Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]O.[F:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:5]=1[C:6](=[O:15])C(=O)[NH:8]2.[OH-].[Na+].Cl>>[NH2:8][C:9]1[CH:10]=[C:11]([F:13])[CH:12]=[C:4]([F:3])[C:5]=1[C:6]([OH:15])=[O:1]
Reactant: O=C1Nc2cc(F)cc(F)c2C1=O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(F)cc(F)c1C(=O)O
Temperature: 70 °C

Procedure:
Hydrogen peroxide (35% solution in water, 23 ml) was added dropwise to a stirred solution of 4,6-difluoro-2,3-dioxoindoline (14 g) in a concentrated aqueous sodium hydroxide solution (33%, 115 ml) that was heated to 70° C. The mixture was heated to 70° C. for 15 minutes. The resultant mixture was cooled to 0° C. and the mixture was acidified to pH4 by the addition of concentrated aqueous hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulphate and evaporated to give 2-amino-4,6-difluorobenzoic acid (12 g); NMR Spectrum: (DMSOd6) 6.25 (m, 1H), 6.38 (m, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][C:23]=4[CH3:30])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].OO.FC(F)(F)C([OH:40])C(F)(F)F>ClCCl>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:29])=[O:40])=[CH:24][C:23]=4[CH3:30])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CSc1ccc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)C)CC2)O3)c(C)c1
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: OO
Solvent: ClCCl
Product: Cc1cc(S(C)=O)ccc1-c1ccc2c(c1)CC(C1CCN(C(=O)OC(C)C)CC1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[5-(2-methyl-4-methylsulfanyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester (20 mg), aqueous hydrogen peroxide solution (35%; 3.5 μL) and 1,1,1,3,3,3-hexafluoro-2-propanol (200 μL) is stirred at room temperature for 2 h. The reaction mixture is diluted with dichloromethane and extracted with sodium thiosulfate solution (10%; 2 mL). The organic phase is washed with brine, dried over MgSO4 and the solvent is evaporated. The residue is chromatographed on silica gel (dichloromethane/methanol 95:5) to give the title compound. Yield: 9 mg (43% of theory); LC (method 2): tR=1.45 min; Mass spectrum (ESI+): m/z=442 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][C@H:5]([CH3:8])[N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Br-].[Na+].C(=O)(O)[O-].[Na+].Cl[O-].[Na+]>ClCCl.CC1(C)N([O])C(C)(C)CCC1>[CH:2]([C@@H:3]1[CH2:7][CH2:6][C@H:5]([CH3:8])[N:4]1[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[O:1]
Reactant: C[C@H]1CC[C@@H](CO)N1C(=O)OC(C)(C)C
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: C[C@H]1CC[C@@H](C=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of (2S,5S)-tert-butyl 2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate (5.15 g, 23.9 mmol) in dichloromethane, was added TEMPO (0.075 g, 0.48 mmol), sodium bromide (0.246 g, 2.39 mmol) and sodium bicarbonate (0.442 g, 5.26 mmol). Sodium hypochlorite (2.67 g, 35.9 mmol) of a 6% solution was added and the biphasic mixture was vigorously stirred for 2 hours at room temperature. The reaction mixture was extracted two times with dichloromethane (2×100 mL). The organic layers were combined and washed with saturated sodium thiosulfate solution, dried with sodium sulfate and the solvent was removed in vacuo to yield (2S,5S)-tert-butyl 2-formyl-5-methylpyrrolidine-1-carboxylate (3.9 g, 18.29 mmol, 77%) as a slight colored oil and was used directly in the following step.
Reaction SMILES: [CH2:1]([NH+:4](CCC)[CH2:5][CH2:6]C)[CH2:2]C.[C:11](=[S:13])=[S:12].[CH2:14]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].C(NCC)C>>[CH2:1]([N:4]([CH2:5][CH3:6])[C:11](=[S:13])[S-:12])[CH3:2].[CH2:14]([NH+:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]
Reactant: S=C=S
Reactant: CCCN(CCC)CCC
Agent: CCC[NH+](CCC)CCC
Solvent: CCNCC
Product: CCN(CC)C(=S)[S-]
Temperature: 50 °C

