Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[CH:15][C:14]=2[Cl:20])[CH2:9][CH2:8]1)=[O:6].[CH:21]1([CH:27]=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C([BH3-])#N.[Na+]>CO>[CH:21]1([CH2:27][NH:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[C:14]([Cl:20])=[CH:15][N:16]=[CH:17][C:18]=3[Cl:19])[CH2:11][CH2:12]2)=[O:6])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=CC1CCCCC1
Reactant: NCCNC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(NCCNCC1CCCCC1)C1CCN(c2c(Cl)cncc2Cl)CC1
Reaction time: 2 h
Yield: 23 %

Procedure:
To a solution of N-(2-aminoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide E13 (50 mg, 0.16 mmol) in MeOH (5 mL) was added cyclohexanecarbaldehyde (19 μL, 0.16 mmol). After stirring for 2 h, sodium cyanoborohydride (20 mg, 0.32 mmol) was added and the mixture was stirred for a further 16 h. The solvent was removed under reduced pressure, the residue was dissolved in EtOAc (20 mL), washed with a saturated solution of sodium hydrogencarbonate (25 mL), brine (25 mL), dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 9:1) to furnish the title compound as a white solid (15 mg, 23%), m.p. 174-177° C.; umax (CHCl3)/cm−1 2932, 2856, 1665, 1558, 1457, 1236, 1146, 1037; m/z (ESI) C20H31Cl22N4O requires 413.1869, found [M+H]+ 413.1875.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C1CNCCN1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 111.2 %

Procedure:
A mixture of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (1.0 g, 4.0 mmol), piperazine (860 mg, 10 mmol) and lithium perchlorate (625 mg, 6 mmol) in acetonitrile (15 ml) was heated under reflux for 48 h. The solvent was removed under reduced pressure, the residue was treated with crushed ice and extracted with ethylacetate (3×30 ml). The combined organic extract was washed with water, brine, dried (Na2SO4) and concentrated to give the title compound as thick viscous gum (1.5 g, 78%). The title compound was also prepared by hydrolysis of 2R,3R-2-(2,4-difluorophenyl)-3-(4-ethoxycarbonylpiperazin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol 1 with 2M sodium hydroxide solution.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[C:7]([OH:13])[CH:6]=1)=[O:3].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:1][C:2]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[C:7]([O:13][CH3:14])[CH:6]=1)=[O:3]
Reactant: CC(=O)Nc1cc(O)c(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(NC(C)=O)c(Cl)cc1Cl
Yield: 99.9 %

Procedure:
A stirred mixture of 35.0 g (0.16 mole) of 2,4-dichloro-5-hydroxyacetanilide, 33.1 g (0.24 mole) of potassium carbonate, and 34.1 g (0.24 mole) of methyl iodide in 300 mL of acetone was heated at reflux for approximately 18 hours. The mixture was cooled and filtered. The filtrate was evaporated under reduced pressure to leave 37.4 g of 2,4-dichloro-5-methoxyacetanilide as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[NH:8][C:7]=1[CH3:20])[CH3:2].[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[N:8]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]=1[CH3:20])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(C(=O)OCC)cc12
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1c(C)n(Cc2ccccc2)c2ccc(C(=O)OCC)cc12
Yield: 56.2 %

Procedure:
Using the procedure described in Example 2, Part B, 2.18 g (7.5 mmol) of 5-ethoxycarbonyl-2-methyl-1H-indole-3-acetic acid ethyl ester was reacted with 320 mg (8 mmol) of 60% NaH/mineral oil and 1.0 mL (8.4 mmol) of benzyl bromide to give after silica chromatography (25% ether/hexane→50% ether/hexane) 1.6 g (56%) of 5-ethoxycarbonyl-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ester.
Reaction SMILES: C[O:2]C(=O)C=CC1C2N(C3C=CC=CC=3)C(C(F)(F)F)=NC=2C=CC=1.CN1[CH2:32][CH2:31][N:30]([C:33](=[O:55])[CH:34]=[CH:35][C:36]2[C:44]3[N:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:42]=[N:41][C:40]=3[CH:39]=[C:38]([C:51]([F:54])([F:53])[F:52])[CH:37]=2)[CH2:29][CH2:28]1>>[N:30]1([C:33](=[O:55])[CH:34]=[CH:35][C:36]2[C:44]3[N:43]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:42]=[N:41][C:40]=3[CH:39]=[C:38]([C:51]([F:53])([F:54])[F:52])[CH:37]=2)[CH2:31][CH2:32][O:2][CH2:28][CH2:29]1
Reactant: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Reactant: COC(=O)C=Cc1cccc2nc(C(F)(F)F)n(-c3ccccc3)c12
Product: O=C(C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12)N1CCOCC1
Yield: 60 %

