Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[N:20][N:21]2[C:25](=O)[CH2:24][CH2:23][CH:22]2[CH3:27])[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=1.C(OCC)(=O)C.O>CN(C)C=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:25]3[CH2:24][CH2:23][CH:22]([CH3:27])[N:21]3[N:20]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)CC(=NN1C(=O)CCC1C)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccc(F)cc2)nn2c1CCC2C
Temperature: 100 °C
Reaction time: 4 h
Yield: 67.6 %

Procedure:
23.2 g (71.2 mmol) of caesium carbonate are added to a solution of 10.4 g (35.6 mmol) of methyl 3-(4-fluorophenyl)-3-[(2-methyl-5-oxopyrrolidin-1-yl)imino]propanoate in 100 ml of dimethylformamide. The reaction mixture is stirred at room temperature for 30 min and at 100° C. for 4 h. Ethyl acetate/water is then added, the organic phase separated off and the aqueous phase is extracted with 3×100 ml of ethyl acetate. The combined organic phases are dried over Na2SO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 6.6 g (64%) of the desired product; log P(HCOOH): 2.84; 1H-NMR (ppm): δ (DMSO-d6)=1.44 (d, 3H), 2.14-2.17 (m, 1H), 2.76-2.78 (m, 1H), 2.98-3.08 (m, 2H), 3.68 (s, 3H), 4.46 (m, 1H), 7.21-7.24 (m, 2H), 7.73-7.76 (m, 2H); LC-MS: m/z=275 [M+H]+.
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH2:5].COCCOC.Cl.[CH2:13]([NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:13]([NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]2[O:33][CH2:3][CH2:4][N:5]=2)=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Reactant: NCCBr
Agent: Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCCCNc1ccc(C2=NCCO2)cc1

Procedure:
To a slurry of 15 g. of 2-bromoethylamine hydrobromide in 150 ml. of 1,2-dimethoxyethane are added simultaneously solutions of 31 g. of 4-(4-tetradecenylamino)benzoyl chloride hydrochloride in 60 ml. of 1,2-dimethoxyethane and 50 cc. of triethylamine (dropwise). Upon addition of 0.5 g. of 4-dimethylaminopyridine the mixture is stirred at room temperature overnight. The solution is refluxed for one hour and filtered. The solid is oven dried and partitioned between methylene chloride and water. The layers are separated and the organic phase dried over magnesium sulfate. The organic layer is concentrated and the residue collected and crystallized from cyclohexane and recrystallized from acetonitrile to yield the product.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]2=[N:6][C:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:4]2[N:3]=1.[CH3:15][N:16]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:2]2[CH:14]=[CH:13][C:5]3=[N:6][C:7]4[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=4[N:4]3[N:3]=2)[CH2:18][CH2:17]1
Reactant: Clc1ccc2nc3c(n2n1)CCCC3
Reactant: CN1CCCNCC1
Product: CN1CCCN(c2ccc3nc4c(n3n2)CCCC4)CC1

Procedure:
A mixture was prepared from 5.0 g of 2-chloro-6,7,8,9-tetrahydropyridazino[1,6-a]benzimidazole and 30 ml of 1-methylhomopiperazine and this was stirred and heated at reflux for 18 hours. The reaction mixture was then cooled and excess amine was removed by distillation to leave a tan solid residue. This solid was partitioned between methylene chloride and an aqueous 1% solution of sodium hydroxide. The methylene chloride layer was separated and the solvent was evaporated under reduced pressure to leave a residual solid. This solid was recrystallized from a mixture of ethanol and water to give 2-(4-methyl-1-homopiperazinyl)-6,7,8,9-tetrahydropyridazino[1,6-a]benzimidazole melting at about 106°-107° C.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=O.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1([C:25]([NH2:27])=[NH:26])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:27]=[C:25]([C:22]2([C:16]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=3[Cl:14])[CH2:24][CH2:23]2)[NH:26][C:2]=1[CH3:13]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: N=C(N)C1(c2ccc(Cl)cc2Cl)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(C2(c3ccc(Cl)cc3Cl)CC2)nc1-c1ccc(Cl)cc1Cl
Temperature: 85 °C
Reaction time: 12 h

