidine-2-carboxylate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH2:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([F:14])[C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A80) and (R)-3-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.