Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[C:24]([N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)[C:25]#[N:26])=[CH:19][CH:18]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O.O.O.O.C([O-])(=O)C.[Na+]>C(Cl)Cl.C(O)C>[C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[C:24]([N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)[C:25]#[N:26])=[CH:19][CH:18]=3)[N:14]=2)[NH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)n4cncn4)cc3)nc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(Nc3ccc(C=C(C#N)n4cncn4)cc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.4 %

Procedure:
To a 25 ml one necked round bottom flask, 3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)-2-(1H-1,2,4-triazol-1-yl)acrylonitrile (0.052 g, 0.95 mmole) was taken in CH2Cl2 (5 mL). TFA (1.5 mL) was added drop wise at 0° C. After completion of the addition, the reaction mass was warmed up to RT and stirred for 16 hrs at the same temperature. After completion of the reaction, CH2Cl2 was distilled out to get solid. The solid was taken in ethanol (10 mL) and sodium acetate trihydrate (0.130 g, 0.95 mmole) was added at RT. The reaction mixture was stirred for 20 hrs at RT. After completion of the reaction the ethanol was distilled out under vacuum. To the residue, water (20 mL) was added and stirred for 15 min, filtered and wash with water and n-pentane. The solid was dried under vacuum to yield 21 mg of 3-(4-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)-2-(1H-1,2,4-triazol-1-yl)acrylonitrile.
Reaction SMILES: S(Cl)(Cl)=O.ClC1C(C(O)=O)=C(C2C=CC=CC=2)C=CN=1.[CH2:21]([NH2:24])[CH2:22][NH2:23].CS(O[CH2:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=1)(=O)=O>C1COCC1.CN(C=O)C>[F:38][C:37]([F:39])([F:40])[C:35]1[CH:36]=[C:31]([CH:32]=[C:33]([C:41]([F:44])([F:42])[F:43])[CH:34]=1)[CH2:30][NH:23][CH2:22][CH2:21][NH2:24]
Reactant: CS(=O)(=O)OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCCN
Agent: O=C(O)c1c(-c2ccccc2)ccnc1Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (0.15 ml) and DMF (catalytic amount) were added to a THF (5 ml) solution of 2-chloro-4-phenyl-3-pyridinecarboxylic acid (145 mg) and heated under reflux for 2 hours. The solvent was removed by distillation, and the residue was dissolved in THF (5 ml). The resulting solution was added to a mixture of N-[3,5-bis(trifluoromethyl)benzyl]-N'-tert-butoxycarbonylethylenediamine (240 mg), triethylamine (0.26 ml) and THF (10 ml), while cooling with ice, and stirred for 3 hours at room temperature. The N-[3,5-bis (trifluoromethyl)benzyl]-N'-tert-butoxycarbonylethylenediamine used herein was prepared as an oily compound, by reacting ethylenediamine with 3,5-bis(trifluoromethyl)benzyl methanesulfonate in THF to give an oily compound of N- [3,5-bis (trifluoromethyl)benzyl]ethylenediamine, followed by further reacting the compound with di-tert-butyl dicarbonate in the presence of triethylamine in THF.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]1CCCC1=O>>[NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCCC1=O
Reactant: Nc1cccnc1Cl
Product: N#Cc1ncccc1N
Temperature: 185 °C
Reaction time: 2 h

Procedure:
A mixture of 3-Amino-2-chloro-pyridine (5 g) and cuprous cyanide (5 g) in 10 mL of N-Methylpyrrolidone was heated with stirring at 185° C. for 2 h under an atmosphere of nitrogen. The reaction mixture was concentrated in vacuo and concentrated ammonium hydroxide and 10% methanol/methylene chloride were added. The mixture was shaken and filtered, the organic layer separated and the aqueous layer extracted two times with methanol/methylene chloride. The combined organic extracts were dried over magnesium sulfate and the solvent removed in vacuo. The residue was recrystallized from ethyl acetate/hexane to afford 3-Amino-2-cyanopyridine as a tan solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[C:25]([C:26](O)=[O:27])=[CH:24][NH:23][N:22]=1>>[NH2:20][C:21]1[C:25]([C:26]([NH:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][O:14][C:10]2[CH:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[CH:12][N:11]=2)=[O:27])=[CH:24][NH:23][N:22]=1
Reactant: Nc1n[nH]cc1C(=O)O
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: Nc1n[nH]cc1C(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 38 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-amino-4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 172°-174° C., in a 38% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:23]=[CH:24][C:25](Cl)=[N:26][CH:27]=1)([O-:21])=[O:20]>CN(C)C1C=CN=CC=1.CN(C=O)C>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[N:26][CH:27]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3ccc(Nc4ccc([N+](=O)[O-])cn4)cc23)CC1
Yield: 42.5 %