Procedure:
2-Bromo-1-(2,4-dichloro-phenyl)-propane-1-one (28.2 mg, 0.1 mmol), (1-(2,4-Dichloro-phenyl)-cyclopropanecarboxamidine (22.9 mg, 0.1 mmol) and Huenigs Base (20 μl, 0.1 mmol) were dissolved in 1 mL dry DMF and stirred for 12 hours at 85° C. The crude reaction mixture was purified by reversed phase chromatography to provide 4-(2,4-Dichloro-phenyl)-2-[1-(2,4-dichloro-phenyl)-cyclopropyl]-5-methyl-1H-imidazole. (3.9 mg, 9.5%). ESI MS m/z=411.2, 413.2.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.Cl.[O:20]1[C:24]([CH2:25][S:26][CH2:27][CH2:28]N)=[CH:23][CH:22]=[CH:21]1.[O-]CC.[Na+]>C(O)C>[O:20]1[CH:21]=[CH:22][CH:23]=[C:24]1[CH2:25][S:26][CH2:27][CH2:28][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][N:6]=1
Reactant: NCCSCc1ccco1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(NCCSCc2ccco2)ncc1Cc1cccnc1

Procedure:
(b)(i) 2-Nitroamino-5-(3-pyridylmethyl)-4-pyrimidone (12.36 g) was added to a stirred mixture of 2-(5-furylmethylthio)ethylamine hydrochloride (10.65 g) and sodium ethoxide (prepared from 1.26 g sodium) in dry ethanol (300 ml) and the mixture was boiled under reflux for 44 hours and evaporated to dryness. The residue was triturated with water (discarded) and recrystallised from aqueous 2-propanol to give 2-[2-(2-furylmethylthio)-ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 136°-139°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[C:9]([OH:11])=[O:10].N[CH:18](C1C=C(C)C=CC=1)C(O)=O>>[CH3:16][O:15][C:13]([NH:12][CH:8]([C:3]1[CH:4]=[C:5]([CH3:18])[CH:6]=[CH:7][CH:2]=1)[C:9]([OH:11])=[O:10])=[O:14]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1F
Reactant: Cc1cccc(C(N)C(=O)O)c1
Product: COC(=O)NC(C(=O)O)c1cccc(C)c1

Procedure:
Methoxycarbonylamino-m-tolyl-acetic acid was prepared using the procedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid using Amino-m-tolyl-acetic acid. LCMS-ESI+: calc'd for C11H13NO4: 223.08 (M+); Found: 223.90 (M+H+).
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][CH:6]1[C:25](=[O:26])[N:8]2[C:9]([C:22]([OH:24])=[O:23])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH2:20][NH2:21])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[S:4].[C:27](Cl)(=[O:29])[CH3:28]>C(N(CC)CC)C.O.O1CCCC1>[CH3:1][CH2:2][C:3]([NH:5][CH:6]1[C:25](=[O:26])[N:8]2[C:9]([C:22]([OH:24])=[O:23])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH2:20][NH:21][C:27](=[O:29])[CH3:28])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[S:4]
Reactant: CC(=O)Cl
Reactant: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CN)s3)CS[C@H]12
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(C)=O)s3)CS[C@H]12
Yield: 63.8 %

Procedure:
7-methylthioacetamido-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2.0 g.) was dissolved in a mixture of triethylamine (0.9 g.), water (20 ml.) and tetrahydrofuran (30 ml.). To this solution was added dropwise a solution of acetyl chloride (0.53 g.) in tetrahydrofuran (10 ml.) at 0°-5° C. The mixture was stirred at the same temperature for an hour, and then the tetrahydrofuran was distilled off under reduced pressure. The remaining solution was washed with ethyl acetate (100 ml.), adjusted to pH 1 with 10% hydrochloric acid and then extracted with ethyl acetate (200 ml.). The extract was washed with a saturated aqueous solution of sodium chloride, and the ethyl acetate was evaporated under reduced pressure. The residue was washed with acetone and then with ether to give 7-methylthioacetamido-3-(5-acetamidomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.4 g.). m.p. 145°-150° C. (dec.).
Reaction SMILES: OC(C(F)(F)F)=O.F[C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23].[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C.CN(C)C=O>C(OCC)(=O)C>[CH:25]1([NH:31][C:9]2[CH:21]=[CH:20][C:12]([CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][C:10]=2[N+:22]([O-:24])=[O:23])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cc(CN2CCCCC2)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(CN2CCCCC2)ccc1NC1CCCCC1
Yield: 140.2 %