Procedure:
Preparation of tripropylammonium salt of diethyl dithiocarbamateis as follows: 76 grams (1 mole) carbon disulfide and 143 grams (1 mole) tripropylamine are mixed at 10° C. under nitrogen. 80.5 grams (1.1 mole) diethylamine is added slowly and drop wise to the mixture and the mixture is maintained at a temperature below 30° C. Then the mixture is heated to 50° C. for 1 hour. The solution is then stripped out under vacuum to remove the excess amine and for the removal of low volatiles to obtain final product. The acid number (normally below 30) is measured to check the acidity. The product purity (ranging between 85-95%) is measured by LC-MS and NMR.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[Cl:65])[CH2:54][CH2:53]1>CN(C=O)C.O>[Cl:65][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=1[NH:58][CH:55]1[CH2:56][CH2:57][N:52]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][N:10]=2)=[O:13])[CH2:53][CH2:54]1
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2)on1
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (0.075 g, 0.00027 mol) in DMF (2 mL) was added DIPEA (0.171 g, 0.00132 mol), HOBt (0.0448 g, 0.00033 mol) and EDCI.HCl (0.064 g, 0.00033 mol) at ambient temperature. After 2 minutes piperidin-4-yl-(2-chloro-phenyl)-amine dihydrochloride (0.066 g, 0.00027 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using basic aluminium oxide (25% ethyl acetate in hexane) to afford 0.066 g (57%) of 5-phenyl-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 439.15 (M+1)+, 97.26%, 1H NMR (DMSO-d6): δ 8.62 (t, 1H), 7.95 (m, 2H), 7.55 (m, 3H), 7.4 (s, 1H), 7.25 (dd, 1H), 7.2 (m, 2H), 6.85 (d, 1H), 6.6 (t, 1H), 4.9 (d, 1H), 4.4 (d, 1H), 4.2 (d, 2H), 3.9 (d, 1H), 3.7 (m, 1H), 3.2 (m, 1H), 2.8 (m, 2H), 1.95 (t, 2H), 1.4 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]2[N:6]=[C:7](OS(C(F)(F)F)(=O)=O)[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[CH3:28][NH:29][CH3:30]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]2[N:6]=[C:7]([N:29]([CH3:30])[CH3:28])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CNC
Reactant: CCN1c2ncccc2C(OS(=O)(=O)C(F)(F)F)=Nc2c(C)cc(C)nc21
Solvent: CCOC(C)=O
Product: CCN1c2ncccc2C(N(C)C)=Nc2c(C)cc(C)nc21
Reaction time: 72 h

Procedure:
A mixture of 2,4-dimethyl-11-ethyl-6-trifluoromethanesulfonyloxy-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.3 g, 0.75 mmole) and dimethylamine (excess, used as solvent) were placed in a sealed pressure tube and left at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed with water, dried, filtered and concentrated. The 260 mg of product thus obtained was recrystallized from ethyl acetate/hexane to give the title compound, m.p. 150°-152° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[BH4-].[Na+].Cl>ClCCl.C(O)C.CO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)=[CH:16][C:13]([CH2:14][NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: COc1ccc(Nc2ncc(CNc3ccccc3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76.6 %