Procedure:
This was prepared from 3-(3-phenyl-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one to afford the title compound as a white solid (350 mg, 60%), m/z 402.2 (M+H)+.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[C:15]([CH2:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH2:20][CH2:21][C:22](OCC)=[O:23])#[N:16].C(OCC)(=O)C>C1C=CC=CC=1>[OH:23][CH2:22][CH2:21][CH2:20][C:19]1[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=1[CH2:17][C:15]#[N:16]
Reactant: CCOC(=O)CCc1ccccc1CC#N
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: N#CCc1ccccc1CCCO

Procedure:
A 70% solution in benzene of sodium bis(2-methoxyethoxy)aluminum hydride (95.2 g., 0.33 mole of reagent) is added dropwise during one hour to a stirred solution of ethyl o-(cyanomethyl)hydrocinnamate (65.0 g., 0.3 mole) in benzene (250 ml.). The reaction mixture is held at 25°-28° C. by means of a cold water bath. The mixture is stirred at 25°-28° C. for 4 additional hours. Ethyl acetate (5 ml.) is added to destroy excess reducing agent. The mixture is then treated with 250 ml. ice-cold 5% hydrochloric acid. The benzene layer is separated, washed with water, and dried over sodium sulfate. Evaporation of the benzene in vacuo affords [2-(3-hydroxypropyl)phenyl]acetonitrile.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4].[OH-:11].[Na+].CO.O.Cl>C(OCC)(=O)C>[Br:10][C:8]1[C:9]([OH:11])=[C:5]([C:3]([OH:2])=[O:4])[S:6][CH:7]=1
Reactant: COC(=O)c1cc(Br)cs1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1scc(Br)c1O
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A mixture of 4-bromothiophene-2-carboxylic acid methyl ester (500 mg, 2.1 mmol), sodium hydroxide (261 mg, 6.3 mmol) in a mixed solvent of methanol/water (2.5 mL+2.5 mL) was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 2N hydrochloric acid was added to adjust pH to 1, and it was diluted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound (326 mg, 69.4%) as a red brown powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:36])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:35][C:31]1[CH:30]=[C:29]([C:27]2[CH2:26][C:25](=[O:36])[NH:24][C:9]3[CH:10]=[C:11]([C:20]([F:22])([F:23])[F:21])[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])=[CH:13][C:8]=3[N:7]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(Br)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2

Procedure:
) The title compound was prepared from the above described {2-[3-(3-bromo-phenyl)-3-oxo-propionylamino]-5-(isobutyl-methyl-amino)-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (1.01 g, 1.72 mmol) and TFA (6.5 mL) in DCM (20 mL) according to general procedure I step 2. Obtained as a white solid (0.65 g, 81%). MS (ISP) 468.0 [(M+H)+]; mp 186° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[NH:7][C:8](I)([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:9]=[CH:10][CH:11]=1.[CH2:29]([O:31]C=C[Sn](CCCC)(CCCC)CCCC)[CH3:30]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[NH:7][C:8]([C:29](=[O:31])[CH3:30])([O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)CCC1=CC=CC(I)(OCCCC/C=C/c2ccc(OC)cc2)N1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)CCC1=CC=CC(OCCCC/C=C/c2ccc(OC)cc2)(C(C)=O)N1
Temperature: 110 °C
Yield: 23.1 %

