Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:24]#[N:25])([CH2:18][CH2:19][C:20]([O:22]C)=O)[CH2:12][CH2:13]C(OC)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].CO>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([C:24]#[N:25])[CH2:12][CH2:13][C:20](=[O:22])[CH2:19][CH2:18]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of dimethyl 4-(3,4-dimethoxyphenyl)-4-cyanopimelate (11.2 g, 32.1 mmol), sodium hydride (2.31 g, 48.1 mmol) and methanol (1 ml) in 250 ml anhydrous toluene was heated at reflux for 10 hours, cooled to 25° C., quenched with 4 ml acetic acid, washed with H2O, alkali, and brine and dried with MgSO4. The volatiles were removed in vacuo. The residue was recrystallized with hexanes-ethyl acetate. This intermediate was heated at reflux in ethanol, concentrated HCl and 25% aqueous H2SO4 for 10 hours. The volatiles were removed in vacuo. The residue was diluted with water and extracted with ether. The combined organic extracts were washed with water, brine and dried (MgSO4). The volatiles were removed in vacuo. The residue was recrystallized with toluene and then with hexanes-ethyl acetate, mp 111°-12° C. ##STR5##
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([Cl:17])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSc1nc(Cl)c(C(=O)O)c(Cl)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c(C(=O)Cl)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4,6-dichloro-2-methylsulfanylpyrimidine-5-carboxylic acid (2.1 mmol) in CH2Cl2 (20 mL) are added oxalyl chloride (4.2 mmol) and one drop of DMF at 0° C. After stirred at room temperature for 3 h under N2 atmosphere, the reaction mixture is concentrated and dried in vacuo, to give 4,6-dichloro-2-methylsulfanylpyrimidine-5-carbonyl chloride as a yellow crystal.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[N+](N[C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([O:31][CH3:32])[CH:26]=2)=[CH:19][N:18]=1)([O-])=O>C(O)C>[Br:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH:12][C:17]2[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([O:31][CH3:32])[CH:26]=3)=[CH:19][N:18]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCSCc1ncccc1Br
Reactant: COc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)ccn1
Solvent: CCO
Product: COc1cc(Cc2cnc(NCCSCc3ncccc3Br)[nH]c2=O)ccn1