Procedure:
1-(4-Fluoro-3-nitro-benzyl)-piperidine—TFA salt (2.69 g, 0.00764 mol), cyclohexanamine (3.87 mL, 0.0339 mol) and N,N-Diisopropylethylamine (6.00 mL, 0.0344 mol) were dissolved in N,N-dimethylformamide (8.00 mL, 0.103 mol). The mixture was apportioned into four vials and each was microwaved at 300 watts, 130° C. for 7 minutes. The combined reaction mixtures were diluted with ethyl acetate, washed with 5% citric acid, saturated sodium chloride, dried over sodium sulfate and concentrated to give 3.40 g of the title compound as the citrate salt.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:11](N)=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2.S(=O)(=O)(O)[OH:17].C(=O)(O)[O-].[Na+]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:11]([OH:17])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2
Reactant: O=S(=O)(O)O
Reactant: CN(C)CCc1ccc(N)c2[nH]ncc12
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)CCc1ccc(O)c2[nH]ncc12

Procedure:
In an autoclave, 1.2 g of N,N-dimethyl-N-[2-(7-amino-1H-indazol-4-yl)ethyl]amine and 24 ml of 1N sulfuric acid are heated under argon for 16 hours to 180° C. Subsequently the mixture is combined under ice cooling with sodium bicarbonate and extracted by shaking with ethyl acetate/butanol (10:1). The organic phase is dried, concentrated, and the residue is triturated with ethyl acetate, thus obtaining 700 mg of N,N-dimethyl-N-[2-(7-hydroxy-1H-indazol-4-yl)ethyl]amine, mp 233°-234° C., yielding after treatment with methanol and ethereal hydrochloric acid, and recrystallization from methanol/diethyl ether, 680 mg of N,N-dimethyl-N-[2-(7-hydroxy-1H-indazol-4-yl)ethyl]amine, hydrochloride, mp 223°-227° C.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:19])[CH:3]=1.CCN(CC)CC.[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=O.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[CH2:30][C:3]1[C:4](=[O:19])[O:5][C:6]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][C:2]=1[OH:1]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CC(C)CCC1(c2ccccc2)CC(O)=CC(=O)O1
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)CCC1(c2ccccc2)CC(O)=C(Cc2ccccc2Cl)C(=O)O1

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (0.300 g, 1.15 mmol), Et3N (0.17 mL, 1.2 mmol), 2-chlorobenzoyl chloride (0.15 mL, 1.15 mmol), CH2Cl2 (4.0 mL), acetonitrile (4.0 mL), acetone cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (4.0 mL), sodium cyanoborohydride (0.720 g, 11.5 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2) to provide a solid (0.165 g, 51°-53° C.). 1H NMR (400 MHz, DMSO-d6) δ 11.062 (bs, 1 H), 7.425-7.275 (m, 6 H), 7.072 (td, 1 H, J=1.5 Hz, J=7.5 Hz), 6.774 (td, 1 H, J=1.2 Hz, J=7.5 Hz), 6.059 (dd, 1 H, J=1.2 Hz, J=7.5 Hz), 3.428 (AB, 2 H, JAB =16.5 Hz), 3.191 (AB, 2 H, JAB=17 Hz), 1.964-1.884 (m, 2 H), 1.450-1.384 (m, 1 H), 1.163-1.118 (m, 1 H), 0.951 (m, 1 H), 0.802-0.776 (m, 6 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:27][C:28](=[O:30])[CH3:29])[S:14][C:15]=2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[N:31]#[C:32]Br.[OH-].[Na+].C(Cl)Cl>CO.CCOCC>[NH2:31][C:32]1[NH:1][C:2]2[CH:3]=[C:4]([CH2:9][CH2:10][C:11]3[N:12]=[C:13]([NH:27][C:28](=[O:30])[CH3:29])[S:14][C:15]=3[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=3)[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: N#CBr
Reactant: CC(=O)Nc1nc(CCc2ccc(N)c(N)c2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)Nc1nc(CCc2ccc3nc(N)[nH]c3c2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 14 h

