Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][CH:8]([O:19][CH3:20])[C:9]1[NH:13][N:12]=[C:11]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH:10]=1.[Br:21]Br.[Na]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl.C1(C)C=CC=CC=1>[Br:21][C:10]1[C:11]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[N:12][NH:13][C:9]=1[CH:8]([O:7][CH3:6])[O:19][CH3:20]
Reactant: COC(OC)c1cc(-c2nccs2)n[nH]1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(OC)c1[nH]nc(-c2nccs2)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Sodium acetate (0.26 g, 3.17 mmol) was added to a solution of 2-[5-(dimethoxymethyl)-1H-pyrazol-3-yl]-1,3-thiazole (8b) (714 mg, 3.17 mmol) in chloroform (7.7 mL) and acetic acid (7.7 mL). The mixture was stirred at room temperature for 1 hour. After cooling to 0° C., a solution of bromine (0.155 mL, 3.01 mmol) in acetic acid (1.8 mL) was added dropwise. The reaction mixture was stirred at the same temperature for 40 minutes before being diluted with dichloromethane (10 mL). The mixture was neutralized with 2N sodium hydroxyde to pH 6. The layers were separated and the aqueous layer was extracted with dichloromethane (10 mL). The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and co-evaporated with toluene to provide 2-[4-bromo-5-(dimethoxymethyl)-1H-pyrazol-3-yl]-1,3-thiazole (8c) (900 mg, 2.96 mmol, 93%) which was used without further purification.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[C:6]([C:15]2[CH:20]=[CH:19][C:18](F)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)=[N:7][N:8]([CH3:14])[C:9]=1[O:10][CH:11]([F:13])[F:12]>CS(C)=O>[Cl:4][C:5]1[C:6]([C:15]2[CH:20]=[CH:19][C:18]([C:1]#[N:2])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)=[N:7][N:8]([CH3:14])[C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: [C-]#N
Reactant: Cn1nc(-c2ccc(F)c([N+](=O)[O-])c2)c(Cl)c1OC(F)F
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1nc(-c2ccc(C#N)c([N+](=O)[O-])c2)c(Cl)c1OC(F)F
Temperature: 50 °C
Reaction time: 72 h

Procedure:
1.1 g (17 mmol) of potassium cyanide were added to a solution of 5.0 g (15.6 mmol) of 4-chloro-3-(4-fluoro-3-nitrophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 70 ml of dimethyl sulfoxide. The mixture was then stirred at 50° C. for 5 hours and at room temperature for 3 days. The reaction mixture was poured into ice-water and then the product was extracted with methyl tert-butyl ether. The ether phase was dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3:1). Yield: 2.7 g.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C[O:17][C:18](=[O:29])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][C:22]=1[CH3:28]>>[CH3:28][C:22]1[CH:23]=[C:24]([S:27][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:5][CH:4]=2)[CH:25]=[CH:26][C:21]=1[O:20][CH2:19][C:18]([OH:29])=[O:17]
Reactant: ClCc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)COc1ccc(S)cc1C
Product: Cc1cc(SCc2ccc(Oc3ccccc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F with 1-chloromethyl-4-phenoxy-benzene and 2C. MS m/z 321 (M-methylacetate).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH3:14])[N:8]=[CH:9]2)=[C:2]=[S:3].[OH:15][CH2:16][CH:17]1[NH:22][CH2:21][C:20]2[CH:23]=[CH:24][S:25][C:19]=2[CH2:18]1>C(O)C>[OH:15][CH2:16][CH:17]1[N:22]([C:2](=[S:3])[NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[C:7]([CH3:14])[N:8]=[CH:9]3)[CH2:21][C:20]2[CH:23]=[CH:24][S:25][C:19]=2[CH2:18]1
Reactant: OCC1Cc2sccc2CN1
Reactant: Cc1cc2c(N=C=S)cccc2cn1
Solvent: CCO
Product: Cc1cc2c(NC(=S)N3Cc4ccsc4CC3CO)cccc2cn1
Reaction time: 15 h
Yield: 93 %