Procedure:
Reaction of 2-(3-bromo-2-pyridylmethylthio)ethylamine with 1.15 molar equivalents of 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone in refluxing ethanol for 18 hours gave 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone m.p. 70-72° which was boiled under reflux in ethanol containing hydrogen chloride to give 2-[2-(3-bromo-2-pyridylmethylthio) ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone trihydrochloride, m.p. 195-198.5°.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.C([Li])(C)(C)C.[B:18](OCCCC)([O:24]CCCC)[O:19]CCCC>C1COCC1>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([B:18]([OH:24])[OH:19])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OB(O)c1ccc2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a suspension of potassium hydride (35% oil dispersion, 0.84 g, 7.33 mmol) in THF (10 mL) at 0° C. was added a solution 6-bromoindole (1.43 g, 7.20 mmol) in THF (6 mL). The reaction mixture was stirred for 15 min at 0° C., then cooled to -78° C. and t-butyllithium solution (1.7M in pentance, 14.6 mmol) was added quickly dropwise. After stirring for 20 min. at -78° C., a solution of tri-n-butyl borate (3.94 mL, 14.6 mmol) in THF (4 mL) was added quickly. The reaction mixture was stirred for 1 hour at -78° C. and 2hours at 0° C. The reaction was quenched by addition of 1N aqueous HCl (15 mL) and stirring for 30 min at 0° C. The reaction mixture was partitioned between H2O and ether. The aqueous phase was extracted 3 times with ether. The combined ethereal extracts where washed 3 times with cold 1N aqueous NaOH, and then discarded. The basic aqueous extracts where acidified with 1N aqueous HCl and extracted 3 times with ether. The combined organic layers where dried over Na2SO4, filtered, and concentrated in vacuo to give 6-indolylboronic acid (0.86 g) which was used without further purification.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:11][C:10]2=O.[CH3:29][NH:30][CH3:31]>>[CH3:29][N:30]([CH3:31])[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:28])[CH:8]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: CNC
Product: Cc1ccccc1-c1ccc2nc(-n3cc(C(=O)O)cn3)nc(N(C)C)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI/CI): predicted mass C21H19N5O2, 373.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][C:22]([OH:24])=[O:23].C[OH:26]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:19])=[O:26])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CSc1ccc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc1
Reactant: CO
Product: CC1=C(CC(=O)O)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Temperature: 5 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
(Z)-5-fluoro-2-methyl-1-[[4-(methylthio)-phenyl]methylene]-1H-indene-3-acetic acid (5 g, 14.7 mmoles) is dissolved in methanol (40 ml). The solution is added with 5.4 g (14.26 mmoles) of 73% w/w ε-phthalimidoperhexanoic acid, keeping the temperature at about 20° C. After 18 h, the solution is concentrated to 15 ml and cooled to 5° C. The precipitate is filtered and dried. 4.6 g of (Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)-phenyl]methylene]-1H-indene-3-acetic acid (sulindac) is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH:7]1[S:11][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]([CH3:30])[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])=[N:9][CH2:8]1.Cl[CH2:32][C:33](Cl)=[O:34].[OH-].[Na+].Cl>C(O)C.O>[CH3:30][N:21]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][C:12]([C:10]1[S:11][CH:7]([CH2:6][CH2:5][N:4]3[CH2:3][CH2:2][O:1][CH2:32][C:33]3=[O:34])[CH2:8][N:9]=1)=[CH:20]2)[S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23]
Reactant: CN(c1cccc2cc(C3=NCC(CCNCCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(c1cccc2cc(C3=NCC(CCN4CCOCC4=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of N-[2-(5-{2-[(2-hydroxyethyl)amino]ethyl}-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (220 mg) in ethanol (2 mL) and water (1 mL) were added chloroacetyl chloride (95 μL) and 8M aqueous sodium hydroxide solution (310 μL), and the mixture was stirred at the inside temperature of 20° C. or less for 3 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (100 mg, yield 41%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-methanol (10:1, volume ratio).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14]C)=[CH:11][CH:12]=2)[N:7]([CH2:16][CH3:17])[C:6]=1[CH3:18])=[O:4].B(Br)(Br)Br>>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[N:7]([CH2:16][CH3:17])[C:6]=1[CH3:18])=[O:4]
Reactant: CCn1c(C)c(C(=O)NC)c2ccc(OC)cc21
Agent: BrB(Br)Br
Product: CCn1c(C)c(C(=O)NC)c2ccc(O)cc21
Yield: 84.9 %

Procedure:
This material was prepared from 1-ethyl-6-methoxy-2-methyl-1H-indole-3-carboxylic acid methylamide 71d (350 mg, 1.42 mmole) by treatment with BBr3 in a manner as previously described for example 1d to give 280 mg product as white solid (85% yield). 1H NMR (400 MHz, CDCl3) δ 7.48 (1H, d, J=8.3 Hz), 6.73–6.77 (2H, m), 6.01 (1H, bs), 4.04 (2H, q, J=7.2 Hz, 3.03 (3H, d, J=4.9 Hz), 2.66 (3H, s), 1.31 (3H, t, J=7.2 Hz).
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.Cl.CNC.C1COCC1.[I:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>O>[I:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([N:3]([CH3:4])[CH3:2])=[O:26]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cccc(I)c1
Agent: CNC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(I)c1
Reaction time: 18 h

Procedure:
EDCl (1.3 g, 6.6 mmol) was added to a solution of dimethylamine in THF (2 M, 6 mL, 10 mmol) and 3-iodobenzoic acid (1.5 g, 6 mmol). After 18 h stirring the reaction was transferred into water, and then extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The solvent was evaporated to afford the product as a viscous, clear oil. The product was used in the next reaction step without further purification. MS m/z: 276 [M+H].
Reaction SMILES: [CH2:1]([C:3]1[C:4](N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH2:22]([CH:24]1[CH:32]([NH2:33])[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[CH2:25]1)[CH3:23]>>[CH2:1]([C:3]1[C:4]([NH:33][CH:32]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH2:25][CH:24]2[CH2:22][CH3:23])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCC1Cc2cccnc2C1N
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2c3ncccc3CC2CC)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.41, 7.66, 7.58, 7.15, 5.53, 4.89, 3.15, 2.71–2.57, 2.31, 2.01, 1.99, 1.65, 1.34, 1.22, 1.04; HRMS (FAB) calcd for C18H24N4+H 297.2079, found 297.2080.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[C:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15].Cl.[CH3:18][O:19][NH2:20].N1C=CC=CC=1>CCO>[CH3:18][O:19][N:20]=[C:11]([C:3]1[CH:4]=[C:5]([C:9]#[N:10])[C:6](=[O:8])[NH:7][C:2]=1[CH3:1])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC(=O)c1cc(C#N)c(=O)[nH]c1C
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCC(=NOC)c1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C

