Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=CN=1.[NH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=[O:14].ClC1N=CC=C2C=1[C:18]1[CH:38]=[N:37][CH:36]=[CH:35][C:19]=1[C:20]([NH:26][C@@H:27]([C:31]([F:34])([F:33])[F:32])[CH:28]([CH3:30])[CH3:29])=[N:21]2.[OH-].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[CH3:29][CH:28]([CH3:30])[C@@H:27]([NH:26][C:20]1[C:19]2[CH:18]=[CH:38][N:37]=[CH:36][C:35]=2[C:10]2[C:9](=[O:14])[NH:8][CH:13]=[CH:12][C:11]=2[N:21]=1)[C:31]([F:34])([F:32])[F:33]
Reactant: CC(C)[C@@H](Nc1nc2ccnc(Cl)c2c2cnccc12)C(F)(F)F
Reactant: O=c1cccc[nH]1
Agent: [Pd]
Agent: Clc1ccccn1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](Nc1nc2cc[nH]c(=O)c2c2cnccc12)C(F)(F)F
Temperature: 100 °C

Procedure:
The 2-chloro pyridine was converted the pyridone following the procedure of J. Am. Chem. Soc. 2006, 128, 1094-10695. To a solution of 1-chloro-N-[(1R)-2-methyl-1-(trifluoromethyl)propyl]pyrido[4,3-c]-1,6-naphthyridin-6-amine (1100 mg, 3.10 mmol) in dioxane (10 mL) and water (10 mL) was added KOH (696 mg, 12.4 mmol), 1-[2′-(di-tert-butylphosphino)-2,6-diisopropylbiphenyl-4-yl]ethyl (263 mg, 0.62 mmol) and Pd2 (dba)3 (284 mg, 0.31 mmol). The stirring solution was heated to 100° C. overnight. The reaction mixture was cooled and worked up with EtOAc and water. The organic layers were separated, dried with MgSO4, filtered, and concentrated by rotary evaporation. The oily residue was purified by silica gel column chromatography CH2Cl2 to MeOH 30% provided the 6-{[(1R)-2-methyl-1-(trifluoromethyl)propyl]amino}pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one. 1H NMR (600 MHz, CD3OD) δ 11.30 (s, 1H), 9.05 (d, 1H), 8.95 (d, 1H), 7.62 (d, 1H), 6.80 (d, 1H), 5.48 (m, 1H), 2.40 (m, 1H), 1.17 (d, 3H), 1.10 (d, 3H). LRMS (ESI) calc'd for (C16H16F3N4O) [M+H]+, 337.1; found 337.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C([O-])(O)=O.[Na+].CC(C)[CH2:20][C:21](=[O:23])C.ClCC(Cl)=O>O>[C:8]([C:6]1[C:5]([F:11])=[CH:4][C:3]2[O:12][CH2:20][C:21](=[O:23])[NH:1][C:2]=2[CH:7]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)CC(C)C
Reactant: CC(=O)c1cc(N)c(O)cc1F
Agent: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cc2c(cc1F)OCC(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a mixture of 1-(5-amino-2-fluoro-4-hydroxy-phenyl)-ethanone (13.2 g, 78 mmol), NaHCO3 (19.67 g, 234 mmol) in water (90 mL), and 4-methyl-2-pentanone (90 mL) at 0° C. was added 2-chloroacetyl chloride (13.22 g, 8.8 mL, 117 mmol) dropwise. After addition, the reaction mixture was stirred at ambient temperature for 0.5 h and then at 80° C. for 18 h. The mixture was cooled to ambient temperature and filtered to give 6-acetyl-7-fluoro-4H-benzo[1,4]oxazin-3-one as gray solid (12 g, 74%), which was used in next step directly without further purification. 1H NMR (DMSO-d6, 400 MHz): δ 10.90 (s 1H), 7.35 (d, J=7.6 Hz, 1H), 7.02 (d, J=11.6 Hz, 1H), 4.71 (s, 2H), 2.47 (d, J=4.8 Hz, 3H).
