Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[C:17]2[C:9]=1[C:10]1[CH2:11][CH:12]([OH:24])[CH2:13][CH2:14][C:15]=1[NH:16]2.[Cl-].[NH4+].C1C=[N:31]C2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:20]=[CH:19][C:18]([C:21]([NH2:31])=[O:22])=[C:17]2[C:9]=1[C:10]1[CH2:11][CH:12]([OH:24])[CH2:13][CH2:14][C:15]=1[NH:16]2
Reactant: O=C(O)c1ccc(-c2ccccc2F)c2c3c([nH]c12)CCC(O)C3
Reactant: On1nnc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(-c2ccccc2F)c2c3c([nH]c12)CCC(O)C3
Yield: 65.1 %

Procedure:
Step 2 A solution of 5-(2-fluorophenyl)-3-hydroxy-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (0.069 g, 0.213 mmol) in DMF (1.07 mL) was treated with ammonium chloride (0.023 g, 0.427 mmol), HOAT (0.058 g, 0.427 mmol), EDC (0.082 g, 0.427 mmol) and DIEA (0.149 mL, 0.853 mmol) and stirred over a weekend. The mixture was diluted with DCM, washed with 5% hydrochloric acid, NaHCO3 (aq), brine and 10% aqueous lithium chloride, dried and concentrated to give 5-(2-fluorophenyl)-3-hydroxy-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a light yellow foam (0.045 g, 65%). Mass spectrum m/z 325.1 (M+H)+.
Reaction SMILES: C1(C)C=CC(S([NH:10][N:11]=[CH:12][C:13](Cl)=[O:14])(=O)=O)=CC=1.[OH:17][CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:23][CH:22]=1.CN(C)C1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[N+:11](=[CH:12][C:13]([O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:37])=[CH:23][CH:22]=1)=[O:14])=[N-:10]
Reactant: O=C(Nc1ccc(/C=C/CO)cc1)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NN=CC(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)c1ccccc1
Product: [N-]=[N+]=CC(=O)OC/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Glyoxylic acid chloride p-toluenesulfonylhydrazone (1.66 g, 6.35 mmol) was added to a suspension of benzyl 4-[(1E)-3-hydroxyprop-1-enyl]phenylcarbamate (1.0 g, 3.53 mmol) in dichloromethane (25 mL). The mixture was cooled to 0° C. and treated with N,N-dimethylaniline (0.8 mL, 6.35 mmol). After 0.5 h, triethylamine (2.5 mL, 17.6 mmol) was added and the mixture stirred 2 h at 0° C. and warmed to room temperature. The reaction mixture was then concentrated and water was added. The mixture was extracted with two portions of diethyl ether and the combined organic solutions washed with saturated NaHCO3, brine and dried (MgSO4), filtered and concentrated. Purification by silica gel column chromatography (gradient 0-25% EtOAc-hexane) provided the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](Cl)=[O:15].[OH:22][CH2:23][CH2:24][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([O:22][CH2:23][CH2:24][CH2:25][C:26](=[O:27])[N:28]([CH3:30])[CH3:29])=[O:15]
Reactant: CC(OCc1ccc2ccccc2c1)(C(=O)Cl)C(F)(F)F
Reactant: CN(C)C(=O)CCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CCCOC(=O)C(C)(OCc1ccc2ccccc2c1)C(F)(F)F
Reaction time: 48 h
Yield: 34.5 %

Procedure:
A solution of (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride (3.0 g.) in tetrahydrofuran (70 ml.) is added, dropwise at 0° C., to a stirred solution of 4-hydroxy-N,N-dimethylbutyramide (1.20 g.) and triethylamine (2.1 g.) in tetrahydrofuran (35 ml.). The mixture is stored for two days. The solid is filtered off and washed with ether, and the filtrate and washings are evaporated. The residue is dissolved in ether and the solution is washed with water, 0.4 N aqueous sodium hydroxide, and water, dried with magnesium sulphate, and evaporated. The residue is crystallised from a mixture of light petroleum (b.p. 40°-60° C.) and ether to give (±)-3-dimethylcarbamoylpropyl 2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate (1.3 g.) m.p. 42°-43° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[Cl:11])[CH:18]=1)[CH3:13]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CCOC(=O)Cc1cccc(N)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cc(Br)ccc2Cl)c1