Procedure:
A mixture of 1,2-dihydro-6-methyl-2-oxo-5-(1-oxopentyl)-3-pyridinecarbonitrile (0.70 g, 0.0032 mol), methoxyamine hydrochloride (0.32 g, 0.0038 mol) and pyridine (2.0 ml) were heated and stirred at reflux in EtOH (30 ml) overnight. The solution was cooled to room temperature and concentrated on the rotary evaporator. The residue was diluted with H2O and the resulting solid collected by filtration. Recrystallization (MeOH-H2O) gave 0.38 g (48%) m.pt. 159-161.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:38][O:39][C:40]1[CH:41]=[C:42]([OH:48])[CH:43]=[CH:44][C:45]=1[O:46][CH3:47].[C:49]([C:51]1[CH:56]=[CH:55][C:54]([CH:57](O)[CH2:58][CH2:59][CH2:60][N:61]2[CH2:68][CH:67]3[CH2:69][CH:63]([CH2:64][N:65]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:66]3)[CH2:62]2)=[CH:53][CH:52]=1)#[N:50]>C(Cl)Cl>[C:49]([C:51]1[CH:52]=[CH:53][C:54]([CH:57]([O:48][C:42]2[CH:43]=[CH:44][C:45]([O:46][CH3:47])=[C:40]([O:39][CH3:38])[CH:41]=2)[CH2:58][CH2:59][CH2:60][N:61]2[CH2:62][CH:63]3[CH2:69][CH:67]([CH2:66][N:65]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:64]3)[CH2:68]2)=[CH:55][CH:56]=1)#[N:50]
Reactant: CC(C)(C)OC(=O)N1CC2CC(CN(CCCC(O)c3ccc(C#N)cc3)C2)C1
Reactant: COc1ccc(O)cc1OC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(OC(CCCN2CC3CC(C2)CN(C(=O)OC(C)(C)C)C3)c2ccc(C#N)cc2)cc1OC
Reaction time: 3 h
Yield: 21 %

Procedure:
Triphenylphosphine (1.11 g; 4.25 mmol) in 5 mL CH2Cl2 and 1,1′-(azodicarbonyl)dipiperidine (1.07 g; 4.25 mmol) in 15 mL CH2Cl2 were added to a stirred solution of 3,4-dimethoxyphenol (0.65 g; 4.25 mmol) and tert-butyl 7-[4-(4-cyanophenyl)-4-hydroxybutyl]-3,7-diazabicyclo-[3.3.1]nonane-3-carboxylate (from step (x) above; 0.85 g; 2.12 mmol). After 3 h, the precipitate was filtered off, and the filtrate concentrated. The residue was dissolved in aqueous tartaric acid (1 M; 25 mL) and the solution was washed with diethyl ether. The aqueous phase was made basic with and extracted again with diethyl ether. The organic layer from this second extraction was separated, dried (Na2SO4) and then concentrated to give the title compound in 21% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.S(Cl)(Cl)=O.[NH3:21]>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([NH2:21])=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: N
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC

