Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:21]([CH2:30][CH3:31])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1.C(O)C.CO>[Pd].ClCCl>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]([CH2:30][CH3:31])[N:22]([CH2:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=2[N:16]=1
Reactant: CCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CCc1nc2c(N)nc3cc(O)ccc3c2n1CC1CCOCC1
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of 7-benzyloxy-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.76 g, 4.23 mmol), palladium on carbon (1 g), and ethanol (50 mL) was shaken under hydrogen pressure (50 psi, 3.4×105 Pa) on a Parr apparatus overnight. The reaction mixture was diluted with dichloromethane (75 mL) and then filtered through a layer of CELITE filter agent. The filter cake was rinsed with 25% methanol in chloroform (400 mL). The combined filtrates were concentrated under reduced pressure to provide a white solid. This material was slurried with methanol, isolated by filtration, and dried under vacuum to provide 0.98 g of 4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-ol.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[N:13]=[C:12](Cl)[CH:11]=[C:10]([CH3:15])[N:9]=1.[NH2:16][C:17]1[NH:21][N:20]=[C:19]([CH3:22])[CH:18]=1>C(O)C>[Cl:7][C:8]1[N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH3:22])[NH:20][N:21]=2)[CH:11]=[C:10]([CH3:15])[N:9]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2cc(C)[nH]n2)nc(Cl)n1
Temperature: 42 °C
Reaction time: 72 h
Yield: 32.9 %

Procedure:
Solid sodium carbonate (1.2 g, 11.3 mmol) was added to a solution of 2,4-dichloro-6-methylpyrimidine (1.7 g, 10.3 mmol) and 5-amino-3-methyl-1H-pyrazole (1.0 g, 10.3 mmol) in dry ethanol (50 ml) and the mixture heated and stirred at 42° C. for 3 days. The mixture was allowed to cool, the insoluble material was removed by filtration and the filter pad washed with ethanol (10 ml). The volatiles were removed from the filtrate by evaporation, keeping the bath temperature below 40° C. The residue was immediately purified by chromatography on silica gel eluting with methanol/DCM (5:95 increasing in polarity to 20:80) to give the title compound (758 mg, 33%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8])[OH:5])[CH3:2].CCN(C(C)C)C(C)C.[CH3:30][O:31][C:32](=[O:50])[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:36]=1)=[CH2:34]>C(Cl)Cl>[CH3:30][O:31][C:32](=[O:50])[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:36]=1)[CH2:34][P:4]([CH:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH:7]([CH3:9])[CH3:8])([O:3][CH2:1][CH3:2])=[O:5]
Reactant: C=C(C(=O)OC)c1cccc(CNC(=O)OC(C)(C)C)c1
Reactant: CCOP(O)C(NC(=O)OCc1ccccc1)C(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CC(C(=O)OC)c1cccc(CNC(=O)OC(C)(C)C)c1)C(NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a solution of 1-(benzyloxycarbonylamino)-2-methylpropyl-phosphonous acid ethyl ester (6.2 g 20.7 mmol) in 150 ml CH2Cl2 was added DIEA (6.5 mL, 47.5 mmol). The mixture solution was cooled down to 0° C. over an ice-water bath. TMSCI (5.5 mL, 42.0 mmol) was added dropwise under N2. The reaction mixture was stirred at ambient temperature for 2 hours, then cooled to 0° C. again. A solution of 2-(3-(t-butoxycarbonylamino)methylphenyl)-propenoic acid methyl ester (6.7 g, 23.0 mmol) in 15 mL CH2Cl2 was added to the reaction mixture. The resulting reaction mixture was stirred at ambient temperature for 18 hours. The reaction was quenched by 10 mL MeOH, then concentrated in vacuo, and the residue was taken up into 300 mL ethyl acetate. The organic phase was washed with 2 N NaHSO4, water, and brine. The solvent was evaporated in vacuo, and the crude product was purified by flash chromatography on silica gel to afford 2-(3-(t-butoxycarbonylamino)methylphenyl)-3-((1-(benzyloxycarbonyl)amino-2-methylpropyl)(ethoxy)phosphinoyl)propanoic acid methyl ester (10.7 g, 18.1 mmol, 81%) as white solid.
Reaction SMILES: [Na].C([C:4](CC)(C([O-])=O)[C:5]([O-])=[O:6])C.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]=[CH:22][C:23](=[O:25])[CH3:24]>C(O)C>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]1[CH2:4][C:5](=[O:6])[CH2:24][C:23](=[O:25])[CH2:22]1
Reactant: CC(=O)C=Cc1ccc(Cl)cc1Cl
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: O=C1CC(=O)CC(c2ccc(Cl)cc2Cl)C1
Temperature: 0 °C