Procedure:
A mixture of 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.212 g, 0.88 mmol), 5-nitro-2-chloropyridine (0.314 g, 1.98 mmol), and 4-dimethylaminopyridine (0.085 g, 0.7 mmol) in dry DMF (2 mL) was refluxed 8 hours. The solvent was removed in vacuo and the residue was taken up in methylene chloride. The organic phase was washed with saturated 0.5N NaOH and brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (1×4 inches). Gradient elution with from 50% to 90% ethyl acetate/hexane gave an unweighed forerun. Continued elution with ethyl acetate gave 0.136 g of orange oil. Recrystallization from isopropanol followed by recrystallization from nitromethane gave 0.005 g (1.4%) of the title product as orange crystals: mp 121°-125° C. Analysis calculated for C20H21N5O2 ·H2O; C, 62.98; H, 6.08; N, 18.36. Found: C, 62.86; H, 5.84; N, 18.13.
Reaction SMILES: [C@H:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[F:28][C:26]([F:27])([F:29])[C:23]1[N:21]2[N:22]=[C:17]([N:3]3[CH2:4][C@@H:5]4[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:1]([CH2:7][CH2:6]4)[CH2:2]3)[CH:18]=[CH:19][C:20]2=[N:25][N:24]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CNC2
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CN(c1ccc3nnc(C(F)(F)F)n3n1)C2

Procedure:
A mixture of tert-butyl (1S,5R)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give tert-butyl (1S,5R)-3-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH:15]([CH3:17])[CH3:16].[C:18]([Zn]C#N)#[N:19].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[OH-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CN(C=O)C>[CH:15]([N:6]1[C:7]2[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:2]([C:18]#[N:19])[C:3]=2[CH:4]=[CH:5]1)([CH3:17])[CH3:16]
Reactant: CC(C)n1ccc2c(Br)cc(C(F)(F)F)cc21
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ccc2c(C#N)cc(C(F)(F)F)cc21
Temperature: 120 °C
Yield: 77.2 %

Procedure:
To a 10-mL microwave tube were added 4-bromo-1-(1-methylethyl)-6-(trifluoromethyl)-1H-indole (330 mg, 1.078 mmol), dicyanozinc (146 mg, 1.240 mmol), DMF (4 mL) and water (0.040 mL), and the mixture was degassed for 5 min by bubbling N2. s-Phos (48.7 mg, 0.119 mmol) and tris(dibenzylideneacetone)dipalladium(0) (49.4 mg, 0.054 mmol) were added. The tube was sealed and the mixture was heated at 120° C. for 2.5 h. 1 N NaOH (3 mL) was added and the mixture was extracted with EtOAc (3×). The extract was dried over Na2SO4 and concentrated. The residue was purified using column chromatography (Silica gel, 0 to 70% EtOAc/hexanes) to give the title compound (210 mg, 77%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.61 (m, 6H), 4.79 (spt, J=6.69 Hz, 1H), 6.84 (d, J=3.28 Hz, 1H), 7.59 (d, J=3.28 Hz, 1H), 7.73 (s, 1H), 7.88 (s, 1H). MS: (M+H)+=253.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[N:28]4[C:24]([S:25][CH:26]=[CH:27]4)=[N:23][C:22]=3[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35](=[O:37])[NH2:36])[CH:30]=3)[CH:18]=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[N:28]4[C:24]([S:25][CH:26]=[CH:27]4)=[N:23][C:22]=3[C:29]3[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=3)[C:35]([NH2:36])=[O:37])[CH:18]=[CH:17][N:16]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nccc(-c3c(-c4cccc(C(N)=O)c4)nc4sccn34)n2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)c1
Yield: 107.2 %