Procedure:
4,5-Dimethoxy-2-nitrobenzoic acid (3) was treated with thionyl chloride and then reacted with ammonia to give 4,5-dimethoxy-2-nitrobenzamide (4) as described by F. Nomoto et al. Chem. Pharm. Bull., 1990, 38, 1591-1595. The nitro group in compound (4) was reduced with sodium borohydride in the presence of copper sulfate (see C. L. Thomas, Catalytic Processes and Proven Catalysts, Academic Press, New York (1970)) to give 4.5-dimethoxy-2-aminobenzamide (5) which was cyclized by refluxing with formic acid to give 6,7-dimethoxyquinazoline-4(3H)-one (6). Compound (6) was refluxed with phosphorus oxytrichloride to provide the common synthetic precursor (7).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13]1[C:14]([N+:19]([O-:21])=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[N+:19]([C:14]1[C:13]([S:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[CH:18][CH:17]=[CH:16][N:15]=1)([O-:21])=[O:20]
Reactant: COC(=O)c1ccc(S)cc1
Reactant: O=[N+]([O-])c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(Sc2cccnc2[N+](=O)[O-])cc1
Yield: 84.2 %

Procedure:
Stirred a mixture of methyl 4-mercaptobenzoate (4.46 g, 26.5 mmol), 3-chloro-2-nitropyridine (4.00 g, 25.2 mmol) and cesium carbonate (9.04 g, 27.8 mmol) in DMSO (60 mL) at ambient temperature for 90 minutes. The solution was diluted with water, extracted with EtOAc, dried, and concentrated. The crude solid was suspended in MeOH (80 mL) and triturated for 0.5 hours. The solid was filtered and dried to provide the title compound (6.16 g, 84.1% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH2:12])=[C:6]([O:13][CH3:14])[CH:5]=1.[C:16](Cl)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>N1C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[NH:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:15])=[CH:5][C:6]=1[O:13][CH3:14])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc(OC)c(N)c(OC)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(OC)c(NC(=O)OCc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 50.6 g. of 4-amino-3,5-dimethoxy-benzoic acid methyl ester in 1 liter of absolute pyridine was treated during 30 minutes with 82 g. of carbobenzoxy chloride with stirring and ice-cooling. Thereafter, the mixture was stirred at room temperature for 20 hours. The pyridine was evaporated under vacuum and the residue treated with 1 liter of water and 3N hydrochloric acid to obtain a strongly acidic reaction. The resulting emulsion was extracted with two 1.5 liter portions of ethyl acetate. The ethyl acetate extract was washed with two 800 ml. portions of water, dried over magnesium sulfate and evaporated under vacuum. After recrystallization of the residue from ethyl acetate, there was obtained 2,6-dimethoxy-4-(methoxy-carbonyl)-carbanilic acid benzyl ester having a melting point of 132°-133° C.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:22]2([CH3:23])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:24])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[CH:14]([CH:16]=[O:17])[CH3:15])[CH2:5][C@@H:4]([OH:25])[CH2:3]1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:41](Cl)(=[O:44])[O:42][CH3:43]>C(Cl)Cl>[CH3:43][O:42][C:41]([O:1][C@@H:2]1[C@@:22]2([CH3:23])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:24])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[CH:14]([CH:16]=[O:17])[CH3:15])[CH2:5][C@@H:4]([O:25][C:41]([O:42][CH3:43])=[O:44])[CH2:3]1)=[O:44]
Reactant: COC(=O)Cl
Reactant: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 0 °C

Procedure:
In 1 ml of methylene chloride was suspended 69 mg of 1α,3β-dihydroxypregna-5,7-diene-20-carbaldehyde, followed by addition of 0.3 ml of pyridine, and the mixture was stirred with ice-cooling. Then, 5 mg of dimethylaminopyridine was added and 0.15 ml of methyl chlorocarbonate was further added dropwise. After completion of the addition, the reaction mixture was stirred at ambient temperature for 10 hours. This reaction mixture was poured into ice-water and extracted with diethyl ether. The extract was serially washed with cold 1N-HCl, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 61 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carbaldehyde.
Reaction SMILES: Cl[CH2:2][CH:3]1[S:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]([CH3:12])([CH3:11])[S:4]1.[OH-].[Na+].[CH3:15][NH2:16]>>[CH3:11][C:5]1([CH3:12])[CH2:6][C:7]([CH3:10])([CH3:9])[S:8][CH:3]([CH2:2][NH:16][CH3:15])[S:4]1
Reactant: CC1(C)CC(C)(C)SC(CCl)S1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Product: CNCC1SC(C)(C)CC(C)(C)S1
Temperature: 100 °C