Procedure:
To a solution of 2.3 g of sodium in 200 ml of ethanol is added 15.7 g of diethylmalonate followed by a suspension of 20 g of 1-(2,4-dichlorophenyl)-1-butene-3-one in 100 ml ethanol. The mixture is heated under reflux for 2 hrs and then concentrated to dryness in vacuo. The solid is partitioned between 200 ml water and 200 ml ether. The ether layer is discarded and 20 ml 50% NaOH is added to the aqueous layer which is heated under reflux for 2 hrs. The mixture is filtered and the filtrate is made strongly acidic pH <2 with concentrated sulfuric acid. The mixture is heated on a steam bath for 2 hrs. The resulting solid is collected, pulverized and suspended in 500 ml of 10N sulfuric acid and heated on a steam bath for 2 hrs and cooled to 0° C. The solid is collected, washed with water and recrystallized from a mixture of dimethylformamide and ethyl acetate. Drying in vacuo at 80° C. for 6 hrs gives 5-(2,4-dichlorophenyl)cyclohexane-1,3dione; mp 192°-196° C.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]([C:15]1[S:16][CH:17]=[C:18]([CH2:20]SCCC(=N)OC)[N:19]=1)[C:12]([NH2:14])=[NH:13]>CO>[C:1]1([S:7]([NH:10][C:1](=[S:7])[CH2:2][CH2:3][CH2:20][C:18]2[N:19]=[C:15]([NH:11][C:12]([NH2:14])=[NH:13])[S:16][CH:17]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Solvent: CO
Product: N=C(N)Nc1nc(CCCC(=S)NS(=O)(=O)c2ccccc2)cs1

Procedure:
In 8 ml of methanol were dissolved 800 ml of methyl 3-[(2-guanidinothiazol-4-yl)methylthio]propionimidate and 590 mg of benzenesulfonamide and after causing reaction for 24 hours at room temperature, the solvent was distilled off under reduced pressure. The residue formed was purified by a silica gel column chromatography using a mixture of chloroform and methanol (20:1→10:1) to provide 855 mg of amorphous N-benzenesulfonyl-3-(2-guanidinothiazol-4-yl)methylthio propionamide. The product shows the following physicochemical properties:
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17]Br.[NH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH2:20]>CN(C)C=O.O.C(OCC)(=O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:19][N:20]1[CH2:17][CH2:16][C:11]2[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9]1
Reactant: NNc1ccccn1
Reactant: BrCCc1ccccc1CBr
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(NN2CCc3ccccc3C2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.8 %

Procedure:
Triethylamine (10.0 ml) was added to a solution of 1-bromomethyl-2-(2-bromoethyl)benzene (10 g) and 2-hydrazinopyridine (3.9 g) in dimethylformamide (250 ml), and the mixture was stirred, under nitrogen, at ambient temperature for about 20 mins. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was triturated with ethyl acetate to afford 5.3 g (65%) of product. Recrystallization of the product from ethyl acetate gave the analytical sample, mp 116-117° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].B.C1COCC1.O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 3-nitro-5-(trifluoromethyl)benzoic acid (2.0 g, 8.5 mmol) in THF (100 mL) was added borane-THF (17 mL of a 1 M solution in THF, 17 mmol). The reaction was stirred at 60° C. for 24 hours and then poured into H2O (50 mL). The resultant mixture was extracted with EtOAc (100 mL) and the organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 50% EtOAc/hexanes afforded [3-nitro-5-(trifluoromethyl)phenyl]methanol. Rf=0.35 (75% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) 8.44 (s, 1H), 8.40 (s, 1H), 7.98 (s, 1H), 4.91 (s, 2H), 2.07 (bs, 1H).
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C@H:16]([OH:28])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:49])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:28][C@@H:16]1[CH2:17][CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:49])[CH2:19]2)[C@@H:25]2[C@@H:15]1[C@H:6]1[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]1
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CCCCC1C[C@@H](O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1C[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 89 %

