Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S[C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][CH2:11][C:12]3=[O:17])C=CC=CC=1.Cl[C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)C(OO)=O.[S:29]([O-:32])([O-])=[O:30].[Na+].[Na+]>ClCCl>[C:19]1([S:29]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][CH2:11][C:12]3=[O:17])(=[O:32])=[O:30])[CH:20]=[CH:21][CH:26]=[CH:27][CH:28]=1
Reactant: O=S([O-])[O-]
Reactant: O=C1CCc2c(Sc3ccccc3)cccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCc2c1cccc2S(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
The material from Step 1 (0.34 g) is allowed to react with 3-chloroperoxybenzoic acid (0.73 g) in dichloromethane (5 mL) with stirring for 1 hour. The mixture is diluted with dichloromethane, 5% aqueous sodium sulfite solution is added and stirred vigorously for 10 minutes. The phases are separated, the organic phase washed with NaOH solution (0.2 M), dried and the solvent removed to give the desired material (0.39 g). LC (METHOD 5): tR=0.98 min; Mass spectrum: m/z=290 [M+NH4]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][Br:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: O=C(O)c1ccc(CBr)cc1Br
Reaction time: 1 h
Yield: 51.9 %

Procedure:
2-Bromo-4-methylbenzoic acid (33.5 g, 156 mmol, 1 eq) and N-Bromosuccinimide (40.7 g, 233 mmol, 1.5 eq) were dissolved in refluxing 1,2-dichloroethane (600 ml) and a catalytic amount of AIBN was added. The mixture was left stirring under a lamp and under nitrogen for 1 hour. The solvent was removed and the mixture was partitioned between 600 ml of water and 600 ml EtOAc. The organic layer was washed twice with water (600 ml), washed once with brine (600 ml) and then dried with sodium sulfate. The solvent was removed and the crude mixture was triturated with 10% EtOAc/Hexane for 2 hours to give 23.8 g (52%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[N:15][C:10]3[O:11][CH2:12][CH2:13][NH:14][C:9]=3[CH:8]=2)[CH:2]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Br:29])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22].C(N(CC)CC)C.O>ClCCl>[Br:17][C:18]1[CH:19]=[C:20]([C:21]([N:14]2[CH2:13][CH2:12][O:11][C:10]3[N:15]=[CH:16][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][C:9]2=3)=[O:22])[CH:24]=[C:25]([Br:29])[C:26]=1[O:27][CH3:28]
Reactant: c1cncc(-c2cnc3c(c2)NCCO3)c1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cccnc4)cc32)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
In a 10 ml flask, 7-pyridin-3-yl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (30 mg, 0.140 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (50.5 mg, 0.154 mmol) were dissolved in dichloromethane (2 ml). Triethylamine (0.058 ml, 0.42 mmol) was added thereto and then stirred at room temperature for 1 hour. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by preparative TLC eluting a solvent of ethyl acetate:methanol=20:1. Silica gels containing the product were eluted with dichloromethane and the solvent was evaporated to obtain (3,5-dibromo-4-methoxy-phenyl)-(7-pyridin-3-yl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-methanone as white solid (35 mg, 49%).
Reaction SMILES: [Cr:1]([O-])([O-])(=O)=O.[Na+].[Na+].[S:8]([O-:12])([OH:11])(=[O:10])=[O:9].[Na+].C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>>[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[Cr+3:1].[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[Cr+3:1]
Reactant: O=[Cr](=O)([O-])[O-]
Reactant: O=S(=O)([O-])O
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Product: O=S(=O)([O-])[O-]
Product: [Cr+3]

Procedure:
The neutral solution of sodium chromate was poured into an acidating tank, and again the above-mentioned sodium hydrogen sulfate was added, to neutralize to Ph=1.5-2.0, which converted Na2CrO4 to Na2Cr2O7. Next, 2.181 Kg of sucrose crystals were added slowly while continuously agitating to form basic chromium sulfate. No Cr+6 was detected indicating that the reductive reaction had proceeded to completion.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O>CO.[Pt]>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12]
Reactant: Cc1ccccc1OCc1ccccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Product: Cc1ccccc1OCc1ccccc1N
Reaction time: 8 h