Reaction SMILES: ClC1C=C(Cl)C=CC=1[CH:9]1[CH:18]([C:19](O)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[N:10]1C1CCCCC1NS(C)(=O)=O.O1CCCCC1OC1C=C(C=CC=1)CO[NH2:46].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>O.C(OCC)(=O)C.CN(C=O)C>[O:22]=[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]([C:19]([NH2:46])=[O:20])[CH2:9][NH:10]1
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)O)C1c1ccc(Cl)cc1Cl
Reactant: NOCc1cccc(OC2CCCCO2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)C1CNC(=O)c2ccccc21
Reaction time: 3 h

Procedure:
To 400 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid were added 8 ml of DMF, 243 mg of O-[3-(tetrahydro-2H-pyran-2-yl oxy)benzyl]hydroxylamine, 159 mg of HOBt, and 243 mg of WSC, followed by stifling at room temperature for 3 hours. The reaction solution was added with ethyl acetate and water to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. To the residue was added methanol, and concentrated hydrochloric acid was added dropwise thereto under ice-cooling, followed by stirring under ice-cooling for 1 hour. The precipitated crystal was collected by filtration to obtain 275 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[(3-hydroxybenzyl)oxy]-2-{(1SR,2SR)-2-Rmesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [OH-].[Na+].[P:3]([O-:8])([O:6][CH3:7])[O:4][CH3:5].[CH2:9]([O:13][C:14](=[O:17])[CH:15]=[O:16])[CH2:10][CH2:11][CH3:12]>>[CH2:9]([O:13][C:14](=[O:17])[CH:15]([P:3]([O:6][CH3:7])([O:4][CH3:5])=[O:8])[OH:16])[CH2:10][CH2:11][CH3:12]
Reactant: COP([O-])OC
Reactant: CCCCOC(=O)C=O
Agent: [Na+]
Agent: [OH-]
Product: CCCCOC(=O)C(O)P(=O)(OC)OC
Yield: 70 %

Procedure:
1.5 ml of a saturated methanolic sodium hydroxide solution are allowed to run rapidly into 22 g of dimethyl phosphite and 26 g of glyoxylic acid butyl ester. The reaction which proceeds is highly exothermic. The mixture is subsequently stirred at 25° for some hours and worked up by distillation to give 33.6 g of dimethoxyphosphinylhydroxy-acetic acid butyl ester (yield: 70%). Boiling point 0.05 : 75°-82° C. (thin film evaporator). 1H-NMR (CDCl3): δ=0.93 (3H, t, J=5 Hz, CH3), 3.86 (6H, d, J=11 Hz, CH3O), 4.23 (2H, t, J=6 Hz, OCH2) and 4.63 ppm (1H, d, J=18 Hz, P-CH)
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([C:8]([NH:10][NH:11][C:12]([C:14]2[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[O:13])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].I[CH3:29]>CC(C)=O>[CH3:29][S:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][NH:11][C:12]([C:14]2[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[O:13])=[O:9])=[CH:26][CH:27]=1)=[NH:2]
Reactant: CI
Reactant: COC(=O)COc1ccc(C(=O)NNC(=O)c2ccc(C(N)=S)cc2)cc1
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(=O)NNC(=O)c2ccc(C(=N)SC)cc2)cc1
Reaction time: 4 h

Procedure:
Methyl 4-[3-(4-thiocarbamoylbenzoyl)carbazoyl]phenoxyacetate (10.5 g) was suspended in acetone (1 L) and iodomethane (100 ml) was added. The reaction mixture was heated to 40°-45° C. with stirring for 4 hours and then cooled to ambient temperature before a further aliquot of iodomethane (20 ml) was added. The reaction mixture was stirred at ambient temperature overnight. A further aliquot of iodomethane (20 ml) was added and the reaction mixture was heated again to 40°-45° C. with stirring for 3 hours. Removal of the solvents in vacuo yielded methyl 4-[3-[4-(methylthio)carbonimidoylbenzoyl)carbazoyl]phenoxyacetate as an orange-brown solid which was not purified further. A portion of the residue (10 g) was suspended in a mixture of methanol (300 ml) and dichloromethane (300 ml), and covered with a blanket of argon before a solution of dry ammonium acetate (27 g) in methanol (100 ml) was added. The reaction mixture was stirred under argon for 2-3 days. Removal of the solvents in vacuo yielded a solid residue which was crystallised, with filtration, from boiling methanol to give the title compound (8.57 g) as a pale yellow solid; m.p. 208°-210° C. (decomposes); NMR Spectrum (DMSO-d6) 1.76 (3H, s), 3.72 (3H, s), 4.91 (2H, s), 7.06 (2H, d), 8.05 (2H, d), 7.90 (4H, m); Mass Spectrum m/Z 371 (M+H)+; Elemental Analysis: calculated for C18H18N4O5. 