Procedure:
The title compound (II-bt) was prepared in 89% yield from 3,3:17,17-bis(ethylendioxy)-7α-hydroxyandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.34 (d, 1H), 3.75 (m, 1H), 2.50-1.00 (m, 20H), 0.96 (s, 3H), 0.78 (s, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)=[CH:12][C:13](OC)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C(C=CC=1OC)C(C1C=CC2OCOC=2C=1)=O.C(OP(CC#[N:58])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:11]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][O:2][C:3]=3[CH:4]=2)=[CH:12][C:13]#[N:58])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: COc1ccc(C(=O)c2ccc3c(c2)OCO3)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccc3c(c2)OCO3)cc1OC
Temperature: 25 °C

Procedure:
3-(3,4-Dimethoxyphenyl)-3 -(3,4-methylenedioxyphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using 1-(3,4-dimethoxy-benzoyl)-3,4-methylenedioxybenzene (1.43 g, 5 mmol), diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithium hexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3 M) with a reaction time of 1 hour at reflux and 24 hours at room temperature. The crude product was purified by chromatography (silica gel, 2% ethyl acetate/methylene chloride) to afford 0.79 g (51%) of a mixture of the E and Z isomers as an off white solid: mp 121-123° C.; 1H NMR (CDCl3) δ 7.10-6.73 (m, 12 H), 6.13-5.94 (m, 4 H), 5.57 (s, 1 H), 5.53 (s, 1 H), 3.94 (s, 3 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.84 (s, 3 H); 13C NMR (CDCl3) δ 162.3, 151.0, 150.5, 149.6, 149.1, 148.8, 148.5, 147.9, 133.2, 131.6, 130.8, 129.4, 124.3, 123.5, 123.1, 122.1, 118.5, 118.3, 112.6, 111.1, 110.7, 109.9, 108.5, 108.2, 101.6, 101.5, 92.2, 92.2, 56.0, 55.9, 55.9; Anal. Calcd for C18H15NO4. Theoretical: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.61; H, 5.01; N, 4.37.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:20][C:9]2[N:10]([CH3:19])[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])C.CNC>C(O)C>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]2[N:10]([CH3:19])[C:9]3[CH2:20][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][C:8]=3[C:16]=2[CH:15]=1
Reactant: CCOC(=O)C1Cc2c(n(C)c3ccc(OC)cc23)C1
Agent: CNC
Solvent: CCO
Product: COc1ccc2c(c1)c1c(n2C)CC(C(=O)O)C1
Temperature: 100 °C
Reaction time: 96 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-7-methoxy-4-methylcyclopent[b]indole-2-carboxylic acid ethyl ester (6.2 g, 0.023 mole) in 25 ml of ethanol, was added dimethylamine (40% aqueous solution, 10 ml, 0.09 mole). After stirring at 100° C. in a sealed tube for four days, the solution was concentrated to a brown oil (~6 g), which was eluted on a silica gel column with 20% methanol/ethyl acetate via HPLC. The desired fraction was concentrated to a tan solid, 5.0 g, m.p. 162°-164° C.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[N+:7]([O-])[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O>CO.[Pd]>[NH:11]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1
Reactant: CN(C)/C=C/c1c[n+]([O-])ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: c1cc2[nH]ccc2cn1
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a suspension of (E)-N,N-dimethyl-2-(4-nitro-1-oxidopyridin-3-yl)ethenamine (400 mg, Step c) in methanol was added palladium on carbon (50 mg, 10% wet) and the reaction mixture was stirred under hydrogen atmosphere for 2 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to get 1H-pyrrolo[3,2-c]pyridine (98 mg, 44%) as off-white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19](OCC)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19]([NH:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:20])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCN1CCCC1
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Product: O=C(Cn1ncc(-c2ccccc2)c1-c1ccccc1)NCCCN1CCCC1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of 15 g (0.049 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate and 60 mL of N-(3-aminopropyl) pyrrolidine was stirred at 100° C. for 48 hr. The excess aminopropylpyrrolidine was stripped in vacuo and the residue was triturated in ether to yield 5.5 g of product mp 75°-79° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[C:16]1([CH3:19])[CH:15]=[CH:14][C:13]([C:11]2[O:12][C:8]3[C:9](=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=3)[N:10]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(-c2nc3c([N+](=O)[O-])cccc3o2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2nc3c(N)cccc3o2)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
To 4-nitro-2-p-tolylbenzo[d]oxazole (330 mg, 1.30 mmol) in ethanol (20 mL) was added tin (II) chloride (1.23 g, 6.5 mmol). The suspension was stirred at 70° C. for 16 h. After cooling, the solution was poured into ice/water and neutralize with saturated aqueous NaHCO3. The aqueous layer was then extracted twice with ethyl acetate (500 mL). The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 188 mg (65%) of the title compound (LCMS RT=6.76 min, MH+ 225.1)
Reaction SMILES: [ClH:1].Cl.C([N:10]1[CH2:15][CH2:14][O:13][C@@H:12]([CH2:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH2:25][CH3:26])[CH2:11]1)C1C=CC=CC=1.[H][H].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[OH-].[Na+]>C(O)C.O.[Pd]>[ClH:1].[CH2:25]([O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][CH2:16][C@H:12]1[O:13][CH2:14][CH2:15][NH:10][CH2:11]1)[CH3:26]
Reactant: [H][H]
Reactant: CCOc1ccccc1NC[C@H]1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Solvent: O
Product: CCOc1ccccc1NC[C@@H]1CNCCO1