Procedure:
A solution of 495 mg of 3-{6-iodo-3-[6-(4-methoxyphenyl-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester and 397 mg of ethoxyvinyltributyltin in 2 ml of toluene is mixed with 30 mg of bis-triphenylphosphine-palladium(II) chloride and heated for six hours with stirring to 110° C. The reaction mixture is filtered on diatomaceous earth, the filter residue is washed with diethyl ether, the filtrate is mixed with 1.5 ml of 2n hydrochloric acid and stirred for 4 hours at room temperature. The organic phase is separated, dried with sodium sulfate and concentrated by evaporation. 95 mg of 3-{6-acetyl-3-[6-(4-methoxyphenyl-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:55]1([CH2:60][C@@H:61]2[CH2:66][CH2:65][CH2:64][NH:63][CH2:62]2)[CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:63]2[CH2:64][CH2:65][CH2:66][C@@H:61]([CH2:60][N:55]3[CH2:56][CH2:57][CH2:58][CH2:59]3)[CH2:62]2)=[O:32])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: C1CNC[C@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@@H](CN2CCCC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.5 %

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (0.2 g, 0.4 mmol), HOBt (54 mg, 1 eq.), EDAC (77 mg, 1 eq.) in DMF (1.5 mL) was stirred at rt for 10 mins. To the mixture was added (R)-3-pyrrolidin-1-ylmethyl-piperidine (0.2 g, 3 eq.). After stirring at rt for over the weekend, the precipitate was collected by vacuum filtration, washed with water, sodium bicarbonate and water. The solid was then purified on a silica gel column to give 101 mg (46%) of the titled compound.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)[CH2:6]1)=O.C(=O)([O-])[O-].[K+].[K+].[ClH:30].C(OCC)C>CO>[ClH:30].[ClH:30].[N:16]1([CH2:15][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH2:6][NH:5][CH2:14][CH2:13]3)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(N1CCc2cc(CN3CCCCC3)ccc2C1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: c1cc2c(cc1CN1CCCCC1)CCNC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2,2,2-Trifluoro-1-(6-(piperidin-1-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (1.88 g, 5.76 mmol) was dissolved in methanol (23 ml); potassium carbonate (1.99 g, 14.4 mmol) was added and the reaction mixture was stirred for 15 h at RT. The solvent was then removed under vacuum, and the residue was taken up in dichloromethane and washed with water (15 ml). The aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was taken up in an acetone/diethyl ether mixture, and the hydrochloride was precipitated with 2 M hydrogen chloride in diethyl ether (3 equiv.) and, after being filtered out with suction, was dried under vacuum. Yield: 1.62 g (93%)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]1([CH3:21])[CH3:20].[Cl:22]OC(C)(C)C>CO>[Cl:22][N:14]1[C:15]([CH3:19])([CH3:18])[C:16](=[O:17])[N:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:13]1([CH3:21])[CH3:20]
Reactant: COCCOCCOCCCN1C(=O)C(C)(C)NC1(C)C
Reactant: CC(C)(C)OCl
Solvent: CO
Product: COCCOCCOCCCN1C(=O)C(C)(C)N(Cl)C1(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
A solution of 3-(3-(2-(2-methoxyethoxy)ethoxy)propyl)-2,2,5,5-tetramethylimidazolidin-4-one (182 g, 0.60 mmol) in methanol (10 mL) was cooled in ice water for 10 minutes, before neat tert-butyl hypochlorite (0.10 mL, 0.9 mmol, 1.5 equiv.) was added in one portion. High pressure liquid chromatography-mass spectroscopy analysis after 5 minutes showed all starting amine had been consumed. After 20 min, the mixture was concentrated in vacuo to an oil, which was absorbed on silica (1 g). Chromatography on silica (0-4% methanol in dichloromethane) afforded the title compound as a colorless oil (193 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 3.66-3.62 (m, 4H), 361-3.58 (m, 2H), 3.56-3.53 (m, 2H), 3.51 (t, J=6.0 Hz, 2H), 3.38 (s, 3H), 3.35-3.30 (m, 2H), 1.96-1.88 (m, 2H), 1.45 (s, 6H), 1.33 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 172.6, 82.1, 71.9, 70.59, 70.54, 70.13, 68.6, 65.3, 59.0, 38.2, 29.1, 25.1, 23.5; LRMS (ESI/APCI) m/z 337 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[C:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])[CH3:24]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]4[CH2:30][CH2:31][N:26]([C:23](=[O:25])[CH3:24])[CH2:27][CH2:28]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CC(=O)N1CCNCC1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CC(=O)N1CCN(CCCCOc2ccc3c(-c4ccc(Br)cc4)nsc3c2)CC1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 1-Acetylpiperazine were converted to yield 1-(4-(4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl)-piperazin-1-yl)-ethanone as white solid, MS: 488(MH+, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1/[CH:4]=[C:16](/[C:15]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=1)\[C:17]#[N:18]
Reactant: O=Cc1c(F)cccc1F
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2c(F)cccc2F)cc1OC
Yield: 59.5 %