Procedure:
5-Isothiocyanato-3-methylisoquinoline (5.1 g) is added to a solution of (RS)-6-hydroxymethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3.4 g) in absolute ethanol (55 cc). After 15 hours at a temperature of about 20° C., the resulting crystals are filtered off, washed with diisopropyl ether and then dried at 60° C. under reduced pressure (0.1 mm Hg; 0.013 kPa). (RS)-6-Hydroxymethyl-5-[(3-methylisoquinol-5-yl)thiocarbamoyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6.9 g), melting at 190° C., is thus obtained.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>C(Cl)Cl>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(-c2c(-c3ccc(S(N)(=O)=O)cc3)[nH]c3ccccc23)cc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2[nH]c3ccccc3c2-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
300 mg (0.79 m mol) of 2-(4-aminosulfonylphenyl)-3-(4-methoxyphenyl)indole prepared in Example 70 was suspended in 20 ml of CH2Cl2 cooled in an ice-salt bath and the cold solution of 0.41 ml (4.4 m mol) of BBR3 in 5 ml of CH2Cl2 was added in dropwise. When addition was complete, the ice-salt bath was removed and the reaction mixture was stirred at room temperature for 3 h. The solvent was removed and the residue was purified by column chromtography eluting with 3:1 petroleum: ethyl acetate to give 180 mg of title compound as light yellow crystal, yield 62.31%, m.p. 241-243° C. The data of Nuclear Magnetic Resonance shown that: 1HNMR (300 MHz, DMSO)δ:6.80-7.77 (m, 11H, Ar—H), 9.43 (s, 1H, OH), 11.56 (s, 1H, N—H); Anal. Calcd for: C20H16N2O3S: C 56.92, H 4.43, N 7.69; Found: C 56.81, H 4.34, N 7.47.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:33])[NH:14][C:15]1[CH:16]=[C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30]CC)=[O:29])=[CH:24][CH:23]=2)[C:18]([Cl:21])=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[OH-].[Na+].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:33])[NH:14][C:15]1[CH:16]=[C:17]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=2)[C:18]([Cl:21])=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(-c2cc(NC(=O)[C@H]3CCCN3C(=O)OC(C)(C)C)ccc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)O)cc2)c1

Procedure:
(R)-2-(6-Chloro-4′-ethoxycarbonyl-biphenyl-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (985 mg) in 2M NaOH (5 ml) and ethanol (7 ml) was stirred at room temp for 18 h. The ethanol was then evaporated and the residue acidified with HCl. The resulting yellow solid was collected by filtration and dried (672 mg). Material used without purification in next step.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@@H:16]([CH3:43])[CH2:17][N:18]([C:20]1[N:21]([CH2:39][C:40]#[C:41][CH3:42])[C:22]2[C:27](=[O:28])[N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]#[N:37])[N:25]=[CH:24][C:23]=2[N:38]=1)[CH3:19])=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:15][C@@H:16]([CH3:43])[CH2:17][N:18]([C:20]1[N:21]([CH2:39][C:40]#[C:41][CH3:42])[C:22]2[C:27](=[O:28])[N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]#[N:37])[N:25]=[CH:24][C:23]=2[N:38]=1)[CH3:19]
Reactant: CC#CCn1c(N(C)C[C@H](C)NC(=O)OC(C)(C)C)nc2cnn(Cc3ccccc3C#N)c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(N(C)C[C@H](C)N)nc2cnn(Cc3ccccc3C#N)c(=O)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.4 ml trifluoroacetic acid are added dropwise to a solution of 250 mg (S)-2-[N-(2-tert-butyloxycarbonylamino-propyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 5 ml dichloromethane. The solution is stirred for 4 h at ambient temperature, then diluted with dichloromethane and made alkaline with saturated aqueous sodium carbonate solution. The organic phase is separated off, washed with water, dried over magnesium sulphate and evaporated down. The residue is stirred with tert-butylmethylether and after separation of the ether dried in vacuo at 40-50° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7](F)=[CH:6][C:5]=1[NH:15][CH2:16][P:17]([OH:20])(=[O:19])[OH:18])([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([O:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:6][C:5]=1[NH:15][CH2:16][P:17]([OH:20])(=[O:19])[OH:18])([O-:3])=[O:2]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(F)cc1NCP(=O)(O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Oc2ccccc2)cc1NCP(=O)(O)O
Yield: 68.6 %