Procedure:
75 g (0.308 mol) of 2-(2′-methylphenoxymethyl)-nitrobenzene (Example 11a) and 10 g of 5% Pt/C (platinum adsorbed on activated carbon) in 50 ml of methanol are stirred vigorously under a hydrogen blanket for 2 hours. A further 2 g of 5% Pt/C is added and the mixture is stirred overnight. The catalyst is filtered off and replaced by 10 g of fresh catalyst. The mixture is stirred overnight and suction filtered, and the filtrate is evaporated down under reduced pressure. The residue is purified by column chromatography with mixtures of hexane and ethyl acetate. There is obtained 61 g (0.286 mol=93%) of the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([NH2:28])[C@H:8]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH:9]([C:11]1[O:12][C:13]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16](F)[C:14]=2[N:15]=1)[OH:10])([CH3:4])([CH3:3])[CH3:2].[Cl:30]C1C=C(F)C=C([N+]([O-])=O)C=1O.ClC1C=C(Cl)C=C([N+]([O-])=O)C=1O>>[C:1]([O:5][C:6](=[O:29])[CH:7]([NH2:28])[C@H:8]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH:9]([C:11]1[O:12][C:13]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:30])[C:14]=2[N:15]=1)[OH:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)[C@@H](C(N)C(=O)OC(C)(C)C)C(O)c1nc2c(F)cc(Cl)cc2o1
Reactant: O=[N+]([O-])c1cc(F)cc(Cl)c1O
Agent: O=[N+]([O-])c1cc(Cl)cc(Cl)c1O
Product: C=CCOC(=O)[C@@H](C(N)C(=O)OC(C)(C)C)C(O)c1nc2c(Cl)cc(Cl)cc2o1

Procedure:
Compound 718 was prepared by a similar method as that used for compound 714, except compound 711 was replaced with 2,4-dichloro-6-nitrophenol. ##STR97##
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][NH2:16])[N:11]=1.[CH3:20][O:21][C:22]1[C:26](OC)=[N:25][S:24](=[O:29])[N:23]=1>CO>[CH3:20][O:21][C:22]1[C:26]([NH:16][CH2:15][CH2:14][S:13][CH2:12][C:10]2[N:11]=[C:7]([NH:6][C:5]([NH2:17])=[N:4][CH2:3][C:2]([F:1])([F:18])[F:19])[S:8][CH:9]=2)=[N:25][S:24](=[O:29])[N:23]=1
Reactant: NCCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: COC1=NS(=O)N=C1OC
Solvent: CO
Product: COC1=NS(=O)N=C1NCCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 1.5 h

Procedure:
A solution of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[(2-aminoethyl)thiomethyl]thiazole (European Patent Publication No. 30092, Example 2; 2.1 g.) in methanol (20 ml.) was added dropwise to a stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (UK Patent Application No. 2067987, Example 4; 1.1 g.) in methanol (50 ml.) at 5°. The solution was stirred for 1.5 hours at 5°-10°. The intermediate 3-methoxy-4-[2-(2-[2,2,2-trifluoroethyl]-guanidino)thiazol-4-ylmethylthio]ethylamino-1,2,5-thiadiazole 1-oxide was not isolated, but anhydrous ammonia in methanol (6M, 20 ml.) was added. The solution was stirred for 17 hours at 25° and the solvent was evaporated. The residue was purified by chromatography on silica gel using dichloromethane/methanol 9:1 v/v as eluant. The purified product was obtained as an oil which was dissolved in acetone and the solution was treated with an excess of maleic acid in acetone. The salt which precipitated was recrystallized from ethyl acetate/ethanol to give 3-amino-4-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-ylmethylthio]ethylamino-1,2,5-thiadiazole 1-oxide maleate (2.0 g.), m.p. 113° (decomp.) having the following n.m.r. spectrum in d6 dimethylsulphoxide: 2.8 (t, 2H); 3.55 (t, 2H); 3.7 (s, 2H); 4.15 (q, 2H); 6.2 (s, 2H); 6.8 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[C:14]2[C:9](=[C:10]([OH:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1>ClCCl>[CH3:1][N:2]([CH3:3])[C:5]1[C:14]2[C:9](=[C:10]([OH:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1
Reactant: CNC
Reactant: Oc1cccc2c(Cl)ncnc12
Solvent: ClCCl
Product: CN(C)c1ncnc2c(O)cccc12

