Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1([CH3:18])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:17])[C:8]([CH3:16])=[C:9]([OH:15])[C:10]=2[CH3:14])[O:5]1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C)C=O>O>[CH2:21]([O:15][C:9]1[C:10]([CH3:14])=[C:11]2[C:6](=[C:7]([CH3:17])[C:8]=1[CH3:16])[O:5][C:4]([CH:3]([O:2][CH3:1])[O:19][CH3:20])([CH3:18])[CH2:13][CH2:12]2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(OC)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)C1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1

Procedure:
1.47 g (5.25 mmoles) of the chroman obtained in Example 8 were heated at 100° C. with 3.2 g of benzyl bromide, 1.5 g of Na2CO3 and 7 ml of dimethylformamide for 13 hours, and water was then added. This mixture was extracted with heptane, after which the crude product obtained from the extract phase was chromatographed on 50 g of silica gel using a mixture of 1 part by volume of ether and 2 parts by volume of heptane. The following fractions were obtained: F1=1.28 g; F2 (mixed fraction)=0.13 g; F3 (starting material)=0.23 g.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:6]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21]>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:11][C:10]([S:12]([NH:16][C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([O:22][CH3:23])=[O:21])(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Cc1nc(-c2ccc(S(=O)(=O)Cl)s2)cs1
Reactant: COC(=O)c1cccc(N)c1
Product: COC(=O)c1cccc(NS(=O)(=O)c2ccc(-c3csc(C)n3)s2)c1

Procedure:
The title compound was prepared according to General Procedure 1, described in Example 1, with 5-(2-methylthiazol-4-yl)thiophene-2-sulphonylchloride (15.4 mg, 0.055 mmol) and methyl 3-aminobenzoate (7.6 mg, 0.050 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.83 (s, 3H), 2.98-2.99 (s, 3H), 6.59-6.62 (m, 2H), 6.67-6.68 (s, 2H), 6.81-6.84 (m, 1H), 6.93-6.94 (m, 1H). MS (ESI+) m/z 395 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15](=[O:16])[C:14]3[CH:17]=[C:18](I)[CH:19]=[CH:20][C:13]=3[O:12][N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:31]([OH:34])[C:32]#[CH:33]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:15](=[O:16])[C:14]3[CH:17]=[C:18]([C:33]#[C:32][CH2:31][OH:34])[CH:19]=[CH:20][C:13]=3[O:12][N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1noc2ccc(I)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1noc2ccc(C#CCO)cc2c1=O
Temperature: 25 °C

Procedure:
Under an argon atmosphere, a mixture of N-(4-chlorobenzyl)-6-iodo-4-oxo-4H-1,2-benzoxazine-3-carboxamide (Preparation 18, 0.117 g), dichlorobis (triphenyl-phosphine)palladium (12.8 mg), copper(I) iodide (3.7 mg), and triethylamine (1 mL) in THF (6 mL) is cooled in an ice-brine bath. A solution of propargyl alcohol (32 mg) in THF (3 mL) is added slowly via a syringe to the reaction mixture. The reaction mixture is stirred at ice-brine temperature for 2 h and then allowed to warm to room temperature overnight. The mixture is concentrated in vacuo and the residue is flash chromatographed on silica gel (230-400 mesh, 8 g), eluting with 1% methanol in dichloromethane, pooling desirable fractions and concentrating in vacuo provides the title compound as a pale yellow solid. Physical characteristics: m.p. 117-120° C.: 1H NMR (400 MHz, DMSO-d6) δ 4.35, 4.50, 5.55, 7.42, 7.77, 7.97, 9.4; 13C NMR (DMSO-d6) δ 49.2, 49.3, 67.8, 79.4, 81.8, 91.8, 117.5, 119.8, 120.2, 126.6, 128.3, 129.0, 131.6, 137.2, 138.8, 155.2, 159.2, 160.3, 165.2; MS (FAB) m/z 369 (MH+, 99); HRMS (FAB) m/z 369.0645 (C19H13ClN2O4+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CSc1ccc(N)cc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1C(F)(F)F
Reaction time: 24 h

Procedure:
4-Methylsulfanyl-3-trifluoromethyl-phenylamine (828 mg; 4.00 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (876 mg; 4.40 mmol) and sodium triacetoxyborohydride (2.52 g; 12.00 mmol) are suspended in dichloromethane (18 mL) and the resulting mixture is stirred for 1 day. The suspension is then diluted with dichloromethane (50 mL) and is washed with water (30 mL) and aq. sat. ammonium chloride (3×30 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure to deliver the desired product in the presence of remaining traces of solvent (1.8 g; 4.6 mmol).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=[O:39])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:29]([C:31]4[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=4)[C:34]#[N:35])[CH2:28][C:27](=[O:39])[NH:22][C:9]=3[CH:10]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)c(Cl)c2)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccc(Cl)c(Cl)c4)cc3NC(=O)C2)c1