1.0 CH3CO2H. 1.0 CH3OH. 1.0 H2O: C, 52.5%; H, 5.87%; N, 11.7%; found: C, 52.1%; H, 6.0%; N, 11.7%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=1.[H-].[Na+]>CN(C)C=O>[C:11]([O:10][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:17]2[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:22]=2)=[CH:7][CH:6]=1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)ccc1[N+](=O)[O-]
Yield: 82.3 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using t-butyl (4-hydroxyphenyl)carbamate (15.6 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (21 g), sodium hydride (55 wt. %, 3.22 g) and anhydrous N,N-dimethylformamide (130 ml) and the reaction mixture was purified to give the title compound (27.7 g).
Reaction SMILES: [CH:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[C:5]([C:18]1[C:23](N)=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:2].N([O-])=O.[Na+]>CC(C)=O.O>[CH:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[CH2:2]
Reactant: C=Cc1ccccc1C(c1ccccc1)(c1ccccc1)c1c(N)cccc1O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=Cc1ccccc1C(c1ccccc1)(c1ccccc1)c1ccccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
The 2-(vinyltrityl)-3-aminophenol is dissolved in a 50/50 solution of acetone and 50% H2PO3. The solution is chilled to 0° C. NaNO2 (1.0 g, 2.0 equiv.) is dissolved in water (10 mL) and added at a rate to keep the temperature of the reaction mixture below 5° C. The mixture is stirred for an additional 30 minutes. The product 2-(vinyltrityl)phenol is obtained by filtration and dried under vacuum (yield 35-45%). Product is recrystallized from hot acetic acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([SH:12])[S:11][C:7]=2[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>CC(C)=O>[SH:12][C:10]1[S:11][C:7]2[CH:6]=[C:5]([N:4]([CH2:3][CH:2]([CH3:15])[CH3:1])[C:26](=[O:27])[O:28][CH:29]([CH3:31])[CH3:30])[CH:14]=[CH:13][C:8]=2[N:9]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)CNc1ccc2nc(S)sc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CC(C)CN(C(=O)OC(C)C)c1ccc2nc(S)sc2c1
Reaction time: 10 h
Yield: 22 %

Procedure:
Into a 50 ml round bottomed flask were added 6-[(2-methylpropyl)amino]-1,3-benzothiazole-2-thiol (100 mg, 0.42 mmol), acetone (10 ml), N,N-diisopropylethylamine (54.2 mg, 0.42 mmol) and isopropyl chloroformate (51.5 mg, 0.42 mmol). The reaction mixture was stirred for 10 h, filtered, and the solid that was obtained was triturated with diethyl ether to afford 30 mg (59%) of the title compound. 1H NMR (DMSO-d6) δ=0.80 (d, 6H), 1.11 (d, 6H), 1.60 (m, 1H), 3.43 (d, 2H), 4.76 (m, 1H), 7.24 (br s, 2H), 7.60 (s, 1H); ESIMS: m/z 323 (M−H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[C:8](Cl)=[C:7]([C:13]#[N:14])[CH2:6]1)([OH:3])=[O:2].N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[CH:8]=[C:7]([C:13]#[N:14])[CH2:6]1)([OH:3])=[O:2]
Reactant: CC1CN(CC(=O)O)CC(C#N)=C1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC1C=C(C#N)CN(CC(=O)O)C1

Procedure:
To a solution of 43 (24 g, 0.105 mol) in toluene (400 ml) was added azobisisobutyronitrile (6 g) and tri-n-butyltin hydride (90 g). The mixture was refluxed overnight and then evaporated in vacuo. Elution from a column of silica gel with ethyl acetate-heptane (1:2) gave the title compound as an oil. Yield: 10.4 g (0.0538 mol, 51%).