Procedure:
2-Chloromethyl-4,4,6,6-tetramethyl-1,3-dithiane (60 grams) and 40% aqueous methylamine (160 ml) are charged into a pressure vessel and heated, with agitation, at a temperature of about 100° C. for a period of about 16 hours under autogeneous pressure. At the end of this period, the reaction mixture is cooled to room temperature and 16 grams of sodium hydroxide are added. The resulting mixture is extracted with methylene chloride. The extract is dried, then stripped of solvent to yield the desired product N-(4,4,6,6-tetramethyl-1,3-dithian-2-ylmethyl)methylamine.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].S.[OH-].[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:27][C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C(CC(C(=O)c1ccccc1)c1ccccc1)c1ccc(F)cc1
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: Fc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1
Temperature: 20 °C
Yield: 107.6 %

Procedure:
A mixture 49.8 g (0.15 mole) of 1,2-diphenyl-4-p-fluorophenylbutane-1,4-dione, 100 ml of xylene, 30 g (0.0675 mole) of phosphorus pentasulfide and 130 g (3.81 moles) of hydrogen sulfide was heated and stirred in a 1-liter stainless steel autoclave for 4 hours at 157°-185° C. (620-1145 psig). After cooling the vessel to 20° C. and venting the hydrogen sulfide into a sodium hydroxide solution, the residue was stirred with 150 ml of absolute ethanol. Filtration gave 31.5 g (63.6%) of crude product, m.p. 108°-110° C. Recrystallization from 30 ml of dioxane and 90 ml of ethanol gave 24 g of pure 2,3-diphenyl-5-p-fluorophenylthiophene, m.p. 111°-113° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][N:9]=[CH:10][NH:11][C:12](=[O:43])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][C@@H:24]([C:36]([O:38]C(C)(C)C)=[O:37])[NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[CH:17][CH:16]=1>C(Cl)Cl>[NH2:8][N:9]=[CH:10][NH:11][C:12](=[O:43])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][C@@H:24]([C:36]([OH:38])=[O:37])[NH:25][C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCOc1ccc(CCC(=O)NC=NN)cc1)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NN=CNC(=O)CCc1ccc(OCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reaction time: 7 h
Yield: 48.3 %

Procedure:
3 ml of trifluoroacetic acid (TFA) (3 times 1 ml over 6 hours) at +5° C. is added to a solution of 70 mg of the ester obtained in Stage A in 2 ml of CH2Cl2, the reaction medium is agitated for 7 hours then evaporated under reduced pressure after the addition of toluene. 0.5 ml of methanol and 1 ml of ethyl acetate are then added, and after filtration, the filtrate is poured into 10 ml of isopropyl ether to which 2 ml of pentane is added. After filtration, the solid is dried under reduced pressure and 30 mg of expected product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]1([NH2:31])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:31][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1cccc2ccccc12
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1cccc2ccccc12
Yield: 73.2 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and 1-naphthylamine (150 mg, 1.05 mmol)to give 170 mg of the title compound (73%): mp 171°~172° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.06 (bs, 1H), 10.02 (s, 1H), 8.01~8.05 (m, 1H), 7.92~7.97 (m, 1H), 7.78 (d, 1H, J=7.9 Hz), 7.70 (d, 1H, J=6.9 Hz), 7.52~7.61 (m, 2H), 7.49 (d, 1H, J=7.6 Hz), 7.28 (s, 1H), 7.20 (s, 1H), 5.26~5.36 (m, 1H), 3.18 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.91 (dm, 1H, J=17.1 Hz), 2.73~2.85 (m, 2H), 2.17~2.29 (m, 1H), 1.89~2.09 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH:12]1([NH:17][OH:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N+:17]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[O-:18])[CH3:2]
Reactant: CCOc1ccccc1C=O
Reactant: ONC1CCCC1
Product: CCOc1ccccc1C=[N+]([O-])C1CCCC1
Yield: 72.6 %

Procedure:
Using 2-ethoxybenzaldehyde and N-cyclopentylhydroxylamine and following the procedures described herein, the title compound was obtained in 72.6% yield as white crystals, m.p. 87.3° C. (Rf =0.43 on a silica gel plate using hexanes:EtOAc, 2:1, v:v, as an eluant).