Procedure:
Dimethylamine gas is bubbled slowly through a solution of 4-chloro-8-quinazolinol (0.7 g, 3.88 mmol) in dichloromethane, under a nitrogen atmosphere, at 3° C. for 20 minutes. The cooling bath is removed and dimethylamine gas is bubbled through the reaction mixture for an additional 30 minutes. The reaction mixture is then concentrated in vacuo to obtain a grey solid. The solid is washed with water and extracted with 10% sodium hydroxide solution. The combined extracts are acidified to pH 7.0 and extracted with dichloromethane. The organic extracts are combined, dried over MgSO4 and concentrated in vacuo to give the title product as a grey solid, 0.36 g, mp 104°-105° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:40]1([O:46][C:47](Cl)=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1(C)C=CC=CC=1.C(OCC)C>[CH2:9]([O:7][C:6](=[O:8])[C@H:2]([CH:3]([CH3:5])[CH3:4])[NH:1][C:47]([O:46][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:48])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A slurry of 117.15 g (1 mol) of L-valine, 216.3 g (2.0 mol) of benzyl alcohol and 190.22 g (1.02 mol) of p-toluenesulfonic acid monohydrate in 450 mL of toluene was stirred and heated to reflux in an apparatus fitted with a Dean-Stark trap. After 20 hours the reaction was cooled to room temperature. The solution was poured into 1.5 L of ethyl ether, whereupon the p-toluenesulfonic acid salt of the benzyl ester of valine precipitated. To this thick suspension was added 1.3 L of water and solid sodium carbonate until the solution was alkaline. The aqueous phase was washed with ethyl ether, then the organic layers were combined and extracted with 1 L of 3M phosphoric acid. The organic solvent was discarded, and the aqueous layer was made basic by addition of 4.0M sodium hydroxide. Methylene chloride was added and the mixture was cooled to about 0° C., then 133.11 g (850 mmol) of phenylchloroformate was added over a two minute period. The reaction solution was stirred for one hour, the organic layer was separated and 5 mL of N,N-dimethylethylenediamine was added with mixing. The organic solution was washed once with 1 L of 1N HCl, dried over MgSO4, filtered and concentrated in vacuo, to afford 231.5 g of the title product as a clear syrup. NMR (CDCl3) δ:0.91 (d,3H), 1.02 (d,3H), 2.25 (m, 1H), 4.41 (q, 1H), 5.22 (dd,2H), 5.52 (d,1H), 7.12 (m,2H), 7.20 (m,2H), 7.39 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:14]#[N:15])[CH2:10][C@H:9]1[CH2:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[C:19]([C:27]([F:30])([F:28])[F:29])[CH:18]=2)[C:14]2[N:33]=[N:34][NH:35][N:15]=2)[CH2:10][C@H:9]1[CH2:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H](N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of the crude (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butylester (52 mg, 0.11 mmol), sodium azide (72 mg, 1.11 mmol) ammonium chloride (60 mg, 1.11 mmol) in DMF (2 mL) is stirred at 90° C. for 12 hours. The reaction mixture is diluted with water after letting it cool to room temperature. The product is extracted twice with EtOAc. The combined organic layer is washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is passed through silica pad (eluent: n-hexane/EtOAc) to give crude (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (52 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([F:12])[C:8]([CH2:13][C:14]([OH:16])=O)=[CH:7][CH:6]=2.O.[NH2:18][NH2:19]>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([F:12])[C:8]([CH2:13][C:14]([NH:18][NH2:19])=[O:16])=[CH:7][CH:6]=2
Reactant: NN
Reactant: O=C(O)Cc1ccc2ncc(Br)cc2c1F
Solvent: O
Solvent: CO
Product: NNC(=O)Cc1ccc2ncc(Br)cc2c1F