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[N:28]=[C:27](Cl)[S:26][N:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1.O>[CH2:2]([C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:27]3[S:26][N:25]=[C:24]([Cl:23])[N:28]=3)[CH2:19][CH2:18]2)[N:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Clc1nsc(Cl)n1
Reactant: Cc1cc(Cc2ccccc2)nc(NC2CCNCC2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cc2ccccc2)nc(NC2CCN(c3nc(Cl)ns3)CC2)n1

Procedure:
A solution of (4-benzyl-6-methyl-pyrimidin-2-yl)-piperidin-4-yl-amine hydrochloride (159 mg, 0.5 mmol), 3,5-dichloro-[1,2,4]thiadiazol (39 mg, 0.25 mmol) and N,N-diisopropylethylamine (85 L, 0.5 mmol) in tetrahydrofurane (2 mL) was heated to 95° C. 4 hours under nitrogen. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using Et2O as eluent. The title compound was obtained as a colorless oil (52 mg, 52%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]1([C:17]2[C:18]3[CH:19]=[CH:20][C:21]([C:40]([O:42][CH3:43])=[O:41])=[CH:22][C:23]=3[N:24]3[C:30]=2[C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[N:27]([CH3:35])[CH:26]([C:36](OC)=[O:37])[CH2:25]3)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCN(CC)CC>C(Cl)Cl>[CH:11]1([C:17]2[C:18]3[CH:19]=[CH:20][C:21]([C:40]([O:42][CH3:43])=[O:41])=[CH:22][C:23]=3[N:24]3[C:30]=2[C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[N:27]([CH3:35])[CH:26]([CH:36]=[O:37])[CH2:25]3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)N(C)c1ccccc1-3
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C=O)N(C)c1ccccc1-3
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
DMSO (5 eq.) was dissolved in DCM and the solution was cooled to −78° C. At this temperature a 2 M solution of oxalylchloride in DCM (2.5 eq.) was added slowly and the mixture was stirred for 25 min at −78° C. A solution of dimethyl 13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-6,10-dicarboxylate (1 eq.) in DCM (0.09 M) was added slowly at −78° C. and stirring was continued for 25 min at this temperature. Then NEt3 (8 eq.) was added and the resulting slurry was placed into an ice bath at 0° C. The mixture was left stirring for 90 min, then diluted with DCM and extracted with sat. aq. NH4Cl, sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The product was obtained as a deep-yellow solid, which was filtered with DCM over a pad of silica. After evaporation of the solvent the product was obtained as a yellowish solid (quant.). (ES+) m/z 417 (M+H)+.