Procedure:
) 3.18 g of N-(2-nitro-4-trifluoromethyl-5-fluorophenyl)-aminomethanephosphonic acid is stirred together with 3.18 g of sodium carbonate and 2.82 g of phenol in 40 ml of water for 4 hours at a bath temperature of 120° C. After acidification with 4N hydrochloric acid, the precipitated product is suctioned off. 2.69 g of N-(2-nitro-4-TRIFLUOROMETHYL-5-phenoxyphenyl)-aminomethanephosphonic acid is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([OH:17])([CH3:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=1.[CH2:18](Cl)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.FC1C=CC(OC2C=CC=CC=2)=C(C(O)(C)CN2C=CN=C2)C=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([C:9]([OH:17])([CH3:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=1
Reactant: CC(O)(Cn1ccnc1)c1cc(F)ccc1O
Reactant: ClCCc1ccccc1
Agent: CC(O)(Cn1ccnc1)c1cc(F)ccc1Oc1ccccc1
Product: CC(O)(Cn1ccnc1)c1cc(F)ccc1OCCc1ccccc1
Yield: 13.4 %

Procedure:
The general procedure of Example 6 was repeated using 4-fluoro-2-(1-hydroxy-2-(1H-1-imidazolyl)-1-methylethyl)phenol [compound (2-4)] and phenethyl chloride, to thereby yield 2-(5-fluoro-2-(phenyloxy)phenyl)-1-(1H-1-imidazolyl)-2-propanol as a colorless oily product (yield: 13.4%).
Reaction SMILES: [C:1]([NH:6][CH2:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][Si:19]([CH3:30])([O:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13][CH:12]1[OH:31])=[O:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(C)C=CC=CC=1.[C:39]1(=[O:45])[O:44][C:42](=[O:43])[CH2:41][CH2:40]1.C1(C=CC(O)=CC=1)O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:29][Si:26]([CH3:27])([CH3:28])[O:25][Si:19]([CH2:18][CH2:17][CH:14]1[CH2:13][CH:12]([O:31][C:39](=[O:45])[CH2:40][CH2:41][C:42]([OH:44])=[O:43])[CH:11]([O:10][C:8](=[O:9])[CH2:7][NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH2:16][CH2:15]1)([CH3:30])[O:20][Si:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1CCC(=O)O1
Reactant: C=C(C)C(=O)NCC(=O)OC1CCC(CC[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C)CC1O
Agent: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)NCC(=O)OC1CCC(CC[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C)CC1OC(=O)CCC(=O)O
Temperature: 62.5 °C

Procedure:
15 g of 4-(2-(1,1,1,3,5,5,5-heptamethyltrisiloxan-3-yl)ethyl)-2-hydroxycyclohexyl 2-methacrylamidoacetate and 4.6 g of toluene and succinic anhydride are further charged into a round bottom flask equipped with a stirring bar, a reflux condenser, and nitrogen inlet. To this, triethylamine and hydroquinone are added as a catalyst and radical scavenger, respectively, and the reaction mixture is heated to 60-65° C. After completion, the product was vacuum striped, re-dissolved in chloroform, and washed with brine solution. The organic phase was passed over Tulsion T66-MP resin to remove traces of triethylamine and decolorized using activated charcoal. The organic layer was concentrated after removal of the charcoal to yield a pale yellow, viscous product.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.O.[NH2:13][NH2:14]>C(O)C>[Cl:1][C:2]1[C:10]2[C:9]([NH:13][NH2:14])=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: NN
Reactant: Clc1csc2ncnc(Cl)c12
Solvent: CCO
Solvent: O
Product: NNc1ncnc2scc(Cl)c12
Reaction time: 24 h