Procedure:
A solution of (2S)-4-benzyl-2-(2-ethoxyanilino)methylmorpholine dihydrochloride (5 g.) in a mixture of ethanol (50 ml.) and water (5 ml.) is shaken in an atmosphere of hydrogen with palladium on carbon catalyst (0.5 g. 5%) until no more hydrogen is absorbed. The catalyst is removed by filtration and the filtrate is evaporated under reduced pressure when (2S)-2-(2-ethoxyanilino)methylmorpholine dihydrochloride (3.7 g.) is obtained as a hydroscopic solid. The dihydrochloride is dissolved in water (100 ml.), the solution is basified with sodium hydroxide solution and extracted with ether (2 × 100 ml.). The ethereal extract is dried (Na2SO4), filtered and the filtrate is then carefully titrated with an ethereal solution of hydrogen chlroide to give (2S)-2-(2-ethoxyanilino)methylmorpholine hydrochloride, m.p. 158°-159°C. on recrystallisation from ethanol [α]D28 - 2.2° (c,4 in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.O.[NH2:10][NH2:11]>CO>[NH:10]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=1)[NH2:11]
Reactant: NN
Reactant: Clc1cccc(Cl)n1
Solvent: O
Solvent: CO
Product: NNc1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2 g of 2,6-dichloropyridine were dissolved in 60 ml of methanol and mixed with 10 ml of 80% hydrazine hydrate. The solution was firstly stirred for 3 days at room temperature and then refluxed for 10 days. Rotation in took place, the residue was taken up with methanol, followed by rotation in again and finally recrystallization from methanol/water. 0.25 g of 2-hydrazino-6-chloropyridine was obtained.
Reaction SMILES: C(OC1C=CC(N2CCNCC2)=CC=1F)C1C=CC=CC=1.C(Br)CCCCCCC.[F:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([F:40])=[CH:34][C:33]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.Cl[CH2:48][CH2:49][C:50]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:51]>>[F:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([F:40])=[CH:34][C:33]=1[N:41]1[CH2:46][CH2:45][N:44]([CH2:48][CH2:49][C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:51])[CH2:43][CH2:42]1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Reactant: O=C(CCCl)c1ccccc1
Agent: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Solvent: CCCCCCCCBr
Product: COc1cc(F)c(N2CCN(CCC(=O)c3ccccc3)CC2)cc1F
Yield: 101.4 %