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH2:20][OH:21])[CH:10]=2)[NH2:2].C(O[C:28](=[O:30])[CH3:29])(=O)C>N1C=CC=CC=1>[C:4]([O:22][C:7]1[CH:8]=[C:9]([CH2:20][O:21][C:28](=[O:30])[CH3:29])[CH:10]=[C:11]2[C:6]=1[CH:5]([CH2:4][O:3][C:1](=[O:23])[NH2:2])[C:17]1([OH:19])[O:18][N:12]2[CH2:13][CH:14]2[CH:16]1[N:15]2[C:17](=[O:18])[CH3:16])(=[O:3])[CH3:5]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)OCC1c2c(O)cc(CO)cc2N2CC3NC3C1(O)O2
Solvent: c1ccncc1
Product: CC(=O)OCc1cc(OC(C)=O)c2c(c1)N1CC3C(N3C(C)=O)C(O)(O1)C2COC(N)=O
Reaction time: 8 h

Procedure:
To a solution of 6.9-dihydroxy-4-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (21 mg) in pyridine (1 ml) was added acetic anhydride (34 μl), and the mixture was allowed to stand at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo, and the residual oil was subjected to preparative thin layer chromatography, which was developed with a mixture of methanol and chloroform (5:95, v/v) to give 4-acetoxymethyl-11-acetyl-8-carbamoyloxymethyl-9-hydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6-yl acetate (24 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:24]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccccc1Cl
Yield: 36.4 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.45 mL, 3.2 mmol) and 2-chlorobenzoyl chloride (Aldrich, 0.26 g, 1.4 mmol) in 15 mL THF were processed as in Example 132 to afford the title compound (0.13 g, 0.40 mmol, 37% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.28 (s, 3H), 2.32 (s, 3H), 3.31 (s, 3H), 3.76 (t, J=5.3 Hz, 2H), 4.42 (t, J=5.1 Hz, 2H), 7.30-7.46 (m, 3H), 7.77-7.83 (m, 1H); MS (DCI/NH3) m/z 325 (M+H)+; Anal. calculated for C15H17ClN2O2S: C, 55.46; H, 5.28; N, 8.62. Found: C, 55.59; H, 4.81; N, 8.47.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][S:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([N:7]([CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[S:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)NCc2ccco2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(S(=O)(=O)N(Cc2ccccc2)Cc2ccco2)cc1
Temperature: 165 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
4-(N-(furan-2-ylmethyl)sulfamoyl)benzoic acid (Example 5-2b) (140 mg, 0.5 mmol) and Cesium Carbonate (325 mg, 1 mmol) were placed in a microwave vial and dissolved in 2 mL DMF. (Bromomethyl)benzene (170 mg, 1 mmol) was added into the reaction mixture. The reaction was placed in a microwave reactor and heated at 165° C. for 5 minutes. The reaction mixture was dissolved in Ethyl Acetate and washed with water. The organic layer was dried over sodium sulfate and evaporated under vacuum. The crude product was dissolved in 4/1 solution of 6N NaOH (aq)/tetrahydrofuran (3 mL) and stirred at ambient temperature for 6 hours. The solution was acidified with 3N HCl (aq) to a pH of ˜3 and the product was extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The residue was taken up in methanol (3 mL) and purified by reverse phased HPLC (5-95% acetonitrile in H2O gradient:25 minutes). Yield 35%. MS M+H calculated 372.4, found 372.0.
Reaction SMILES: [CH:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O.[CH2:20]([O:22][C:23]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:24])[CH3:21]>C1COCC1>[CH2:20]([O:22][C:23](=[O:24])/[CH:25]=[CH:1]/[CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C1Cc2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A solution of tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (8.4 g, 32.2 mmol) in dry THF (200 mL, 0.16 M) was treated with (ethoxycarbonylmethylene)triphenylphosphorane (12.8 g, 37.0 mmol) in one portion. After stirring at room temperature overnight, the solvent was evaporated, and the resulting residue was dissolved in ether. Heptane was added and the precipitated triphenylphosphine oxide was filtered off. The filtrate was concentrated and purified by flash chromatography (5-20% ethyl acetate in hexane) affording (E)-tert-butyl 3-(3-ethoxy-3-oxoprop-1-enyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as yellow oil (8.7 g, 82%). 1H NMR (CDCl3, 500 MHz) δ 7.21-7.14 (m, 2H), 7.14-7.07 (m, 2H), 6.74 (dd, J1=15.8 Hz, J2=4.8 Hz, 1H), 5.79 (dd, J1=15.8 Hz, J2=1.3 Hz, 1H), 4.72 (d, J=16.5 Hz, 1H), 4.35 (d, J=16.5 Hz, 1H), 4.11 (qw, J=14.4 Hz, 2H), 3.18 (dd, J1=15.8 Hz, J2=6.2 Hz 1H), 2.84 (d, J=15.8 Hz, 1H), 1.49 (s, 9H), 1.23 (t, J=14.4 Hz, 3H). ESI MS found for C19H25NO4 m/z [354.4 (M+23)].