Procedure:
A solution of (3-bromo-5-fluoro-quinolin-6-yl)-acetic acid (800 mg, 2.7 mmol) and hydrazine hydrate (98%, 2 mL) in methanol (15 mL) was heated to reflux for 1 h. The solvent was removed in vaco to obtain a white solid which was washed with methanol and dried to return the title compound (750 mg, 94%) as a white solid. 1H-NMR (DMSO-d6, 300 MHz): 9.34 (s, 1H), 8.996-9.00 (d, 1H), 8.72-8.73 (d, 1H), 7.85-7.88 (d, 1H), 7.73-7.79 (m, 1H), 4.26-4.27 (d, 2H), 3.64-3.66 (d, 2H); MS: m/z 299 [M+H+]+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH2:19]([NH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2)[CH3:20].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:19]([NH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:10]1[CH:11]=[C:12]3[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14])[CH2:25]2)[CH3:20]
Reactant: CCNc1ccc2c(c1)CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCNc1ccc2c(c1)CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3CC)C2
Yield: 49.9 %

Procedure:
177 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 136 mg of 5-ethylaminoisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 1 to produce 138 mg of the target compound.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][C:22]=1[NH:29][C:30](=[O:48])[CH2:31][CH:32]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[C:39]=1[O:46][CH3:47])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.C(OCC)(=O)C>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:23][C:22]=1[NH:29][C:30](=[O:48])[CH2:31][CH:32]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[C:39]=1[O:46][CH3:47])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:18])([CH3:19])[CH3:20]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCCCC(CC(=O)Nc1cc(C=O)ccc1C(C)(C)C)c1cccc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCC(CC(=O)Nc1cc(CCC(=O)OCC)ccc1C(C)(C)C)c1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
1.23 ml (6.22 mmol) of ethyl diethylphosphonoacetate were added dropwise, whilst ice-cooling, over a period of 3 minutes to a suspension of 271 mg (6.22 mmol) of sodium hydride (as a 55% w/w dispersion in mineral oil) in 7 ml of dimethylformamide, and the resulting mixture was then stirred at room temperature for 30 minutes. A solution of 1.37 g (3.11 mmol) of N-(2-t-butyl-5-formylphenyl)-3-(2,3-dimethoxyphenyl)octanamide (prepared as described in Preparation 24), in 6 ml of dimethylformamide was ice-cooled and then added dropwise to the mixture over a period of 3 minutes. The resulting mixture was stirred at room temperature for 1.5 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate, and the diluted solution was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. A solution of the residue in 20 ml of ethanol was stirred at room temperature for 8 hours in an atmosphere of hydrogen and in the presence of 400 mg of 10% palladiun-on-charcoal. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid to remove the catalyst, and the filtrate was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.56 g (yield 98%) of the title compound as an oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:18])=[C:15]([CH3:17])[N:16]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:18])=[C:15]([CH3:17])[N:16]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nc(C)c(C)s2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)sc1C
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(4,5-dimethylthiazol-2-yl)-2-naphthalenyl]ethynylbenzoate (Compound 17) (58.0 mg, 0.13 mmol) and 4 ml of EtOH at room temperature was added aqueous NaOH (1 ml, 1 M, 1 mmol). The resulting solution was warmed to 50° C. for 1 hour and concentrated in vacuo. The residue was suspended in a solution of CH2Cl2 and ether (5:1) and acidified to pH 5 with 1M aqueous HCl. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered and the solvents removed under reduced pressure to give the title compound as a white solid. 1H NMR (d6-DMSO): δ 7.94 (2H, d, J=8.4 Hz), 7.86 (1H, d, J=1.6 Hz), 7.61 (2H, d, J=8.3 Hz), 7.50 (1H, dd, J=1.6, 8.0 Hz), 7.45 (1H, d, J=8.0 Hz), 6.51 (1H, t, J=4.9 Hz), 2.37 (3H, s), 2.36 (2H, d, J=4.6 Hz), 2.32 (3H, s), 1.26 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][N:10](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9]2)=[CH:4][CH:3]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.ClC(OC(Cl)C)=O.CO>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][NH:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCCl
Solvent: CO
Product: Clc1ccc(C2CNC2)cc1

