Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[C:18]([Br:26])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Li+].[BH4-]>C1COCC1.CCOCC.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:25]=[CH:24][C:19]([CH2:20][OH:21])=[C:18]([Br:26])[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(CO)c(Br)c1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
Methyl 4-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-bromobenzoate (4.12 g, 9.9 mmol) was added to a solution of LiBH4 (429 mg, 19.8 mmol) in THF/ether/H2O (20/20/1 mL) and was allowed to stir at 25° C. After 16 hours, the reaction was quenched with H2O (10 mL). The reaction mixture was diluted with dichloromethane (25 mL) and was extracted with 1N HCl (30 mL×3) and brine (30 mL). The organic extracts were dried over Na2SO4 and evaporated. The crude product was purified by chromatography on silica gel (eluting with 0-100% ethyl acetate in hexanes) to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)phenyl)cyclopropanecarboxamide (2.84 g, 74%). ESI-MS m/z calc. 389.0, found 390.1 (M+1)+; retention time 2.91 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:53]([F:56])([F:55])[F:54])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH:12]3[CH2:15][CH:14]([N:16]([CH2:20][C@@H:21]4[C@H:25]5[O:26]C(C)(C)[O:28][C@H:24]5[C@H:23]([N:31]5[C:35]6[N:36]=[CH:37][N:38]=[C:39]([NH:40]CC7C=CC(OC)=CC=7OC)[C:34]=6[CH:33]=[CH:32]5)[CH2:22]4)[CH:17]([CH3:19])[CH3:18])[CH2:13]3)[NH:7][C:6]=2[CH:52]=1>FC(F)(F)C(O)=O.O>[NH2:40][C:39]1[C:34]2[CH:33]=[CH:32][N:31]([C@@H:23]3[CH2:22][C@H:21]([CH2:20][N:16]([CH:14]4[CH2:13][CH:12]([CH2:11][CH2:10][C:8]5[NH:7][C:6]6[CH:52]=[C:2]([Cl:1])[C:3]([C:53]([F:55])([F:54])[F:56])=[CH:4][C:5]=6[N:9]=5)[CH2:15]4)[CH:17]([CH3:19])[CH3:18])[C@@H:25]([OH:26])[C@H:24]3[OH:28])[C:35]=2[N:36]=[CH:37][N:38]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(C(F)(F)F)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)N(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(F)(F)F)c(Cl)cc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-((3aS,4R,6R,6aR)-6-(((3-(2-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (525 mg, 0.683 mmol) was dissolved in a mixture of Trifluoroacetic Acid (9 ml) and Water (1 ml) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, then warmed to RT. After 4 h at RT, the mixture was concentrated. The residue was taken up in 20 ml MeOH and concentrated. This procedure was repeated twice and the residue placed on high vacuum. The material was taken up in 15 ml MeOH (gave a slurry) and was treated with 500 mg K2 CO3 and 15 drops of water. The mixture was allowed to stir for 1 hr, during which time the solution was found to be basic. The mixture was filtered through a fine frit, the solids were washed with 10 ml MeOH and the filtrate was concentrated to yield an off white solid. The material was left on high vacuum overnight. The crude material was purified by flash chromatography (SiO2, eluting with 12% 7N NH3 in CH3OH/CH2Cl2) to give a colorless glass/stiff foam. 1H NMR (400 MHz, MeOD) δH ppm 8.06 (s, 1 H), 7.89 (d, J=2.07 Hz, 1 H), 7.69 (d, J=2.28 Hz, 1 H), 7.21 (dd, J=3.42, 1.76 Hz, 1 H), 6.59 (d, J=3.52 Hz, 1 H), 4.33 (t, J=6.84 Hz, 1 H), 3.89 (q, J=5.25 Hz, 1 H), 3.03 (m, 0.5 H), 2.89 (m, 2 H), 2.70 (m, 0.5 H), 2.49 (m, 1 H), 2.40 (m, 2 H), 2.27 (br. s., 2 H), 2.16 (d, J=7.26 Hz, 4 H), 2.06 (m, 2 H), 1.91 (m, 2 H), 1.62 (m, 1 H), 1.52 (m, 1 H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([C:38]1[CH:49]=[CH:48][C:41]([C:42](N(OC)C)=[O:43])=[CH:40][N:39]=1)#[N:37]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:42]([C:41]2[CH:48]=[CH:49][C:38]([C:36]#[N:37])=[N:39][CH:40]=2)=[O:43])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1ccc(C#N)nc1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3ccc(C#N)nc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and 6-cyano-N-methoxy-N-methylnicotinamide.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)[CH:8]=[O:9].[C:11]1([N:17]2[C:21](O)=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[Cl:3][C:21]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]=1[CH:8]=[O:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Solvent: O
Product: O=Cc1c(C(F)(F)F)nn(-c2ccccc2)c1Cl
Yield: 79.3 %