Procedure:
2,6-Difluorobenzaldehyde (284 mg) and 3,4-dimethoxybenzyl cyanide (354 mg) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (358 mg, yield: 40%).
Reaction SMILES: Cl[C:2]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[CH:6][CH:5]=1)=[O:3].[CH3:24][NH:25][CH3:26]>C1(C)C=CC=CC=1>[CH3:24][N:25]([CH3:26])[C:2](=[O:3])[C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[CH:6][CH:5]=1
Reactant: CNC
Reactant: Cc1cc(CCCCCCCOc2ccc(C(=O)Cl)cc2)on1
Solvent: Cc1ccccc1
Product: Cc1cc(CCCCCCCOc2ccc(C(=O)N(C)C)cc2)on1

Procedure:
A solution of 8.0 g of 5-[7-(4-chlorocarbonylphenoxy)heptyl]-3-methylisoxazole in 50 ml of dry toluene was saturated with dimethylamine gas over a 30 minute period. The reaction mixture was concentrated in vacuo, and the residue was dissolved in ether. The ether solution was boiled, treated with petroleum ether until turbid and cooled to produce 6.0 g of N,N-dimethyl-4-[7-(3-methyl-5-isoxazolyl)heptyloxy]benzamide, m.p. 58°-59° C.; MIC vs. polio-2 virus in vitro=2.5 μg/ml.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].S(=O)(=O)(O)O.[CH3:18]O>>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:18])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CO
Reactant: N#Cc1cccc(CC(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(C#N)c1
Temperature: 70 °C
Yield: 84 %

Procedure:
To the solution 2-(3-cyanophenyl)acetic acid (700 mg, 43.4 mmol) in methanol was slowly added sulfuric acid (0.42 mL, 4.34 mmol) at room temperature. The reaction mixture was refluxed for 3 h at 70° C. under nitrogen atmosphere. TLC showed complete consumption of starting material. The reaction mixture was cooled to room temperature. Solvent was removed in vacuo and extracted with ethyl acetate. The organic part was washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford crude product which was purified by column chromatography to afford methyl 2-(3-cyanophenyl)acetate (660 mg, 84%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:22][C@H:23]2[C@@H:27]3[O:28][C:29]([CH3:32])([CH3:31])[O:30][C@@H:26]3[C@@H:25]([CH2:33][OH:34])[CH2:24]2)=[N:12][C:13](S(C)(=O)=O)=[N:14][C:15]=1[O:16][CH3:17].[CH3:35][CH2:36][Mg+].[Br-]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:22][C@H:23]2[C@@H:27]3[O:28][C:29]([CH3:31])([CH3:32])[O:30][C@@H:26]3[C@@H:25]([CH2:33][OH:34])[CH2:24]2)=[N:12][C:13]([CH2:35][CH3:36])=[N:14][C:15]=1[O:16][CH3:17]
Reactant: COc1nc(S(C)(=O)=O)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1-c1nc2ccccc2s1
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCc1nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c(-c2nc3ccccc3s2)c(OC)n1
Temperature: 0 °C