Procedure:
To a suspension of N-{4-[2-(3,4-diaminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (70.8 mg) in MeOH (0.7 ml) was added cyanogen bromide (25.3 mg), then the mixture was stirred for 14 h at 20° C. To the reaction mixture was added 1N—NaOH (0.239 ml) and the mixture was concentrated in vacuo. To the residue was added CHCl3:MeOH=10:1 (10 ml), and an insoluble material was removed by filtration. The filtrate was purified by flash column chromatography over NH silica gel with CHCl3/MeOH (100:1→10:1) as an eluent to give colorless oil. The oil was solidified with CH2Cl2: Et2O=2:1 to give N-{4-[2-(2-amino-1H-benzimidazol-6-yl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide as a white solid.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:33])[C@H:7]([CH3:32])[CH2:8][C@@H:9]([C@@H:11]1[CH2:26][C@H:25]([CH3:27])[CH2:24][CH2:23][CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][S:16](=[O:29])(=[O:28])[CH2:15][C@@H:14]([CH3:30])[C:13](=[O:31])[NH:12]1)[OH:10])[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([NH:5][C:6](=[O:33])[C@H:7]([CH3:32])[CH2:8][C@@H:9]([C@@H:11]1[CH2:26][C@H:25]([CH3:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][S:16](=[O:28])(=[O:29])[CH2:15][C@@H:14]([CH3:30])[C:13](=[O:31])[NH:12]1)[OH:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H]1C[C@H](C)CCC=CCCCCS(=O)(=O)C[C@@H](C)C(=O)N1
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H]1C[C@H](C)CCCCCCCCS(=O)(=O)C[C@@H](C)C(=O)N1

Procedure:
A solution of 74 mg (0.15 mmol) (2R,4S)-N-butyl-4-(-(3S,6S,8R)-3,8-dimethyl-1,1,4-trioxo-1lambda*6*-thia-5-aza-cyclohexadec-11-en-6-yl)-4-hydroxy-2-methyl-butyramide in 5 ml MeOH is stirred in the presence of 20 mg 10% Pd—C under a hydrogen atmosphere for 1 h. The mixture is filtered over a pad of celite and the solvent evaporated. The residue is crystallized from toluene and the title compound is isolated as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25](O)=[O:26]>>[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25]([NH:13][CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([O:16][CH2:17][CH3:18])[CH:4]=2)[CH2:8][CH2:9]1)=[O:26]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: Nc1cncc(C(=O)O)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(N)c3)CC2)ccc1Cl
Yield: 37 %

Procedure:
The title compound (0.18 g, 37%) was prepared analogously to example 28 from 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine and 5-aminonicotinic acid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1.[CH:18](=[O:20])[CH3:19]>C1COCC1>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[C:11]=1[CH:18]([OH:20])[CH3:19]
Reactant: Clc1cc(Cl)cc(Cl)c1
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)cc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of LDA (3 mL, 6 mmol) in THF (5 mL) was added 1,3,5-trichlorobenzene (0.91 g, 5.0 mmol) in THF (3 mL) at −78° C. under nitrogen, the resulting mixture was stirred at −78° C. for 1 h, then a solution of acetaldehyde (0.33 g, 7.5 mmol) in THF (3 mL) was added. The mixture was slowly warmed to rt. The mixture was quenched with water (10 mL), and diluted with EtOAc (50 mL). The organic phase was separated, washed with brine (10 mL), and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography (Hex:EtOAc=95:5→90:10) to give the title compound as a colorless oil. 1H NMR (CDCl3): δ 1.62 (d, J=6.8 Hz, 3H), 2.76 (d, J=9.9 Hz, 1H, —OH), 5.55 (m, 1H), 7.32 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[S:14]([Cl:13])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc(OC)cc(OC)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(S(=O)(=O)Cl)c(OC)c1
Yield: 47.2 %

Procedure:
According to a method described in [C. M. Paleos et al., J. Org. Chem. 39(24), 3594, (1974)], 16.8 g (0.1 mole) of 1,3,5-trimethoxybenzene was reacted with 35.0 g of chlorosulfonic acid in 250 ml of chloroform at −5 to 0° C., and after the reaction, the reaction solution was treated after a conventional manner, and 15.2 g of the residue was crystallized from n-hexane, filtered and dried to give 12.6 g of 2,4,6-trimethoxybenzenesulfonyl chloride as a pinkish prism crystal.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]([F:25])([F:24])[C:5]([F:23])([F:22])[O:6][C:7]([F:21])([F:20])[C:8]([F:19])([F:18])[C:9]([F:17])([F:16])[CH2:10][O:11][CH2:12][CH2:13][CH2:14]Cl.[CH2:28]([C:37]1[CH:38]=[N:39][C:40]([C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)=[N:41][CH:42]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:28]([C:37]1[CH:38]=[N:39][C:40]([C:43]2[CH:44]=[CH:45][C:46]([O:49][CH2:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([F:17])([F:16])[C:8]([F:19])([F:18])[C:7]([O:6][C:5]([F:23])([F:22])[C:4]([F:25])([F:24])[O:3][C:2]([F:27])([F:26])[F:1])([F:21])[F:20])=[CH:47][CH:48]=2)=[N:41][CH:42]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)COCCCCl
Product: CCCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(4-(2-(trifluoromethoxy)tetrafluoroethoxy)-2,2,3,3,4,4-hexafluorobutoxy)propyl chloride (6.7 g, 14.6 mmol, prepared from 1,3-dicloropropane and 4-(2-(trifluoromethoxy)tetrafluoroethoxy)-2,2,3,3,4,4-hexafluorobutanol) with 5-nonyl-2-(4-hydroxyphenyl)pyrimidine (4.32 g, 14.6 mmol). The resulting crude product was purified by recrystallization from ethanol, Kugelrohr distillation, followed by chromatography on silica, eluting with hexane/ethyl acetate (10 vol. % ethyl acetate) to provide a yield of 4.3 g.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=O)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:31])[CH3:30])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][CH2:22][C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:31])[CH3:30])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)c1cccs1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1NCc1cccs1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 61 %