Procedure:
5-Chloro-4-chlorothieno[2,3-d]pyrimidine (1.38 g, 6.73 mmol) and hydrazine monohydrate (5.0 ml, 103 mmol) in absolute ethanol (20 ml) were heated at 75° C. After stirring for 24 h, the solution was concentrated to yield 5-chloro-4-hydrazinylthieno[2,3-d]pyrimidine. Method [6] Retention time 0.35 min by HPLC (M+=201 and 203).
Reaction SMILES: C1C(S(N)(=O)=O)=C(Cl)C(Cl)=CC=1S(N)(=O)=O.CCN[C@@H]1C2C=C(S(N)(=O)=O)SC=2S(=O)(=O)[C@@H](C)C1.[CH3:36][C:37](/[N:39]=[C:40]1\[N:41](C)[N:42]=[C:43]([S:45]([NH2:48])(=[O:47])=[O:46])[S:44]\1)=[O:38].CC(CN[C@@H]1C2C=C(S(N)(=O)=O)SC=2S(=O)(=O)CC1)C.C1C(NC(OCCO)=O)=CC=C(S(N)(=O)=O)C=1>>[CH3:36][C:37]([NH:39][C:40]1[S:44][C:43]([S:45]([NH2:48])(=[O:47])=[O:46])=[N:42][N:41]=1)=[O:38]
Reactant: CC(=O)/N=c1/sc(S(N)(=O)=O)nn1C
Agent: CC(C)CN[C@H]1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Agent: CCN[C@H]1C[C@H](C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Agent: NS(=O)(=O)c1cc(Cl)c(Cl)c(S(N)(=O)=O)c1
Product: CC(=O)Nc1nnc(S(N)(=O)=O)s1

Procedure:
AL4414A; diclofenamide; dorzolamide; methazolamide; sezolamide; sulocarbilate.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[Cl:22])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl>>[ClH:22].[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CNCCN1
Reactant: CCCCc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Agent: Cl
Product: CCCCc1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1
Yield: 46 %

Procedure:
1-(4-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 and subsequently treated with hydrochloric acid as described in Example 44 to afford 1-(4-butylphenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde hydrochloride (46% yield) as a cream solid. ESI/MS 362 (M+H); RT=3.02 min; NMR 10.13 (1H, s); 8.12 (1H, d, J=9 Hz); 7.48 (4H, s); 7.21 (2H, m);694(1H, d, J=9 Hz); 3.41 (4H, br m); 2.97 (4H, br m); 2.74 (2H, t); 1.64 (2H, p);1.37(2H, m); 0.97 (3H, t).
Reaction SMILES: ClC1C=C2C(C=CC(C)=N2)=CC=1O.[Br:14][C:15]1[C:24]([O:25]C)=[C:23]([CH3:27])[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([C:28]([F:31])([F:30])[F:29])=[N:20]2>>[Br:14][C:15]1[C:24]([OH:25])=[C:23]([CH3:27])[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([C:28]([F:29])([F:30])[F:31])=[N:20]2
Reactant: COc1c(C)cc2nc(C(F)(F)F)ccc2c1Br
Agent: Cc1ccc2cc(O)c(Cl)cc2n1
Product: Cc1cc2nc(C(F)(F)F)ccc2c(Br)c1O

Procedure:
Compound 7B was prepared following the procedure used to prepare compound 1C of Example 1, except that 5-bromo-6-methoxy-7-methyl-2-(trifluoromethyl)quinoline (7A) was used instead of compound 1B. LCMS-ESI+ (m/z): 306.1, 308.1 (M+H)+.
Reaction SMILES: N12CCCN=C1CCCCC2.[O:12]=[S:13]1(=[O:28])[CH:18]([CH3:19])[CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[C:23]([S:24]([NH2:27])(=[O:26])=[O:25])[C:15]=2[O:14]1.[CH3:29][N:30]=[C:31]=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[O:28]=[S:13]1(=[O:12])[CH:18]([CH3:19])[CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[C:23]([S:24]([NH:27][C:31]([NH:30][CH3:29])=[O:32])(=[O:25])=[O:26])[C:15]=2[O:14]1
Reactant: CC1Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)NS(=O)(=O)c1cccc2c1OS(=O)(=O)C(C)C2
Reaction time: 2 h
Yield: 91 %