Procedure:
(R)-3-{4-[6-(3-carbamoyl-phenyl)-imidazo[2,1-b]thiazol-5-yl]-pyrimidin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.289 mmol) was dissolved in 3 mL of ethyl acetate and treated with 3 ml of 3.0 M HCl in ethyl acetate at room temperature (RT) overnight. Solid product was filtered, washed ethyl acetate and dried under vacuum overnight to provide 0.130 g (97%) of the title compound as a yellow solid. M.p.=202-205° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 9.35 (br. s, 1H), 9.20-8.25 (bs, 3H), 8.12-8.09 (m, 2H), 7.98-7.968.0 (m, 1H), 7.74-7.72 (m, 1H), 7.57-7.52 (m, 2H), 7.25 (bs, 1H), 6.40 (d, J=6.0 Hz, 1H), 4.31 (br. s, 1H), 3.40 (d, J=9.2 Hz, 1H), 3.16-3.13 (m, 1H), 2.94-2.90 (m, 2H), 2.03-1.97 (m, 1H), 1.96-1.89 (m, 1H), 1.89-1.80 (bs, 1 H), 1.66-1.60 (m, 1H); LCMS: 459 [M+H]. calc. for C21H21N7OS.3.14(HCl).0.25(EtOAc) C, 47.52; H, 4.74; N, 17.63. Found C, 47.57; H, 4.44; N, 17.52; LCMS: 420 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=O.CCN(CC)CC.[Cl-].CC(C)(C#C)C.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1.Cl>N1C=CC=CC=1.CC#N>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([NH:37][C:38]1[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=1)=[O:20]
Reactant: Nc1ccc(O)cc1
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Agent: C#CC(C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: c1ccncc1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)Nc2ccc(O)cc2)C(C)(C)CCC1
Reaction time: 3.5 h
Yield: 96.5 %

Procedure:
To a 250 milliliter round bottom flask was charged 2.00 grams (6.67 mmol) of retinoic acid and 20 milliliters of CH3CN. The slurry was cooled to an external temperature of 0-10° C. while 1.0 milliliters of Et3N (7.3 mmol) was charged via syringe. To the slurry was added 0.96 milliliters (7.0 mmol) of 2,2-dimethylbutyrichloride via syringe over about 10 minutes. A thick, unstirrable slurry formed. Ten milliliters of additional CH3CN was added to improve the stirring. After about 3.5 hours, the activation was judged to be complete by HPLC analysis. To the slurry was added 2.0 milliliters of pyridine via syringe. 4-aminophenol (1.53 grams, 14.0 mmol) was then added as a solid in 2 portions over about 15 minutes. After stirring for 2 hours, the reaction was held overnight in the refrigerator (about 0-10° C.). The following morning the reaction was judged to be complete by HPLC analysis. At an external temperature of 0-10° C., 20 milliliters of 3M HCl was added dropwise over about 15 min. After stirring for about 15 minutes, about 20 milliliters of solvent was removed via rotary evaporation (45° C. bath temperature). The slurry was filtered, washed twice with 10 milliliters of water and once with 15 milliliters of heptane. The dark brown solid was dried at about 40° C. overnight on a high vacuum pump to give 2.52 grams of fenretinide (97% yield, 97% pure by area, 1.4% retinoic acid).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[CH:25]=[CH:24][C:23]2[C:22]3=[CH:26][CH:27]=[N:28][N:21]3[CH:20]=[CH:19][C:18]=2[C:17]=1[C:29]([O:31][CH3:32])=[O:30])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:22]3=[CH:26][CH:27]=[N:28][N:21]3[CH:20]=[CH:19][C:18]=2[C:17]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1ccn1nccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(N)ccc2c1ccn1nccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
TFA (3 mL) was added to a solution of methyl 8-[bis-(tert-butoxycarbonyl)amino]-pyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 7, 0.280 g) in DCM (3 mL) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was stirred with saturated aqueous sodium bicarbonate solution for 30 minutes and then the organic layer was separated, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give methyl 8-aminopyrazolo[5,1-a]isoquinoline-7-carboxylate (0.140 g) as a glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](B(O)O)[CH:7]=[CH:6]2.Br[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:17]1[CH:18]=[C:19]([NH2:20])[CH:21]=[CH:22][CH:23]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Reactant: Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc2cc(-c3cccc(N)c3)ccc2c1
Temperature: 25 °C
Yield: 75 %

Procedure:
6-methoxy-naphthalene-2-boronic acid (0.140 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.06 g in 75% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8]COC.CC(O)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:17]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COCOc1ccc(N2CCN(CCc3ccccc3)CC2)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Oc1ccc(N2CCN(CCc3ccccc3)CC2)cc1Cl
Reaction time: 4.5 h
Yield: 49.5 %