Procedure:
Prepared from (3-amino-3′,4′-dichloro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G21) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (150 mg).
Reaction SMILES: Cl.[OH:2][C@H:3]([C:11]1[C:12]([CH3:21])=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[O:15][CH2:14]2)[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl[C:23]1[N:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1>>[OH:2][C@H:3]([C:11]1[C:12]([CH3:21])=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[O:15][CH2:14]2)[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)[CH2:7][CH2:6]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CN2CCN(c3ccc(C#N)cn3)CC2)ccc2c1COC2=O

Procedure:
(R)-6-(4-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)nicotinonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 10 starting from (R)-5-(1-hydroxy-2-(piperazin-1-yl)ethyl)-4-methylisobenzofuran-1 (3H)-one hydrochloride (INTERMEDIATE 12) and 6-chloropyridine-3-carbonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15](=[O:18])[NH:16][N:17]=[C:13]3[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11]([CH3:29])=[C:10]2[C:30]([OH:32])=[O:31])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]([CH3:62])[CH2:59][CH2:60]O>CN(C=O)C>[CH3:57][N:58]([CH3:62])[CH2:59][CH2:60][O:31][C:30]([C:10]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[N:14]2[C:15](=[O:18])[NH:16][N:17]=[C:13]2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=2)[C:11]=1[CH3:29])=[O:32]
Reactant: CN(C)CCO
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OCCN(C)C)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
To a solution of Example 9 (32 mg, 0.073 mmol) in DMF (1 mL), was added diiosopropylethylamine (125 μL, 0.73 mmol) followed by HATU (30 mg, 0.080 mmol). After 1 hour, N,N-dimethylethanolamine (73 μL, 0.73 mmol) was added, and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by reverse phase HPLC using a gradient 20-70% acetonitrile in water with 0.1% ammonia to yield the title compound as a white solid (4 mg).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)([CH3:14])[CH3:13])[CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)([CH3:13])[CH3:14])[CH:7]=1
Reactant: COc1ccc(C(C)(C)c2cc(Br)ccn2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(c1ccc(O)cc1)c1cc(Br)ccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
BBr3 (1M in DCM, 23 mmol, 8 eq) is added dropwise to a cold (0° C.) solution of 4-bromo-2-[1-(4-methoxy-phenyl)-1-methyl-ethyl]-pyridine (Step 31.3) (0.878 g, 2.87 mmol) in DCM (42 mL), under an argon atmosphere. The reaction mixture is stirred for 1 h at 0° C., allowed to warm to rt, stirred for 18 h, cooled to 0° C. and quenched by addition of anhydrous MeOH. The mixture is concentrated, diluted with a 6M aqueous solution of HCl, stirred for 1 h, neutralized to pH 7 and extracted with DCM. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is used without purification.
Reaction SMILES: [C-]#N.[Na+].C(O)C.[C:7]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])#[N:8].[CH3:17][S:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>O>[C:7]([C:9]1[CH:10]=[C:11]([C:12](=[O:13])[CH:23]([OH:24])[C:22]2[CH:25]=[CH:26][C:19]([S:18][CH3:17])=[CH:20][CH:21]=2)[CH:14]=[CH:15][CH:16]=1)#[N:8]
Reactant: CSc1ccc(C=O)cc1
Reactant: N#Cc1cccc(C=O)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSc1ccc(C(O)C(=O)c2cccc(C#N)c2)cc1
Yield: 61 %