Procedure:
To a solution of compound 6 (0.36 g, 1.1 mmol) in 1,2-dichloroethane (10 mL) containing proton sponge (0.02 g), cooled in an ice-water bath under an argon atmosphere, was added dropwise 1-chloroethyl chloroformate (0.3 mL, 3.1 mmol). The resultant solution was boiled at reflux for 4 hours, cooled and was concentrated in vacuo. The residue obtained was mixed with methanol (10 mL) and heated under reflux for 2 hours, then cooled and concentrated in vacuo to give the hydrochloride salt of 3-(4-chlorophenyl)azetidine (7) which was used without further purification.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].F[C:23]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[O:18][C:23]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])=[O:10])[CH:19]=[CH:20][CH:21]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(O)c2)c1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.3 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-(3-hydroxyphenyl)benzamide (5.0 g, 17.8 mmol) produced in Example 1(i) and methyl 2-fluoro-5-nitrobenzoate (3.55 g, 17.8 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (3.68 g, 26.7 mmol), and the mixture was stirred at room temperature for 16 hr. Insoluble material was filtered off and washed with ethyl acetate (200 mL). The filtrate and washings were combined and washed successively with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (8.45 g, 98%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[N:7]=[CH:8][C:9]([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[N:10][CH:11]=1.[ClH:26].O1CCOCC1.C(OC(C)C)(C)C>O1CCOCC1>[ClH:26].[ClH:26].[NH:15]1[CH2:16][CH2:17][C@@H:13]([NH:12][C:9]2[N:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:25])=[N:7][CH:8]=2)[CH2:14]1
Reactant: COC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: COC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R)-3-({5-[(1E)-3-methoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-pyrrolidinecarboxylate (830 mg) in dioxane (8.3 mL) was added 4N HCl/dioxane (6.0 mL), which was stirred at room temperature for 1 hour. To the reaction mixture was added diisopropylether, and the precipitate was filtered to give methyl (2E)-3-{5-[(3R)-3-pyrrolidinylamino]-2-pyrazinyl}acrylate dihydrochloride (742 mg) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([S:21][C:22]([F:25])([F:24])[F:23])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=O)[CH3:6].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].O.S>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([S:21][C:22]([F:25])([F:24])[F:23])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[S:28])[CH3:6]
Reactant: COC(=O)CN(C)C(=O)c1cccc2c(SC(F)(F)F)c(OC)ccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CN(C)C(=S)c1cccc2c(SC(F)(F)F)c(OC)ccc12
Yield: 73.4 %

Procedure:
N-[[6-Methoxy-5-(trifluoromethylthio)-1-naphthalenyl]carbonyl]-N-methylglycine methyl ester (2.0 g, 5.4 mmoles) was dissolved in dry pyridine (40 ml). Phosphorus pentasulfide (2.37 g, 10.7 mmoles) was added to the pyridine solution. The mixture was heated at refluxed for 4 hr and then poured into warm water at 50° to 80° C. (caution: evolution of copious quantities of H2S). The mixture was extracted with ethyl acetate. The extract was washed successively with 3 N aqueous HCl, water, a saturated aqueous solution of NaHCO3, water and brine, dried (MgSO4) and concentrated to dryness. The residue was recrystallized from ethanol-water to give 1.6 g of the title compound; mp 121°-123° C.; NMR (CDCl3) δ 3.00 (s, 3H), 3.75 (s, 3H), 4.00 (s, 3H), 4.35 and 4.5 (d, 2H), 7.0-8.5 (m, 5H).