Procedure:
33.6 g (219.1 mmoles) of phosphorus oxychloride was added to 7.7 g (105.2 mmoles) of N,N-dimethylformamide with ice-cooling. Thereto was added, at room temperature, 20 g (87.7 mmoles) of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol. The resulting mixture was refluxed for: 1 hour with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water with ice-cooling, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 19.1 g (yield: 79.1%) of 5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde as white crystals.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:35])[F:34])[CH2:6][NH:7][C:8]([C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:9].Cl[C:38]1[S:39][C:40]2[C:45]([Cl:46])=[N:44][C:43]([CH:47]3[CH2:49][CH2:48]3)=[N:42][C:41]=2[N:50]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:34])[F:35])[CH2:6][NH:7][C:8]([C@H:10]1[CH2:15][N:14]([C:38]2[S:39][C:40]3[C:45]([Cl:46])=[N:44][C:43]([CH:47]4[CH2:48][CH2:49]4)=[N:42][C:41]=3[N:50]=2)[CH2:13][CH2:12][N:11]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:17])=[O:18])=[O:9]
Reactant: Clc1nc2nc(C3CC3)nc(Cl)c2s1
Reactant: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a mixture of the crude product (about 0.095 mmol) obtained in Step 5 and 2,7-dichloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidine (24 mg) in chloroform (1.0 ml) was added N,N-diisopropylethylamine (42 μl) at room temperature. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:10) to give the title compound (52 mg). 1H-NMR (CDCl3, 300 MHz) δ: 1.03-1.09 (2H, m), 1.17-1.22 (2H, m), 2.18-2.27 (1H, m), 3.14-3.35 (2H, m), 3.43-3.53 (1H, m), 3.96 (1H, d, J=13.6 Hz), 4.22-4.36 (2H, m), 4.45-4.69 (3H, m), 6.97-7.06 (3H, m), 7.20 (1H, t, J=8.5 Hz), 7.83 (2H, d, J=8.3 Hz), 8.02 (2H, d, J=8.3 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:17](=[O:20])[CH2:18][Cl:19])[C:12]([O:14][CH2:15]C)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:21]/[C:22](/[CH3:28])=[CH:23]\[C:24]([O:26][CH3:27])=[O:25].[CH3:29]CO>>[NH2:21][C:22](=[C:23]([C:24]([O:26][CH2:27][CH3:29])=[O:25])[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH:11]([C:12]([O:14][CH3:15])=[O:13])[C:17](=[O:20])[CH2:18][Cl:19])[CH3:28]
Reactant: CCO
Reactant: COC(=O)/C=C(/C)N
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CCl
Product: CCOC(=O)C(=C(C)N)C(c1cccc([N+](=O)[O-])c1)C(C(=O)CCl)C(=O)OC

Procedure:
A mixture of ethyl 2-(m-nitrophenylmethylene)-4-chloro-3-oxobutanoate (80 g) and methyl 3-aminocrotonate (32.7 g) in EtOH (800 ml) is heated to reflux temperature for 15 minutes, then, without isolating the formed intermediate, 2-amino-7-chloro-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-oxo-2-heptene, the mixture is cooled at 0° C. and acidified with aqueous concentrated HCl (3 ml). After two hours the reaction mixture is neutralized with a few drops of a saturated NaHCO3 solution and evaporated to dryness. The residue is dissolved in AcOEt (400 ml), washed with water (4×50 ml), dried on Na2SO4 and concentrated in vacuum. The residue is dissolved in Et2O to give 80 g of 2-chloromethyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (m.p. 119°-120° C.).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CC1[CH:8]=[N:9][C:10]2[CH:11]([CH3:17])[CH2:12][CH2:13][CH2:14]C=2C=1.[Si]([N:25]=[C:26]=[S:27])(C(C)(C)C)(C)C>CCCCCC.O1CCCC1.C1C=CC=CC=1>[CH3:4][C:3]1[CH:8]=[N:9][C:10]2[C:11]([CH3:17])([C:26](=[S:27])[NH2:25])[CH2:12][CH2:13][CH2:14][C:1]=2[CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)N=C=S
Reactant: Cc1cnc2c(c1)CCCC2C
Reactant: [Li]CCCC
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cnc2c(c1)CCCC2(C)C(N)=S
Yield: 75 %