Procedure:
Sodium cyanide (3 mmol, 0.147 g) was added to a mixture of ethanol (30 ml), water (30 ml), 3-cyanobenzaldehyde (30 mmol, 3.93 g) and 4-(methylthio)benzaldehyde (30 mmol, 4.0 ml). The reaction was stirred at reflux 30 minutes, diluted with water (20 ml) and extracted with ethyl acetate (250 ml). The organic layer was separated, dried over magnesium sulfate, concentrated, and the residue purified by silica gel chromatography (2:1 hexane:ethyl acetate), affording the title compound as a solid (5.2, 61%).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:18][Mg]Br.O1CCCC1.Cl>CCOCC>[N:1]1([CH:6]([C:10]2[CH:11]=[CH:12][C:13]([CH:14]([OH:15])[CH3:18])=[CH:16][CH:17]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1ccc(CO)cc1)n1ccnc1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(c1ccc(C(C)O)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
460 mg of the aldehyde of example 5 in 8 ml of ether is mixed with 1.5 ml of a 3M methyl magnesium bromide solution in ether with ice cooling and is stirred for 20 hours at room temperature; 10 ml of tetrahydrofuran is added and heated to 60° C. in 6 hours. It is added to 1M of hydrochloric acid, extracted with ether, then the water phase is alkalized with potassium carbonate and extracted with ether. After drying and concentration by evaporation of this ether phase, the residue is chromatographed on silica gel (methylene chloride/methanol (95:5)). 300 mg of the title compound is obtained.
Reaction SMILES: [C:1]1([C:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH:14]([C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:15]([O:17]CC)=[O:16])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(OCC)(=O)C>[OH-].[Na+].C(O)C>[C:35]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH:14]([C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:15]([OH:17])=[O:16])[N:10]=[CH:9]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCOC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
The mixture of ethyl 3-[1-(triphenylmethyl)imidazol-4-yl]-2-(3,4-methylenedioxyphenyl)propionate (730 mg) in 1N sodium hydroxide aqueous solution (4.1 ml) and ethanol (10 ml) was stirred at ambient temperature for 3 hours. The resulting solution was neutralized with 1N hydrochloric acid (4 ml) followed by dilution with ethyl acetate, and then the organic layer was washed with brine. Drying, filtering and removal of the solvents afforded 3-[1-(triphenylmethyl)-imidazol-4-yl]-2-(3,4-methylenedioxyphenyl)propionic acid (650 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH:44]=[CH:43][CH:42]=[C:41]1B(O)O)=[O:39])([CH3:36])([CH3:35])[CH3:34]>CCCCCCC.CCOC(C)=O>[C:33]([O:37][C:38]([N:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[C:2]1[CH:3]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[C:5]([N:8]([C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[C:12]([C:20]([F:22])([F:23])[F:21])[CH:11]=2)[CH3:25])=[CH:6][N:7]=1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(-c2cccn2C(=O)OC(C)(C)C)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, from N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 12) and 1-(tert-butoxycarbonyl)pyrrole-2-boronic acid (CAS RN 135884-31-0) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light yellow oil (18%). MS (ESI): m/z=604.202 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:16])(=O)/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[C:5]([Cl:3])(=[O:16])[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCC=CC(=O)Cl

Procedure:
Thionyl chloride (8 ml) was added to trans-2-decenoic acid (3.4 g, 0.02 mol) followed by refluxing on a hot water bath for 2 hours. An excessive thionyl chloride was evaporated in vacuo to give 2-decenoic acid chloride. Pyridine (1 ml) was added to a solution of N,N-dimethylaminoethanol (2.0 g, 0.022 mol) in tetrahydrofuran (30 ml) followed by dropping into a solution of 2-decenoic acid chloride in tetrahydrofuran (20 ml). The reaction solution was heated to reflux on a hot water bath for 3 hours, tetrahydrofuran was evaporated in vacuo, water and ethyl acetate were added to the residue to partition and an ethyl acetate layer was collected therefrom. The ethyl acetate layer was washed with water and evaporated followed by purifying by silica gel column chromatography (developer: chloroform) to give the aimed compound as a light brown oily product.
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:25])([F:24])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[CH:17][N:18]=2)=[CH:10][CH:9]=1.[CH2:26]([O:28][C:29](Cl)=[O:30])[CH3:27]>CCCCCC.O1CCCC1.C(OCC)C>[CH2:26]([O:28][C:29]([C:21]1[S:20][C:19]([C:16]2[S:15][C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([F:6])([F:24])[F:25])=[CH:13][CH:12]=3)=[N:18][CH:17]=2)=[CH:23][CH:22]=1)=[O:30])[CH3:27]
Reactant: FC(F)(F)c1ccc(-c2ncc(-c3cccs3)s2)cc1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(-c2cnc(-c3ccc(C(F)(F)F)cc3)s2)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
Under a dry nitrogen atmosphere, 1.6 ml of a 2.5 M solution of n-butyllithium in n-hexane was added dropwise to a stirred, cold (-78° C.) solution of 1.0 g (0.0032 mole) of 2-(4-trifluoromethylphenyl)-5-thien-2-ylthiazole in 15 ml of tetrahydrofuran. This mixture was stirred at -78° C. for two hours and then was added to a stirred, cold (-78° C.) solution of 0.70 g (0.0064 mole) of ethylchloroformate in 20 ml of tetrahydrofuran. After complete addition the mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The mixture was diluted with 100 ml of diethyl ether and was washed in succession with an aqueous, saturated ammonium chloride solution, water, and an aqueous, saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure, leaving a solid. This solid was purified by column chromatography on silica gel, eluting with methylene chloride:n-hexane (60:40) to yield 0.56 g of 5-(5-ethoxycarbonylthien-2-yl)-2-(4-trifluoromethylphenyl)thiazole as a solid, compound 1 of Table 1.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[CH2:14]2)[C:9]([F:20])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[CH:21]1[CH2:23][CH2:22]1.S(=O)(=O)(O)O.[CH2:33](O)[CH3:34]>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[CH2:14]2)[C:9]([F:20])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([O:26][CH2:33][CH3:34])=[O:25])=[CH:6][N:7]2[CH:21]1[CH2:23][CH2:22]1
Reactant: CCO
Reactant: CC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCN1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCNC(C)C3)c(F)c(N)c2c1=O