Procedure:
Compound 8 (100 mg, 0.197 mmol) was dissolved in THF (2 ml) and cooled to 0° C. EtMgBr (0.592 ml, 0.592 mmol, 1.0 M in THF) was added dropwise and stirred at 0° C. The reaction was quenched at 0° C. with sat. NH4Cl, diluted with water and EtOAc. The aqueous layer was extracted with EtOAc three times, dried (MgSO4), filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel, eluting with CH2C2/MeOH to give the title compound as a colorless solid. 1H NMR (CDCl3) δ 10.58 (d, J=6.0 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.46 (t, J=6.8 Hz, 1H), 7.33 (t, J=6.8 Hz, 1H), 4.75-4.69 (m, 2H), 4.63-4.61 (m, 1H), 4.16 (s, 3H), 3.84 (d, J=6.8 Hz, 1H), 2.76 (q, J=6.8, 1.2 Hz, 2H), 2.61-2.53 (m, 1H), 2.45-2.41 (m, 1H), 1.81-1.75 (m, 1H), 1.75 (s, 3H), 1.34 (s, 3H), 1.33 (t, J=6.8 Hz, 3H); LCMS 2.61 min, 457 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([C:15]3C=CC(F)=CC=3)=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[C:24]([CH3:30])[CH:23]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(=O)C(OC)=C(C3C=CC(SC)=C(C)C=3)C=N2)C=CC=1.FC1C=CC([Mg]Br)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[C:24]([CH3:30])[CH:23]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2-c2ccc(F)cc2)cc1C
Agent: COc1c(-c2ccc(SC)c(C)c2)cnn(-c2cccc(Cl)c2)c1=O
Agent: Fc1ccc([Mg]Br)cc1
Product: CSc1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2C)cc1C

Procedure:
2-(3-Chlorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio)phenyl]-3 (2H)-pyridazinone, was prepared according to the method of Example 228, starting with 2-(3-chlorophenyl)-4-methoxy-5-[3-methyl-4-(methylthio)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone and substituting 4-fluorophenyl magnesium bromide in place of cyclohexylmagnesium chloride (yield: 180 mg, 94%). 1H NMR (300 MHz, CDCl3) δ 2.25 (s, 3H), 2.56 (s, 3H), 7.28–7.45 (m, 6H), 7.58–7.63 (m, 1H), 7.71–7.74 (m, 1H), 7.82 (s, 1H). MS (APCI+) m/z 343 (M+H)+ and m/z 360 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([OH:19])(C)[CH3:17])=[N:8]2)=[C:4]([CH3:22])[CH:3]=1.ClC1C=CC(CN2C3C(=CC=CC=3)C(C=O)=N2)=C(C)C=1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]([OH:19])[CH3:17])=[N:8]2)=[C:4]([CH3:22])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1Cn1nc(C(C)(C)O)c2ccccc21
Agent: Cc1cc(Cl)ccc1Cn1nc(C=O)c2ccccc21
Product: Cc1cc(Cl)ccc1Cn1nc(C(C)O)c2ccccc21

Procedure:
The product was obtained using the method described for the preparation of compound 10b, but using as starting material compound 12a (0.4 mol) instead of compound 10a.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:18])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)S[CH2:9][CH2:8][CH:7]2[CH2:15][O:16][CH3:17])(=[O:3])[CH3:2].OO.[S:21](S([O-])=O)([O-:23])=[O:22].[Na+].[Na+]>C(O)(=O)C>[C:1]([C:4]1[C:5]([CH3:18])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:21](=[O:23])(=[O:22])[CH2:9][CH2:8][CH:7]2[CH2:15][O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: COCC1CCSc2c(C)cc(C(C)=O)c(C)c21
Reactant: O=S([O-])S(=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COCC1CCS(=O)(=O)c2c(C)cc(C(C)=O)c(C)c21
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture containing 0.30 g (1.1 mmol) of 6-acetyl-4-methoxymethyl-5,8-dimethylthiochroman, 0.39 ml of a30 wt % hydrogen peroxide aqueous solution and 0.3 ml of acetic acid was allowed to react at 60° C. for 2 hours, and further allowed to react at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, and a 2 wt % sodium hydrosulfite aqueous solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride aqueous solution. An organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off to give 0.32 g (yield 94%) of the titled compound as a crude product.