Procedure:
5-Bromo-2-chlorobenzoic acid (132 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: [C:1]([NH2:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O.[OH-].[Na+]>OS(O)(=O)=O>[CH2:2]([C:1]1[O:7][CH:13]=[C:11]([CH2:10][Cl:9])[N:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(N)=O
Reactant: O=C(CCl)CCl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCc1nc(CCl)co1
Temperature: 120 °C
Yield: 19.2 %

Procedure:
The synthesis of 3 was performed similarly to example 1 above. The solids, hexanoamide (5 g) and 1,3-dichloroacetone (5.5 g), were mixed together in a round bottomed flask and heated at 120° C. under an argon atmosphere for 2 hours. The mixture was cooled to 25° C. for 1 hour, followed by the addition of concentrated H2SO4 (50 mL). The resulting syrup was poured onto ice and the pH was adjusted to 10 with NaOH (1M). The resulting solution was extracted with CHCl3, dried (Na2SO4) and evaporated to yield a brown liquid (1.56 g). This material was chromatographed according to Still et al. (J. Org. Chem., 1978, 43, 2923) on silica gel in EtOAc to yield 3 as a yellow liquid (1.4 g).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[OH:25][C:26]1[C:35]([N:36]([CH3:38])[CH3:37])=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][CH2:29][NH:30][CH2:31]2>>[F:22][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([C:19]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][CH:34]=[C:35]([N:36]([CH3:38])[CH3:37])[C:26]=4[OH:25])[CH2:31]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1nc(-c2cccc(C(F)(F)F)c2)nc2ccccc12
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3cccc(C(F)(F)F)c3)nc3ccccc13)C2
Yield: 5 %

Procedure:
Reaction of 2-(3-(trifluoromethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 55 (5% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.71 and 2.77 (2s, 6H), 2.85 and 3.11 (2t, 2H), 3.59 and 4.22 (2t, 2H), 4.49 and 5.11 (2s, 2H), 6.36 and 6.86 (2d, 1H), 6.99-7.17 (m, 2H), 7.62-7.70 (m, 2H), 7.77-7.80 (m, 1H), 7.96-8.07 (m, 2H), 8.16-8.21 (m, 1H), 8.82-8.96 (m, 2H); MS (ESI) m/z 493 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:22]=4[O:23][CH:24]([CH3:30])[C:25]([O:27]CC)=[O:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+]>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:22]=4[O:23][CH:24]([CH3:30])[C:25]([OH:27])=[O:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(C)Oc1c(COc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)cccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(COc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c1OC(C)C(=O)O
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of ethyl 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}-6-methoxyphenoxy}propionate (2.30 g) in a mixed solvent of tetrahydrofuran (30 ml)and methanol (15 ml) was added 1N sodium hydroxide solution (6.8 ml) at room temperature. The solution was stirred for two hours and concentrated under reduced pressure. The residue was diluted with water and acidified with 1N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate to give 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}-6-methoxyphenoxy}propionic acid (2.17 g) as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C@@H:9]([NH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=3)=[O:15])[CH2:10][O:11][CH3:12])=[N:8][C:4]=2[CH:3]=1.CN(C(O[N:39]1N=NC2C=[CH:43][CH:44]=[CH:45][C:40]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.N1CC=CC1.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C@@H:9]([NH:13][C:14](=[O:15])[C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:39]4[CH2:40][CH:45]=[CH:44][CH2:43]4)=[O:22])=[C:18]([C:25]([F:26])([F:28])[F:27])[CH:17]=3)[CH2:10][O:11][CH3:12])=[N:8][C:4]=2[CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COC[C@H](NC(=O)c1ccc(C(=O)O)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: C1=CCNC1
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 23 %

Procedure:
Prepared analogously to Example 1g from 4-{N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethyl]aminocarbonyl}-2-trifluoromethylbenzoic acid, TBTU, diisopropylethylamine, and 3-pyrroline in tetrahydrofuran. Yield: 23%; C23H20ClF3N4O3 (492.88); mass spectrum: (M+H)+=493/495 (chlorine isotope) and (M−H)−=491/493 (chlorine isotope).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccccc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (58 mg, 81%), MS (ISP) m/z=288.5 [(M+H)+], mp 265.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([F:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([F:10])[CH:3]=1
Reactant: C1COCCN1
Reactant: Fc1cc(Br)ccc1CBr
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1CN1CCOCC1