Procedure:
A 1.55 molar solution of butyl lithium in hexane (12.9 ml, 20 mM) maintained below 10° was treated with a solution of 5,6,7,8-tetrahydro-3,8-dimethylquinoline (3.22 g, 20 mM) in tetrahydrofuran (10 ml). After 0.5 hours a 22% solution of t-butyldimethylsilyl isothiocyanate in benzene (13.7 g, 20 mM) was added dropwise. After a further 0.5 hours the reaction was quenched with water (100 ml.) then acidified (to pH1). After 1 hour the layers were separated, the aqueous layer basified (to pH9) and extracted with dichloromethane (2×50 ml). The organic extracts were dried and evaporated. Recrystallisation of the residue from toluene gave the title thioamide (3.3 g, 75%) mp. 160°-2°
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13].C1(C)C=CC=CC=1.C(C(C)=[O:30])C>C(O)(C)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13].[C:12]([OH:14])(=[O:13])[C:11]1[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:30]
Reactant: CCC(C)=O
Agent: CCCCCCCCCCCC(=O)OCC(O)CO
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1O
Yield: 10 %

Procedure:
A fluid solution of 20.0% Lauricidin, 10.0% salicylic acid, and 10.0% DOSS surfactant in isopropanol was prepared by stirring the mixture until the Lauricidin was dissolved. 20% of the fluid solution was combined with 80% of the hardcoat mixture described in Examples 1-11 (i.e., 100 parts of 3M 906 Hardcoat with 12 parts toluene and 12 parts methyl ethyl ketone). The combined solution was coated and cured as described in Examples 1-11. The resulting multi-layer film was clear and transparent. The resulting multi-layer film was then tested for microbial load reduction, as described above in Examples 1-11, and gave 100% microbial load reduction for gram positive pathogens and 99.4% microbial load reduction for gram negative pathogens.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][O:6][CH2:5]1.Cl[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[O:6]1[CH2:7][CH2:8][C@H:4]([O:3][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:5]1
Reactant: O[C@H]1CCOC1
Reactant: ClCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CO[C@H]2CCOC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A 3-neck flask under a nitrogen-line was charged with anhydrous THF (600 mL) through a canule. NaH (60% dispersion in mineral oil, 21.16 g, 0.529 mol, 1.5 eq) was suspended in the solvent under vigorous stirring. (S)-(+)-3-hydroxytetrahydrofuran (34.14 g, 0.388 moL, 1.1 eq) was added and stirred at room temperature for 30 minutes. 2-Chloromethylpyridine (1a; 45.00 g, 0.353 mol, 1 eq) was added neat and the mixture was stirred at reflux for 16 hours. The reaction mixture was cooled to room temperature and quenched with 520 mL saturated aqueous ammonium chloride solution. THF was removed under reduced pressure and the aqueous residue was extracted with 2×800 mL ethyl acetate. The combined organic extracts were washed with 250 mL saturated brine, dried over Na2SO4 and evaporated to dryness. The brown oily residue was taken up in 520 mL acetonitrile and remaining mineral oil was extracted with 330 mL hexane. Acetonitrile was evaporated in vacuo to leave a brown residue, yield 87%; LC-MS Retention time 1.22 min; (M+H)+ 180.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[N+:22]([O-])=O>CO.[Pd].[H][H]>[CH3:1][NH:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[NH2:22]
Reactant: CNc1ccc(C(=O)C2(CC(=O)OC)CCCCC2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(C(=O)C2(CC(=O)OC)CCCCC2)cc1N

Procedure:
Prepared analogously to Example 1c from methyl [1-(4-methylamino-3-nitro-benzoyl)-cyclohexyl]-acetate and palladium on activated charcoal/hydrogen in methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=C)[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6]2.C[OH:18]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([CH:13]=[O:18])=[CH:11][C:10]2[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: C=Cc1cc2c(nc1OC)CCC(=O)N2C
Reactant: CO
Solvent: ClCCl
Product: COc1nc2c(cc1C=O)N(C)C(=O)CC2
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A 1.1 g (5.0 mmol) solution of 6-methoxy-1-methyl-7-vinyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one in 50 ml of methylene chloride and 10 ml of methanol was cooled to −70° C. Ozone (via an ozone generator) was bubbled into the solution until a blue color was achieved. The reaction mixture was stirred at −70° C. for 30 minutes and quenched with 4.0 ml of dimethyl sulfide. The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into 50 ml of water. The organic layer was dried (Na2SO4) and evaporated. This residue was chromatographed on silica using 10:1 chloroform/ethyl acetate as the elutant. Appropriate fractions were combined to yield 0.52 g of 2-methoxy-5-methyl-6-oxo-5,6,7,8-tetrahydro-[1,5]naphthyridine-3-carbaldehyde. TLC Rf=0.4 (1:1 ethyl acetate:hexane). 1H NMR (CDCl3) δ 10.18 (s, 1H), 7.7 (s, 1H), 4.05 (s, 3H), 3.3 (s, 3H), 3.0 (m, 2H), 2.7 (m, 2H). Mass spectrum: m/e=221.1, (p+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](Cl)=[N:6][OH:7].[CH3:12][CH:13]([OH:16])[C:14]#[CH:15].C(N(CC)CC)C>C1C=CC=CC=1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH:15]=[C:14]([CH:13]([OH:16])[CH3:12])[O:7][N:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C#CC(C)O
Reactant: ON=C(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(O)c1cc(-c2cccc(Cl)c2)no1
Temperature: 0 °C