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C12(O)CC3(O)CC(CC(O)(C3)C1)C2.C(OC=C)(=O)C.[CH:26]([O:28][C:29]12[CH2:38][C:33]3([O:39]C=C)[CH2:34][CH:35]([CH2:37][C:31]([O:42]C=C)([CH2:32]3)[CH2:30]1)[CH2:36]2)=[CH2:27].C(OC12CC3CC(OC=C)(CC(O)(C3)C1)C2)=C>C1(C)C=CC=CC=1>[CH:26]([O:28][C:29]12[CH2:30][C:31]3([OH:42])[CH2:37][CH:35]([CH2:34][C:33]([OH:39])([CH2:32]3)[CH2:38]1)[CH2:36]2)=[CH2:27]
Reactant: C=COC12CC3CC(OC=C)(C1)CC(OC=C)(C3)C2
Agent: C=COC12CC3CC(O)(C1)CC(OC=C)(C3)C2
Agent: O=C([O-])[O-]
Agent: OC12CC3CC(O)(C1)CC(O)(C3)C2
Solvent: C=COC(C)=O
Solvent: Cc1ccccc1
Product: C=COC12CC3CC(O)(CC(O)(C3)C1)C2
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (6.7 mg, 0.01 mmol) and sodium carbonate (64 mg, 0.6 mmol) in toluene (1.0 ml), 1,3,5-adamantanetriol (1 mmol) and vinyl acetate (9 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 5 hours. The reaction mixture was analyzed by gas chromatography to find that 1,3,5-tris(vinyloxy)adamantane, 3,5-bis(vinyloxy)-1-adamantanol, and 5-vinyloxy-1,3-adamantanediol were produced in yields of 52%, 18%, and 8%, respectively, with a conversion from 1,3,5-adamantanetriol of 97%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][C:11]=2[N+:12]([O-])=O)[CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[NH2:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:6]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCC2CC2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)Cc1ccc(N)c(OCC2CC2)c1
Reaction time: 6 h
Yield: 84 %

Procedure:
To a stirred solution of compound ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (10 g), in dry MeOH (100 mL), Pd(OH)2 (2 g) was added and the mixture was reduced under an H2 atmosphere for 6 h at room temperature. The mixture was filtered a pad of Celite™ washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (7.5 g) as a thick liquid. 1H-NMR (CDCl3, 200 MHz): 0.38 (m, 2H), 0.61 (m, 2H), 1.23 (m, 1H), 1.23 (t, 3H), 3.51 (s, 2H), 3.80 (d, 2H), 4.16 (q, 2H), 6.72 (m, 3H).
Reaction SMILES: C[Si](Br)(C)C.C[O:7][P:8]([C:12](=[O:17])[CH2:13][CH2:14][NH:15][OH:16])(=[O:11])[O:9]C>C(#N)C>[OH:16][NH:15][CH2:14][CH2:13][C:12]([P:8](=[O:7])([OH:11])[OH:9])=[O:17]
Reactant: COP(=O)(OC)C(=O)CCNO
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: O=C(CCNO)P(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0,2 mol trimethylsilylbromide are slowly added to a solution of 0,1 mol 3-(N-hydroxyamino)-propionylphosphonic acid dimethylester in 100 ml of absolute acetonitrile. After 3 hours of stirring at room temperature the solution is concentrated and taken up in 50 ml methanol. After stirring for 30 minutes it is concentrated again. 3-(N-hydroxyamino)-propionylphosphonic acid may be further be converted without purification.