Procedure:
Production Example 38 was repeated except that 1-(4-benzyloxy-3-fluorophenyl)piperazine and n-octyl bromide were replaced with 1-(2,5-difluoro-4-methoxyphenyl)piperazine (228 mg) and 3-chloro-1-phenylpropan-1-one (169 mg), to provide crude 3-[4-(2,5-difluoro-4-methoxyphenyl)piperazin-1-yl]-1-phenylpropan-1-one (365 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:15][C:3]1[C:4]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:28])([CH3:17])([CH3:18])[CH3:19]
Reactant: Cc1cccc(Nc2ccccc2)c1N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cccc(Nc2ccccc2)c1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
To a solution of 3-methyl-N1-phenylbenzene-1,2-diamine (381 mg, 1.92 mmol) in anhydrous DCM (10 mL) were added (S)-2-tertbutoxycarbonylaminopropionic acid (399 mg, 2.11 mmol), HOBt (285 mg, 2.11 mmol), 4-methylmorpholine (464 μL, 4.22 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (405 mg, 2.11 mmol). The mixture was stirred at RT for 2 h then additional amounts of (S)-2-tertbutoxycarbonylaminopropionic acid (145 mg, 0.77 mmol) and of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol) were added. Stirring was continued for 18 h and then additional amounts of (S)-2-tertbutoxycarbonylaminopropionic acid (545 mg, 2.88 mmol), HOBt (285 mg, 2.11 mmol), 4-methylmorpholine (464 μL, 4.22 mmol) and of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (553 mg, 2.88 mmol) were added. Stirring was continued for 24 h and then the crude mixture was purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) affording [(S)-1-(2-methyl-6-phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester as an orange oil (395 mg, 56%). LCMS: RT 3.69 min [M+H]+ 370.2.
Reaction SMILES: C1([OH:7])C=CC=CC=1.[CH2:8]([O:12][C:13]1[CH:18]=[CH:17]C=CC=1)[CH:9]1[O:11][CH2:10]1>>[CH2:13]([O:12][CH2:8][CH:9]1[O:11][CH2:10]1)[CH:18]1[O:7][CH2:17]1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Oc1ccccc1
Product: C(OCC1CO1)C1CO1

Procedure:
Such a mono(chlorohydrin ether) as that of formula V is then mixed with up to an equimolar amount of a bis(chlorohydrin ether) of a polyhydric phenol, and subjected to dehydrochlorination. The materials obtained, described as synthetic high molecular weight products of resinous character, are of a complex nature and generally solids of melting point 43° C. or more. Presumably, if, e.g., phenyl glycidyl ether were used, the product obtained on dehydrochlorination would contain, amongst other compounds, a glycidyl ether of a mono-secondary alcohol formed in the following manner ##STR3##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:11]2[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[S:14][C:10]=2[C:9](=[O:19])[N:8]([OH:20])[C:7]1=[O:21].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[C:4]([CH2:5][N:6]2[C:11]3[C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[S:14][C:10]=3[C:9](=[O:19])[N:8]([OH:20])[C:7]2=[O:21])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=c1c2sc3ccccc3c2n(Cc2cccc(Br)c2)c(=O)n1O
Product: O=c1c2sc3ccccc3c2n(Cc2cccc(-c3ccccc3)c2)c(=O)n1O

Procedure:
1-(3-Bromo-benzyl)-3-hydroxy-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was treated with phenylboronic acid according to general procedure C. The title compound was obtained as a yellow solid following purification by preparative HPLC. 1H NMR (d6-DMSO, 300 MHz) δ 5.79 (s, 2H); 7.26-7.69 (m, 10H); 8.00 (d, J=9 Hz, 1H); 8.13 (d, J=8 Hz, 2H); Ret. time=3.19 min., m/z=399.0.
Reaction SMILES: O[CH:2]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]2[O:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[CH:19][CH:18]=1)[CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:10][C:9]1[O:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1[CH2:4][CH:3]=[CH:2][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]2[O:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[CH:19][CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCC(O)c1ccc(CCC2OC(=O)NC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CC=Cc1ccc(CCC2OC(=O)NC2=O)cc1
Reaction time: 2 h
Yield: 76.7 %

Procedure:
A mixture of 5-[2-[4-[1-hydroxy-3-(5-methyl-2-phenyl-4-oxazolyl)propyl]phenyl]ethyl]-2,4-oxazolidinedione (0.32 g), p-toluenesulfonic acid monohydrate (p-TsOH.H2O) (0.145 g) and toluene (40 ml) was stirred under refluxing conditions for 2 hours. The reaction mixture was washed with an aqueous solution of sodium hydrogen carbonate and water, dried (MgSO4) and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography. From the fraction eluted with chloroform-methanol (100:2), 5-[2-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1-propenyl]phenyl]ethyl]-2,4-oxazolidinedione (0.235 g, 77%) was obtained, which was then recrystallized from dichloromethane-isopropyl ether to yield colorless needles having a melting point of 175°-176° C.