Procedure:
To 1-(3-chloro-4-methoxymethoxyphenyl)-4-phenethyl-piperazine (214 mg), 2-propanol (1 mL) and tetrahydrofuran (1 mL) were added, followed by cooling with ice and addition of conc. hydrochloric acid (0.5 mL). Raising the temperature back to the ambient level, the mixture was stirred for 4.5 hours. The reaction mixture was poured in saturated saline solution, rendered weakly alkaline with saturated aqueous sodium hydrogencarbonate solution, and the product was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the resulting crude product was purified on TLC (developer, chloroform: acetone=5:1) to provide 2-chloro-4-(4-phenethylpiperazin-1-yl)phenol (93 mg).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([N:10]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH:22]=[CH:21]2)=[O:12])[C:6](OC)=[O:7].B.[Na].Cl>C(O)C>[CH3:1][S:2][CH2:3][CH2:4][CH:5]([N:10]([CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH:22]=[CH:21]2)=[O:12])[CH2:6][OH:7]
Reactant: COC(=O)C(CCSC)N(CC1CCCCC1)C(=O)CCCCOc1ccc2[nH]c(=O)ccc2c1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CSCCC(CO)N(CC1CCCCC1)C(=O)CCCCOc1ccc2[nH]c(=O)ccc2c1
Reaction time: 2 h
Yield: 51.6 %

Procedure:
In 80 ml of ethanol is dissolved 1.6 g of 6-{4-[N-(3-methylthio-1-methoxycarbonylpropyl)-N-cyclohexylmethylaminocarbonyl]butoxy}carbostyril. Thereto is added 3.2 g of sodium boron hydride. The mixture is stirred for 2 hours at 50°-60° C. The reaction mixture is neutralized with diluted hydrochloric acid and concentrated. The residue is extracted with a mixture of chloroform and methanol (10:1). The extract is purified by means of a silica gel column chromatography (eluant; chloroform:methanol=20:1). The resulting residue is recrystallized from a mixed solvent of dichloromethane-ethyl acetate-diethyl ether to obtain 0.78 g of 6-{4-[N-(3-methylthio-1-hydroxymethylpropyl)-N-cyclohexylmethylaminocarbonyl]butoxy}-carbostyril.
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]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH3:21])[CH:13]=1)=O.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[N:22][CH:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH3:21])[CH:13]=1
Reactant: CCCOc1cccc(C(=O)c2nc3ccccc3s2)c1
Reactant: CN1CCC(N)CC1
Product: CCCOc1cccc(C(=NC2CCN(C)CC2)c2nc3ccccc3s2)c1

Procedure:
Condensation of benzothiazol-2-yl(3-propoxyphenyl)methanone with 4-amino-1-methylpiperidine as described in example 37B gives [benzothiazol-2-yl(3-propoxyphenyl)methylene](1-methylpiperidin-4-yl)amine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[CH:34][N:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-ethoxy-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M37) (203 mg, 0.38 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (148 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25](=[O:38])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:39]>O1CCOCC1>[ClH:39].[ClH:39].[F:37][C:34]([F:35])([F:36])[O:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:25]([C:18]2[C:19]([C:21]([F:22])([F:23])[F:24])=[N:20][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:16][CH:17]=2)=[O:38])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NC2CCNCC2)nc1C(F)(F)F

Procedure:
A solution of 4-[5-(4-trifluoromethoxy-phenylcarbamoyl)-4-trifluoromethyl-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.92 g, 1.67 mmol) in 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 450.3 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>O.C(O)C>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=2)=[O:12])=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: Cc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=CC(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3.75 h
Yield: 92.2 %

Procedure:
To a solution of 0.97 g of sodium hydroxide in 9.7 ml of water was added 27.1 ml of ethanol. A solution of 2.563 g of p-methylacetophenone in 4 ml of ethanol was added dropwise to the mixture, followed by dropwise addition of a solution of 2.30 g of p-methylbenzaldehyde in 4 ml of ethanol. The resulting mixture was stirred at room temperature for 3.75 hours, and the solid matter was filtered, washed with cold water and ethanol and thoroughly desiccated to give 4.16 g of 4,4'-dimethylchalcone.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][CH:3]=1.[Li+].[BH4-].Cl>C1COCC1>[I:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(I)cc1
Reaction time: 0.5 h

Procedure:
Methyl 4-iodobenzoate (5 g, 19.07 mmol) was suspended in THF (100 mL). LiBH4 (40 mmol) was added slowly, via syringe. Reaction mixture was heated to 60° for 4 days. 1N HCl was added slowly. Reaction mixture was stirred for 1/2 hour then was extracted 3 times with EtOAc. The organic layers were combined, washed with saturated NaHCO3, brine, dried (MgSO4), filtered and concentrated to give 4-iodobenzyl alcohol as a white solid.