Procedure:
6.54 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene are added to 12.1 g (0.0436 mole) of 3,4-dihydro-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide in dioxane. While cooling with ice, 2.65 ml of methyl isocyanate are added dropwise. The reaction mixture is stirred for 2 hours at 20° to 25° C., then diluted with water, neutralised with 10 ml of 5% sodium carbonate solution, and filtered. Acidification of the filtrate yields 12.0 g (91% of theory) of N-(3,4-dihydro-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonyl)-N'-methylurea.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]4[C:32]=3[C:31]3[C@@H:30]([CH2:33][C:34]#[N:35])[CH2:29][CH2:28][C:27]=3[S:26]4)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[OH:36][Li].O.OO>CO>[N:11]1([CH:14]2[CH2:15][CH2:16][CH:17]([O:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]4[C:32]=3[C:31]3[C@@H:30]([CH2:33][C:34]([NH2:35])=[O:36])[CH2:29][CH2:28][C:27]=3[S:26]4)[CH2:18][CH2:19]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC(Oc3ncnc4sc5c(c34)[C@@H](CC#N)CC5)CC2)CC1
Reactant: [Li]O
Agent: OO
Solvent: CO
Solvent: O
Product: NC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNCC5)CC4)c3c21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl-4-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)piperazine-1-carboxylate (260 mg, 0.52 mmol, 1.00 equiv) in methanol (15 mL) were added LiOH.H2O (150 mg, 3.57 mmol, 6.84 equiv), H2O2 (30%) (0.8 mL). The resulting solution was stirred for 4 h at 0° C. The reaction was then quenched by the addition of 10 mL of Na2SO3 (aq.). The resulting solution was extracted with 3×30 mL of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 120 mg (45%) of tert-butyl 4-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)piperazine-1-carboxylate as a yellow oil.
Reaction SMILES: C[O-].[Na+].C([O:12][CH2:13][C@@H:14]1[C@@H:19]([CH2:20][O:21]C(=O)C2C=CC=CC=2)[CH2:18][C@@H:17]([N:30]2[CH:38]=[N:37][C:36]3[C:31]2=[N:32][CH:33]=[N:34][C:35]=3[NH2:39])[C@H:16]([OH:40])[CH2:15]1)(=O)C1C=CC=CC=1.CO.Cl>C1COCC1>[OH:12][CH2:13][C@@H:14]1[C@@H:19]([CH2:20][OH:21])[CH2:18][C@@H:17]([N:30]2[CH:38]=[N:37][C:36]3[C:31]2=[N:32][CH:33]=[N:34][C:35]=3[NH2:39])[C@H:16]([OH:40])[CH2:15]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1C[C@H](COC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)C[C@H]1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@H](CO)[C@@H](CO)C[C@H]1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.4 %

Procedure:
Sodium methoxide (40 mg, 0.74 mmole) was added to a solution of 9-[(1R,2R,4S,5S)-4,5-bis(benzoyloxymethyl)-2-hydroxycyclohexyl]-adenine (185 mg, 0.37 mmole) in a solvent mixture consisting of anhydrous methanol (4 ml) and anhydrous THF (4 ml) under ice cooling. After stirring the resulting mixture at room temperature for 5 hours, the reaction mixture was neutralized with dilute hydrochloric acid, and the solvent was distilled off therefrom under reduced pressure. The residue was purified by Diaion HP-20 column chromatography (methanol concentration gradient) to obtain 9-[(1R,2R,4S,5S)-4,5-bis(hydroxymethyl)-2-hydroxycyclohexyl]-adenine (109 mg, Yield 100%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]1[O:9][CH2:8]1>[Fe]>[OH:9][CH2:8][CH2:7][O:5][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3]
Reactant: C1CO1
Reactant: C=C(C)C(=O)O
Agent: [Fe]
Product: C=C(C)C(=O)OCCO
Temperature: 70 °C