Procedure:
5-Amino-1-cyclopropyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was suspended in absolute ethanol. Concentrated sulfuric acid was added to the suspension and the mixture was refluxed for 10 hours with stirring. After evaporation of ethanol, chloroform and a 20% aqueous sodium hydroxide solution were added to the residue, and the mixture was adjusted to pH 9. The organic layer was separated and chloroform was evaporated under reduced pressure. The resulting crystals were collected by filtration to give ethyl 5-amino-1-cyclopropyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate, m.p. 132°-134° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][CH:18]([C:20](=O)[CH2:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH3:19]>>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:20]([CH:18]([CH3:19])[CH3:17])[C:21]([C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)C(=O)CC(=O)C(C)C
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Product: CC(C)C(=O)c1c(C(C)C)nc2ccc(Br)cc2c1-c1ccccc1
Reaction time: 96 h
Yield: 46 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 2,6-dimethyl-3,5-heptanedione according to the method of example 1, except that the reaction time was of 96 h and the residue was purified by chromatography on aminated silica gel with heptane/ethyl acetate (85:15). Yield: 46%. MS: m/z=395/397 (M).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][SH:15].[Na]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:14]([S:15][CH:14](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[NH2:11])[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[NH2:11]
Reactant: Nc1ccccc1CS
Reactant: C#Cc1ccc(F)cc1F
Agent: [Na]
Product: Nc1ccccc1C(/C=C\c1ccc(F)cc1F)SC(/C=C\c1ccc(F)cc1F)c1ccccc1N

Procedure:
A solution of 2,4-difluorophenylacetylene (0.02 mol), 2-aminobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-difluorostyryl-2-aminobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([N:11](N[C@@H](C3C=CC=CC=3)C)[CH2:12][CH2:13][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([NH:11][CH2:12][CH2:13][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](NN1CCO[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H]2NCCO[C@@H]2C1
Reaction time: 4 h

Procedure:
A mixture of 417 mg of cis-8-tert-butoxycarbonyl-5-[(1R)-1-phenylethylamino]-2-oxa-5,8-diazabicyclo[4.3.0]nonane 14a and 200 mg of 10% palladium on charcoal in 50 ml of ethanol was shaken under a pressured hydrogen atmosphere of 4.5 kg/cm2 for 4 hours. Then further 100 mg of 10% palladium on charcoal was added and hydrogenation was carried out under the above-mentioned condition. Throughout the reaction, the reaction vessel was heated by irradiation with a tungsten lamp. The catalyst was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was subjected to silica gel column chromatography. From an eluant of chloroform containing 10% methanol, the titled compound 15a weighing 286 mg was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH2:12]Br)=[CH:6][C:5]=1[O:14][CH2:15][CH3:16].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH2:12][N:18]=[N+:19]=[N-:20])=[CH:6][C:5]=1[O:14][CH2:15][CH3:16]
Reactant: CCOc1cc(CBr)c(C#N)cc1C(=O)NC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(CN=[N+]=[N-])c(C#N)cc1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After next dissolving N1-methyl-4-(bromomethyl)-5-cyano-2-ethoxybenzamide in dimethylformamide (100 ml), sodium azide (6 g) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to yield the title compound (15.5 g).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18])[CH2:2]C(C)C.OC1C=CC2C(=CC=CC=2)C=1C=O.BrCC#[N:35]>>[CH:17]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:1][C:2]#[N:35])=[O:18]
Reactant: CC(C)CCOc1ccc2ccccc2c1C=O
Reactant: N#CCBr
Agent: O=Cc1c(O)ccc2ccccc12
Product: N#CCOc1ccc2ccccc2c1C=O

Procedure:
Prepared according to the Procedure for 2-(isopentyloxy)-1-naphthaldehyde using 2-hydroxy-1-naphthaldehyde and bromoacetonitrile.