Procedure:
3-Chloro-benzohydroximoyl chloride (e.g. Kim, Jae Nyoung; Ryu, Eung K; J. Org. Chem. (1992), 57(24), 6649-50) (2.84 g, 14.8 mmol) was suspended in benzene (50 ml) and cooled to 0° C. 3-Butyn-2-ol (2.10 g, 29.9 mmol) and triethylamine (1.89 ml, 26.7 mmol) were added. The mixture was heated to 60° C. for 1.5 houes, cooled and diluted with benzene and 1N aqueous hydrochloric acid. After stirring, the separated benzene layer was evaporated to dryness and the crude purified via flash chromatography over silica using heptane/ethyl acetate=5/1 giving after drying in vacuo the title compound (0.49 g, 15%). 1H NMR (CDCl3), δ (ppm): 1.64 (d, 3 H), 5.07 (dq, 1 H), 6.50 (s, 1 H), 7.40 (m, 2 H), 7.68 (m, 1 H), 7.79 (m, 1 H),
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.O1[CH2:14][CH2:13][NH:12]C1=O>COCCOCCO>[CH3:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:14][CH2:13][NH2:12])=[CH:5][CH:4]=1
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N)cc1
Agent: Cl
Solvent: COCCOCCO
Product: Cc1ccc(NCCN)cc1
Temperature: 170 °C
Yield: 76 %

Procedure:
A mixture of 4-methylaniline hydrochloride (15.0 g, 0.10 mole), 2-oxazolidinone (8.7 g, 0.10 mole) and 40 ml of 2-(2-methoxyethoxy)ethanol was heated in an oil bath to 170° C. for four hours. On cooling to room temperature, a solid formed. Workup as described in Examples 1 and 8, followed by distillation at 110° C. to 120° C. (1.5 mm Hg) gave a 76 percent yield of the material as a clear liquid which slowly solidified on standing at ambient temperatures to a low-melting solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([NH:25][CH3:26])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][C:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl.O>[NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([N:25]([CH3:26])[C:40]([C:34]4([CH3:33])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:41])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: CN[C@H](Cc1ccccn1)CN1CCN(c2cccc3[nH]ccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)C1(C)CCCCC1)[C@H](Cc1ccccn1)CN1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C

Procedure:
To a solution of (2R)-1-[4-(1H-indol-4-yl)piperazin-1-yl]-N-methyl-3-pyridin-2-ylpropan-2-amine (349 mg.; 1 mmol, from Example 20) in dichloromethane (10 mL) at 0° C. is added a solution of potassium carbonate (690 mg.; 5 mmol) in water (1.6 mL), followed by a solution of 1-methyl-1-cyclohexanecarbonyl chloride (160 mg.; 1 mmol) in dichloromethane (1.6 mL). The reaction mixture is stirred while allowing to warm to ambient temperature over 1 hour, diluted with dichloromethane (20 mL), and the layers allowed to separate. The organic layer is dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue is purified by flash chromatography on silica gel (10% methanol/ethyl acetate) to yield the free base of the title compound. The fumarate salt is prepared by treatment with an equimolar amount of fumaric acid in ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].S(C1C=CC(C)=CC=1)(O[CH2:13][CH2:14][F:15])(=O)=O.N1C(C)=CC=CC=1C>CN(C=O)C.C(OCC)(=O)C>[F:15][CH2:14][CH2:13][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Nc1cccc(F)c1
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FCCNc1cccc(F)c1
Yield: 10.1 %