Procedure:
By using N-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-2-thiophenecarboxamide, the title compound was synthesized according to Example 2b. Yield: 61%. Melting point: 101-103° C. (Methanol)
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[S:7][C:6]=1[C:15]([NH2:17])=[O:16].C([O-])(O)=O.[Na+].[C:23]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CC1C=CC(S(O)(=O)=O)=CC=1.[O-]S([O-])(=O)=O.[Mg+2]>CN(C=O)C.CCOC(C)=O>[CH3:3][N:4]1[C:5]2[CH:9]=[C:8]([C:10]3[CH:14]=[N:13][NH:12][CH:11]=3)[S:7][C:6]=2[C:15](=[O:16])[NH:17][C:23]21[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2
Reactant: O=C1CCCCC1
Reactant: CNc1cc(-c2cn[nH]c2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1c2cc(-c3cn[nH]c3)sc2C(=O)NC12CCCCC2
Yield: 16.5 %

Procedure:
A mixture of 3-(methylamino)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide dihydrochloride (145 mg, 0.491 mmol), saturated aqueous NaHCO3 (50 mL) and EtOAc (50 mL) was shaken well. The organic layer was collected, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was mixed with cyclohexanone (2 mL, 19.3 mmol), PTSA (93 mg, 0.491 mmol), MgSO4 (118 mg, 0.982 mmol) and DMF (2 mL). This mixture was stirred at 80° C. overnight. The mixture was poured into saturated aqueous NaHCO3 and extracted with 3:1 EtOAc/THF (100 mL), and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH) to afford a yellow solid. This solid was triturated with EtOAc/hexane, and the precipitate was collected by filtration to afford the title compound (24.5 mg, 16%) as a yellow solid:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.Cl[CH2:23][CH2:24][CH2:25][N:26]([CH3:31])[CH:27]1[CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:27]1([N:26]([CH3:31])[CH2:25][CH2:24][CH2:23][O:21][C:18]2[CH:19]=[CH:20][C:15]([C:9]3([CH2:8][NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:16][CH:17]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CN(CCCCl)C1CCC1
Reactant: Oc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCOc1ccc(C2(CNc3ccccn3)CCOCC2)cc1)C1CCC1
Yield: 29.6 %

Procedure:
4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol (386 mg, 1.36 mmol), N-(3-chloropropyl)-N-methylcyclobutanamine (241 mg, 1.496 mmol) and potassium carbonate (280 mg, 2.03 mmol) were stirred in DMF (2 ml) at 45° C. for 24 hours until complete. Reaction was partitioned between ethyl acetate (40 ml) and saturated sodium bicarbonate solution (50 ml), then the organic layer washed with water (50 ml). Organic layer separated and dried over sodium sulphate, filtered and concentrated in vacuo. Crude product purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 90:10:1 by volume) to give the title compound (165 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 1.55-1.72 (m, 2H), 1.80-1.99 (m, 6H), 2.00-2.09 (m, 2H), 2.10-2.20 (m, 4H), 2.40 (t, 2H), 2.80 (quintet, 1H), 3.50 (d, 2H), 3.54-3.62 (m, 2H), 3.78-3.88 (m, 2H), 4.00 (m, 3H), 6.20 (d, 1H), 6.50 (t, 1H), 6.92 (d, 2H), 7.22 (d, 2H), 7.32 (t, 1H), 8.00 (d, 1H). LRMS APCI+ m/z 410 [MH]+. HRMS ESI+ m/z 410.2794[MH]+.