Procedure:
The procedure of Example 4 is repeated, except with less catalyst (1.9 g, 46% iron), with methacrylic acid (2.0 g) used in place of acrylic acid, and slightly less ethylene oxide added (3.8 g). The reactor is heated to 70° C. for 1 hour. The results for the product hydroxyethylmethacrylate (HEMA) are presented in Table 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18]2[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.[ClH:32]>C(OCC)(=O)C>[ClH:32].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18]2[O:17][CH2:16][CH2:15][NH:14][CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2F)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A mixture of tert-butyl 9-(2-fluorophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (150 mg, 0.437 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (103 mg, 84.4%) as a solid.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[O:14])C(=O)[NH:10]2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=1.Cl>[OH-].[Na+]>[Cl:3][C:4]1[CH:12]=[C:11]([NH2:10])[C:7](=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=1)[C:8]([OH:14])=[O:1]
Reactant: OO
Reactant: O=C1Nc2cc(Cl)cc([N+](=O)[O-])c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Cl)cc([N+](=O)[O-])c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
4 ml of a 30% hydrogen peroxide solution are added dropwise at room temperature to 3.8 g (16.7 mmol) of 6-chloro-4-nitro-indoline-2,3-dione in 60 ml of sodium hydroxide solution. The mixture is stirred for 2 hours at room temperature, acidified to pH 2 to 3 with 4N hydro-chloric acid, filtered and dried. 3.18 g (87.8% of theory) of 4-chloro-6-nitro-anthranilic acid having a melting point of 202°-205° are obtained.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:16][CH:2]([CH3:4])[CH3:3])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Cl)ccc1OC(C)C
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of 2-iodo-propane (2.2 ml, 22 mmol), methyl 5-chloro-2-hydroxy-benzoate (2.0 g, 10.7 mmol), potassium carbonate (3.0 g, 10.9 mmol), and acetonitrile (40 ml) was heated under reflux for 3 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium chloride solution (100 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane-hexane (1:3 followed by 1:2 followed by 1:1) to provide methyl 5-chloro-2-isopropoxy-benzoate (1.2 g, 49% yield).
Reaction SMILES: [Br:1][C@H:2]1[C@H:21]([OH:22])[CH2:20][CH2:19][C@@:18]2([CH3:23])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:17]2[C:16](=[O:24])[CH2:15][C@@:14]2([CH3:25])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:11](=[O:13])[CH3:12].[Br:26]Br>CO.O>[Br:1][C@H:2]1[C@H:21]([OH:22])[CH2:20][CH2:19][C@@:18]2([CH3:23])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:17]2[C:16](=[O:24])[CH2:15][C@@:14]2([CH3:25])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:11](=[O:13])[CH2:12][Br:26]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4[C@@H](Br)[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: BrBr
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@@H](O)[C@H](Br)[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4β-Bromo-3α-hydroxy-5α-pregnane-11,20-dione (945 mg) in dry methanol (70 ml.) at 10° was treated with a solution of bromine (0.125 ml.) in methanol (5 ml.) dropwise over 7 hours, at such a rate that the bromine colour was taken up during the addition. The reaction solution was then stirred at room temperature for 30 minutes until it became colourless, and it was then diluted with water (300 ml.) and the white precipitate was extracted into methylene chloride. The organic solution was washed with water, dried over sodium sulphate and evaporated to a white foam (1.2 g.) which was purified by preparative T.L.C. in ethyl acetate/benzene 1/3 the upper (major) band giving 660 mg. of a white solid which was triturated with ether to give title compound (580 mg.) as white crystals, m.p. 164°-166°, [α]D + 76° (c 1.35).