Procedure:
4-Bromo-2-fluorobenzyl bromide (3.0 g) and morpholine (2.15 ml) were stirred in dimethylformamide (30 ml) at ambient temperature for 18 h. The mixture was partitioned between diethyl ether (80 ml) and water (80 ml). The aqueous phase was extracted further with diethyl ether (80 ml) and the combined organic phases were dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0–30% ethyl acetate/iso-hexane to give the product as a colourless oil (2.92 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C.C(Cl)Cl>CS(C)=O.CO>[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CS(C)=O
Product: CN1CCC(Nc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Yield: 43.6 %

Procedure:
Dissolve 1-chloro-4-nitro-2-(trifluoromethyl)benzene (1.0 g, 4.44 mmol) in DMSO (5 mL), add 1-methylpiperidin-4-amine (0.56 g, 4.89 mmol) and DIEA (1.72 g, 13.3 mmol) and stir the reaction at 80° C. overnight. TLC (DCM:MeOH=10:1) shows the reaction is complete. Add water, extract with EtOAc (10 mL×3), combine the organic layers, wash with water and brine sequentially, and dry over anhydrous Na2SO4. Concentrate under reduced pressure to get the crude product. Purification by chromatography (silica gel, MeOH:DCM=1:15) affords the title compound (587 mg, 44%). MS: (M+1): 304.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17](Cl)=[O:18])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:18])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12
Reactant: C1COCCN1
Reactant: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)Cl
Product: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)N1CCOCC1
Yield: 82 %

Procedure:
[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl) -4-methyl-thiazol-5-yl]-morpholin-4-yl-methanone (532 mg, 82%) was prepared from 2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carbonyl chloride and morpholine in a procedure analogous to Example 20. C16H14ClN3O2S2: APCI m/z 380.0/382.1 (pos.).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:12]([CH2:22]OS(C)(=O)=O)[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[N:28]([CH2:22][C@@H:12]1[CH2:11][C@@H:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:14][N:13]1[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1COS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CN=[N+]=[N-]
Temperature: 50 °C
Reaction time: 16 h

Procedure:
330.0 mg (0.75 mmol) tert. Butyl (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-methanesulphonyloxymethyl-pyrrolidine-1-carboxylate are dissolved in 20 ml DMF and combined with 146.6 mg (2.3 mmol) sodium azide. The mixture is stirred at 50° C. for 16 hours. Then a further 73 mg (1.12 mmol) sodium azide are added and the mixture is stirred for a further two hours at 50° C. Then it is concentrated i. vac. The residue is combined with water/sat. Saline solution and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=S)C.[CH2:12](C1C=CC=CC=1)[CH3:13]>>[CH2:12]([C:10]1[CH:11]=[CH:3][C:4]([C:5]#[N:7])=[CH:8][CH:9]=1)[CH3:13]
Reactant: CCc1ccccc1
Reactant: CCc1ccccc1C(N)=S
Product: CCc1ccc(C#N)cc1

Procedure:
In a polyethylene vessel having a capacity of 1 liter, at -20° C and with agitation, 46 g of ammonium thiocyanate (0.6 mol) and subsequently 53 g of ethylbenzene (0.5 mol) are added in portions to 0.5 l of 98% hydrofluoric acid. Subsequently, agitation is continued for 20 hours at room temperature, and the reaction mixture is then poured onto ice, thus causing the separation of a precipitate which slowly crystallizes. The precipitate is suction-filtered and washed with water. By steam distillation, about 10 g of ethylbenzene are recovered from the precipitate. After drying, 66 g (0.4 mol) of ethyl-thiobenzamide having a slightly yellow color and a melting point of 115 - 117° C are obtained, which corresponds to a conversion rate of 80% relative to the ethylbenzene used. The yield, relative to converted ethylbenzene, is 95% of the thoeretical yield. The product can be recrystallized from toluene or chlorobenzene. The gas chromatogram shows that substitution by the thioamide group has occured in p-position at a rate of more than 95%. The 4-ethylbenzonitrile may be obtained from the thioamide in known manner using alkali, thereby splitting off H2S.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[OH:24])[CH2:4][CH3:5])[CH3:2].[Cl:25][CH2:26][C:27](Cl)=[O:28].C(N(CC)CC)C>C1COCC1>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[O:24][C:27](=[O:28])[CH2:26][Cl:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1O
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1OC(=O)CCl