Procedure:
3-Fluoroaniline (1.4 g, 11.6 mmol, 1.2 mL) and 2-fluoroethyl tosylate (12; prepared according to Example 2(a)) (2.5 g, 11.6 mmol) and lutidine (1.24 g, 11.6 mmol) were stirred and heated in DMF (5 mL) at 100° C. overnight. The reaction was allowed to cool and then diluted with ethyl acetate (100 mL). This was washed with, water (3×40 mL) and the organics were dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (10% B, 100 g, 12 CV, 60 mL/min) to afford 184 mg (10%) of (2-fluoro-ethyl)-(3-fluoro-phenyl)-amine (43) as a yellow oil. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 3.37 (1H, q, J=6 Hz, NCH2CH2F), 3.46 (1H, q, J=6 Hz, NCH2CH2F), 4.12 (1H, s, br, NH), 4.54 (1H, t, J=3 Hz, NCH2CH2F), 4.69 (1H, t, J=3 Hz, NCH2CH2F), 6.31-6.50 (3H, m, NCCHCHCH), 7.10-7.25 (1H, m, NCCHCF).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]3[C:23]([C:14]=2[S:13][C:12]1=S)=[CH:22][CH:21]=[CH:20][CH:19]=3.C1(C)C=CC(S(OC)(=O)=O)=CC=1.[CH2:37]([N:39]1[C:43](=[O:44])[CH2:42][S:41][C:40]1=[S:45])[CH3:38].C(#N)C>C(N(CC)CC)C>[CH2:37]([N:39]1[C:43](=[O:44])[C:42](=[C:12]2[N:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:15]3[CH:16]=[CH:17][C:18]4[C:23]([C:14]=3[S:13]2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:41][C:40]1=[S:45])[CH3:38]
Reactant: CCN1C(=O)CSC1=S
Reactant: COCCOCCOCCn1c(=S)sc2c3ccccc3ccc21
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN1C(=O)C(=C2Sc3c(ccc4ccccc34)N2CCOCCOCCOC)SC1=S
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.9 g of 3-methoxyethoxyethoxyethylnaphtho[2,1-d]thiazoline-2-thion and 1.8 g of methyl p-toluenesulfonate were fed into a 50 ml short-neck flask provided with a reflux condenser. The resultant mixture was heated at 120° C. for 4 hours. After cooling the reaction mixture to room temperature followed by addition of 0.8 g of 3-ethylthiazolidine-4-on-2-thion and 24 ml of acetonitrile, the resultant mixture was cooled to 5° C., and 1.0 g of triethylamine was added thereto. After stirring at 10° C. for 24 hours, yellow precipitates thus obtained were suction-filtered, washed with 10 ml of acetonitrile three times, and dried to obtain the intended compound.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[C:27]1([NH2:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([NH:33][S:12]([N:9]2[CH2:10][CH2:11][C:6]3([C:2](=[O:1])[N:3]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=4)[CH2:4][CH2:5]3)[CH2:7][CH2:8]2)(=[O:14])=[O:13])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccccc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Nc1ccccc1)CC2

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and phenylamine. MS (ESI): 440.4 (MH+).
Reaction SMILES: [CH:1]1([C:6]2([CH3:22])[CH2:14][C:13]3[C:8](=[C:9]([Cl:20])[C:10]([Cl:19])=[C:11]([NH:15][CH2:16][C:17]#[N:18])[CH:12]=3)[C:7]2=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+:24]>>[ClH:19].[CH:1]1([C:6]2([CH3:22])[CH2:14][C:13]3[C:8](=[C:9]([Cl:20])[C:10]([Cl:19])=[C:11]([NH:15][CH2:16][C:17](=[NH:24])[NH2:18])[CH:12]=3)[C:7]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [NH4+]
Reactant: CC1(C2CCCC2)Cc2cc(NCC#N)c(Cl)c(Cl)c2C1=O
Agent: [Cl-]
Product: CC1(C2CCCC2)Cc2cc(NCC(=N)N)c(Cl)c(Cl)c2C1=O
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium metal (0.1 g, 4 mg-atom) was added to methanol (50 ml) to form a solution of sodium methoxide. To this solution was added [(2-cyclopentyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)amino]acetonitrile (3.37 g, 10 mmole; see Example 3), and the mixture was stirred for one hour at room temperature. Ammonium chloride (0.6 g, 11 mmole) was added and the mixture was stirred for 16 hours. The mixture was concentrated to dryness in vacuo, and the resultant residue was triturated with boiling benzene, then collected by filtration. The solid was dissolved in ethanol and the resultant solution was diluted with diethyl ether. The precipitate that formed was collected by filtration and dried to yield the title compound.