Procedure:
6-(6-Methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (122 mg, 0.274 mmol) was suspended in dichloromethane (1.5 mL) and ethanol (1.5 mL), and aniline (0.080 mL, 0.88 mmol) and tetraisopropoxytitanium (0.25 mL, 0.84 mmol) were added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (70° C.-74° C.) and stirred under nitrogen for 45 minutes. Then, the reaction was cooled to room temperature and treated with sodium borohydride (39.8 mg, 1.05 mmol), along with MeOH (about 1 mL). The reaction was stirred at room temperature for 45 minutes, and then MeOH (about 1 mL) and aqueous 5N HCl (0.55 mL) were added. The reaction flask was put in a preheated oil bath (50° C.-61° C.), stirred for 3.5 hours, and then cooled to room temperature. The resulting suspension was diluted with DCM and MeOH and filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM, MeOH, and a 1:1 mixture of these 2 solvents. The filtrate was concentrated, treated with water, and filtered, and the solid was washed with water, collected, and washed with DCM. The solid was then purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((phenylamino)methyl)pyridin-2-amine (92.0 mg, 77% yield). MS (ESI pos. ion) m/z 439 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 12.56 (br s, 1H), 9.77 (s, 1H), 8.62 (s, 1H), 8.52 (d, J=2.54 Hz, 1H), 8.29 (d, J=1.56 Hz, 1H), 8.15 (dd, J=8.90 Hz, 2.64 Hz, 1H), 7.10 (t, J=7.82 Hz, 2H), 6.85 (d, J=9.00 Hz, 1H), 6.71 (d, J=7.63 Hz, 2H), 6.60 (t, J=6.85 Hz, 1H), 4.29 (s, 2H), 3.85 (s, 3H), 2.85 (s, 3H).
Reaction SMILES: CN(C)[C:3]([S:5][C:6]1[C:11]2=[N:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15](=[O:16])[N:10]2[CH:9]=[CH:8][CH:7]=1)=[O:4].[C:23]1([CH2:29]C(Cl)=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCCl.[I-].[Zn+2].[I-]>[CH2:29]([C:3]([S:5][C:6]1[C:11]2=[N:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15](=[O:16])[N:10]2[CH:9]=[CH:8][CH:7]=1)=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cnc2c(SC(=O)N(C)C)cccn2c1=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: CCOC(=O)c1cnc2c(SC(=O)Cc3ccccc3)cccn2c1=O
Yield: 58 %

Procedure:
To a solution of 0.129 g of 9-(dimethylcarbamoyl)thio-3ethoxycarbonyl-4H-pyrido[1,2-a]pyrimidin-4-one Ib-85 in 5 ml of 1,2-dichloroethane are added 65 μl of phenylacetyl chloride and 0.13 g of zinc iodide, and the resultant mixture is refluxed in a nitrogen stream for 45 minutes. After cooling, the reaction mixture is shaken with N-hydrochloric acid and the organic layer is washed with saturated brine in order, dried and concentrated in vacuo. The residue is chromatographed on a column of silica gel, eluting with ethyl acetate, whereby 0.118 g of the titled compound Ie-84 is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([NH2:32])=[O:31])[CH:25]=2)=[C:21]([F:35])[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:18][C:19]2[CH:34]=[CH:33][C:22]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]([NH2:32])=[O:31])[CH:25]=3)=[C:21]([F:35])[CH:20]=2)=[O:16])[C:9]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccn(Cc2ccccc2)c1=O
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(Oc2ccc(NC(=O)c3cccn(Cc4ccccc4)c3=O)cc2F)ccn1
Reaction time: 12 h
Yield: 69.2 %

Procedure:
A homogeneous solution of 1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.10 g, 0.41 mmol, 1.0 eq), 4-(4-amino-2-fluorophenoxy)picolinamide (0.10 g, 0.41 mmol, 1.0 eq) and TBTU (0.17 g, 0.45 mmol, 1.1 eq) in DMF (2 mL) was treated with DIPEA (0.18 mL, 1.0 mmol, 2.5 eq) at room temperature and the reaction mixture was stirred for 12 h. The reaction mixture was quenched with 10% aqueous LiCl (15 mL) and the resulting solution was extracted with ethyl acetate (4×40 mL). The combined organic extracts were washed with 10% aqueous LiCl (4×50 mL), dried (Na2SO4), filtered and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, eluting with ethyl acetate) to afford the product (0.13 g, 67%) as a solid. 1H NMR (DMSO-d6) δ 12.26 (s, 1H), 8.49-8.56 (m, 2H), 8.33-8.36 (m, 1H), 8.15 (br m, 1H), 8.03-8.07 (m, 1H), 7.74-7.75 (m, 1H), 7.51-7.54 (m, 1H), 7.41-7.46 (m, 4H), 7.20-7.24 (m, 3H), 6.71 (dd, 1H, J=6.89 Hz), 5.32 (s, 2H) HRMS(ESI+), Calcd.: 477.1374, found: 477.1378.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cc(Br)c2cccnc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cc(Br)c2cccnc2c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
To a solution of 5-bromo-8-hydroxyquinoline-7-carboxylic acid (0.402 g) of Preparation 2 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirred overnight. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried to yield 0.157 g of the title product as an off-white solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([N:11]1[C:19]([OH:20])=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH2:22]Cl)=[N:15][C:16]=2[NH2:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C=O)C>[CH2:4]([N:11]1[C:19]([OH:20])=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH2:22][C:1]#[N:2])=[N:15][C:16]=2[NH2:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: Nc1nc(CCl)nc2c1nc(O)n2Cc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 80 °C
Reaction time: 7 h
Yield: 82.6 %