Procedure:
The title compound was prepared by reacting 4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ol with chloroacetyl chloride/triethylamine in THF at 0° C. to rt. 1H NMR(CDCl3) d 6.84(s, 2H), 6.15(s, 1H), 4.3(s, 2H(, 4.0(d, 1H), 3.3(m, 1H), 2.28(s, 3H), 2.17(s, 3H), 2.08(s, 6H), 1/6-1.7(m, 4H), 0.9(t, 6H) ppm.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:19]([Mg]Br)[CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1.CCOCC>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCC[Mg]Br
Reactant: O=Cc1cccc(-c2ccc(C(F)(F)F)cc2)n1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 6-[4-(trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (300 mg, 1.19 mmol) in dry toluene (12 mL) under nitrogen was cooled to 0° C. (ice/water bath) and treated with n-pentylmagnesium bromide (0.66 mL of a 2M solution in Et2O, 1.31 mmol) and the resulting mixture was stirred at 0° C. for 2 hours. The reaction was then quenched by the cautious addition of aqueous HCl (2M, 2 mL) and the solvent was removed under vacuum and the residue partitioned between EtOAc (2×50 mL) and aqueous HCl (2M, 50 mL). The organic solution was washed with water (60 mL) then brine (60 mL), dried (MgSO4) and reduced. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 99:1 to 19:1) afforded the title compound as a colourless oil (131 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:19][CH:18]=[C:17]([CH2:20][CH2:21][OH:22])[C@@H:7]2[C@H:8]([O:11][CH:12]([O:14][CH2:15][CH3:16])[CH3:13])[O:9][CH:10]=1)=[O:4].N1C=CC=CC=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:19][CH:18]=[C:17]([CH2:20][CH2:21][O:22][C:29](=[O:31])[CH3:30])[C@@H:7]2[C@H:8]([O:11][CH:12]([O:14][CH2:15][CH3:16])[CH3:13])[O:9][CH:10]=1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CCO)[C@H]12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CCOC(C)=O)[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
1.63 g of the above (1S,4aS,7aR)-1-[1-(ethoxy) ethoxy]-7-[2-(hydroxy) ethyl]-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester were dissolved in dichloromethane followed by addition of 1.7 ml of pyridine and DMAP. Next, 1.0 ml of acetic anhydride were added followed by stirring for 3 hours at room temperature. The reaction mixture was then extracted with ether. After washing the organic phase with 2N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless oil from the hexane-ether eluate in the form of (1S,4aS,7aR)-7-[2-(acetoxy) ethyl]-1-[1-(ethoxy) ethoxy]-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid methylester (1.65 g, yield: 89%). The physicochemical properties of this compound are described below.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:16]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[C:15](=[O:21])[N:14]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:16]3([CH2:17][CH2:18][CH2:19][CH2:20]3)[C:15](=[O:21])[N:14]([CH:22]3[CH2:23][CH2:24][N:25]([S:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=4)(=[O:37])=[O:36])[CH2:26][CH2:27]3)[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C23CCCC3)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C)c4)CC3)C(=O)C23CCCC3)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 4-(3,4-dimethoxyphenyl)-2-(piperidin-4-yl)-2,3-diazaspiro[4.4]non-3-en-1-one hydrochloride (compound B10*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][N:35]([CH3:40])[CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[CH3:34][N:35]([CH3:40])[CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: CN(C)C1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CN(C)C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
To 310 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 100 mg of 3-(dimethylamino)azetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 15 minutes. After adding 1 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 87 mg of the title compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 4-fluoro-3-nitro aniline (1.00 g, 6.41 mmol) in anhydrous CH2Cl2 (25 ml) was added pyridine (1.52 g, 19.23 mmol) and the solution was cooled to 0° C. under argon. Benzoyl chloride (0.90 g, 6.41 mmol) was added slowly and the solution was then allowed to slowly warm to room temperature and stir for 24 h. The solution was poured into 1NHCl and the organic layer was separated. The aqueous layer was extracted 3× with ethyl acetate (50 ml). The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography, eluting with hexane/ethyl acetate (4:1) to give N-(4-fluoro-3-nitro-phenyl)-benzamide. (1.60 g, 96%)