Procedure:
After sodium cyanide (0.20 g, 4.08 mmol) and 9-benzyl-2-chloromethyl-8-hydroxyadenine (0.20 g, 0.69 mmol) were added to DMF (10 ml), the mixture was stirred at 80° C. for 7 hours. After removing the solvent, the residue was poured into water and the solution was neutralized with concentrated hydrochloric acid. The solution was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=100/1˜50/1) and washed with methanol to give 9-benzyl-2-cyanomethyl-8-hydroxyadenine (0.16 g, 0.57 mmol) as a pale yellow solid. Thus obtained 9-benzyl-2-cyanomethyl-8-hydroxyadenine (0.08 g, 0.29 mmol) was added to a mixed solvent of 5% sodium hydroxide solution (20 ml) and methanol (10 ml), and the mixture was stirred at 60° C. for 8 hours. After the mixture was neutralized with concentrated hydrochloric acid, the solvent was removed. The residue and sulfuric acid (1 ml) were added to methanol (50 ml), and the mixture was refluxed for 3 hours under stirring. After being neutralized with saturated sodium hydrogencarbonate solution in an ice bath, the solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=100/1˜30/1) and washed with methanol to give the captioned compound (0.02 g, 0.06 mmol) as a white solid.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O.FC(F)(F)C(O)=O.C(N(CC)CC)C>C(O)C>[F:1][C:2]1[C:3]([NH2:15])=[CH:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:7]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(F)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN(c2ccc(N)c(F)n2)CC1

Procedure:
To a suspension of 1-(6-fluoro-5-nitropyridin-2-yl)-4-methylpiperazine.trifluoroacetic acid salt (0.38 g, 1.1 mmol) in ethanol (30 mL) is added triethylamine dropwise with agitation until all of the solid had dissolved. The mixture is then degassed with dry ice and treated with an aqueous slurry of Raney nickel (approx 1.5 mL). After shaking under 50 psi of hydrogen, the reaction mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give 2-fluoro-6-(4-methyl-piperazin-1-yl)-pyridin-3-ylamine (contaminated with triethylammonium trifluoroacetate) as a red wine colored solid.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.C(OC([N:26]1[CH2:33][CH2:32][CH:31]2[CH:28]([NH:29][CH2:30]2)[CH2:27]1)=O)(C)(C)C.Cl[C:35]1[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([N:42]([CH3:44])[CH3:43])[N:36]=1.ClC1C=NC2C(=CC=CC=2)N=1>>[CH:28]12[N:29]([C:35]3[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([N:42]([CH3:44])[CH3:43])[N:36]=3)[CH2:30][CH:31]1[CH2:32][CH2:33][NH:26][CH2:27]2
Reactant: Cc1cc(Cl)nc(N(C)C)n1
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Agent: Clc1cnc2ccccc2n1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: Cc1cc(N2CC3CCNCC32)nc(N(C)C)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, substituting (1R,6S)-(3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester for 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester and (4-chloro-6-methyl-pyrimidin-2-yl)-dimethyl-amine for 2-chloro-quinoxaline in Step A. MS (ESI) mass calcd. for C13H21N5, 247.34. m/z found 248.1 [M+H]+. 1H NMR (CDCl3): 5.40 (s, 1H), 4.21-4.10 (m, 1H), 3.85 (t, J=7.4, 1H), 3.63-3.49 (m, 2H), 3.33 (s, 1H), 3.09 (d, J=9.3, 7H), 2.97-2.52 (m, 2H), 2.19 (s, 3H), 2.09-1.97 (1H), 1.77-1.59 (m, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[N:30]=[CH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[N:30]=[CH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:28]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1cc2ccccc2cn1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2cc3ccccc3cn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 3-bromoacetylisoquinoline (Preparation is described in Example 220).
Reaction SMILES: [NH2:1][C:2]1[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([N:21]=[C:22]=[O:23])[CH:18]=[CH:19][CH:20]=1.O>CS(C)=O>[O:12]=[C:8]1[NH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:22]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:24])[F:25])[CH:16]=2)=[O:23])[C:10](=[O:11])[NH:9]1
Reactant: Nc1c(C(=O)O)[nH]c(=O)[nH]c1=O
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1c(C(=O)O)[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Amino-orotic acid (0.86 g) was dissolved in DMSO (10 ml), treated with 3-trifluoromethylphenylisocyanate (0.9 ml) and after an hour with another 0.5 ml. The reaction was stirred for three days at room temperature. Water was added and the mixture was filtered and washed with water. The residue was slurried in water, treated with NaOH and worked through until basic. Filtration and acidification of the filtrate provided a precipitate, which was filtered, washed with water and dried. Recrystallisation from 96% EtOH provided 2,6-dioxo-5-[3-(3-trifluoromethyl-phenyl)-ureido]-1,2,3,6-tetrahydro-pyrimidine-4-carboxylic acid (330 mg). Mp. >300° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[C:23]([OH:28])(=[O:27])[C@H:24]([CH3:26])[OH:25]>CC(C)=O>[CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[C:4]=2[CH:3]=1.[C:23]([O-:28])(=[O:27])[CH:24]([CH3:26])[OH:25]
Reactant: C[C@H](O)C(=O)O
Agent: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Solvent: CC(C)=O
Product: CC(O)C(=O)[O-]
Temperature: -20 °C

Procedure:
To a clear solution of 5.0 g of olanzapine base in 150 ml acetone was added, at room temperature, a solution of 1.44 g of L-(+)-lactic acid in 50 ml of acetone. The reaction mixture was stirred at −20° C. and the solid was isolated. Yield: 3.36 g (52%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:9][C:10]1([CH3:17])[C:14]([CH3:16])([CH3:15])[O:13][BH:12][O:11]1>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:17])[C:14]([CH3:16])([CH3:15])[O:13][B:12]([CH:2]=[CH:1][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[O:11]1
Reactant: C#Cc1cccnc1
Reactant: CC1(C)OBOC1(C)C
Solvent: Cc1ccccc1
Product: CC1(C)OB(C=Cc2cccnc2)OC1(C)C
Temperature: 50 °C

Procedure:
Commercially available 3-ethynyl-pyridine 3b (1.03 g, 10 mmol) and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (7.26 mL, 50 mmole) in toluene (40 mL) were combined with carbonylchlorohydridotris(triphenylphosphine) ruthenium (II), RuHCl(CO)(PPh3) (476 mg, 0.50 mmol) at ambient temperature and the reaction mixture was heated at 50° C. in an oil-bath for 16 h. The toluene was evaporated and the crude compound was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, and water. The organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude product was eluted with a gradient of 10:1 to 2:1 hexane/ethyl acetate by flash chromatography to yield 3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-vinyl]-pyridine Compound 3c (2.2 g, 95% yield) as a yellow syrup. 1H NMR (300 MHz, CDCl3) δ 8.75 (d, 1H), 8.54 (dd, 1H), 7.83 (dt, 1H), 7.39 (d, 1H), 7.31 (dd, 1H), 6.27 (d, 1H), 1.34 (s, 12H); MS (ESI) m/z: 232.14 (M+H+).
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].[CH2:6]1[C:11](=O)N(Br)[C:8](=O)[CH2:7]1>CC1(C)N([O])C(C)(C)CCC1.C(OCC)(=O)C>[CH2:8]([CH2:2][CH:1]=[O:4])[CH2:7][C:6]1[CH:11]=[CH:8][CH:7]=[CH:6][CH:11]=1
Reactant: CC(=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=CCCCc1ccccc1
Yield: 125.2 %

Procedure:
β-Phenethylalcohol (2.0 g, 16.4 mmol), sodium acetate (2.0 g, 24.6 mmol), TEMPO (26 mg, 0.16 mmol) and ethyl acetate (15 ml) were put in a 50-ml egg plant type flask. The suspension was cooled to less than 10° C. in an ice bath, and thereto was added NBS (3.2 g, 18.0 mmol) divided in two portions. The insoluble materials were filtered off and the filtrate was washed with 5% aqueous sodium bicarbonate solution. The crude product was purified by distillation to give phenethylacetaldehyde (1.67 g, yield 85%).