Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38](Cl)=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1cnc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 2-Chloro-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.14) (244 mg, 0.9 mmol) according to general procedure II. Obtained as an orange solid (110 mg, 18%). MS (ISP) 590.3 [(M+H)+]; mp 252–253° C.
Reaction SMILES: [C:1]1([P:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2([Li])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][C:25]([NH:28][Si:29](Cl)([CH3:31])[CH3:30])([CH3:27])[CH3:26]>C1COCC1>[CH3:24][C:25]([NH:28][Si:29]([CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([P:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9]1)([CH3:31])[CH3:30])([CH3:27])[CH3:26]
Reactant: [Li]C1(P(c2ccccc2)c2ccccc2)C=Cc2ccccc21
Reactant: CC(C)(C)N[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CC(C)(C)N[Si](C)(C)C1C=C(P(c2ccccc2)c2ccccc2)c2ccccc21
Reaction time: 8 h
Yield: 98 %

Procedure:
(1-(Diphenylphosphino)-1H-indenyl)lithium (4.45 g, 14.53 mmol) dissolved in 40 mL of THF was added within 15 minutes to a 100 mL THF solution of N-(tert-butyl)-N-(1-chloro-1,1-dimethylsilyl)amine (3,37 g, 20.34 mmol). After stirring overnight a red solution resulted. Solvent was removed under vacuum to give a red oil. The residue was extracted with 35 mL of hexane and filtered. Hexane was removed leaving 6.12 g of red oil. Yield 98 percent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[OH-].[K+].[ClH:21].[Cl:22][CH2:23][C:24]1[C:25]([NH:35][CH3:36])=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([CH3:34])=[CH:29][CH:28]=2.Cl.CO>C1(C)C=CC=CC=1>[ClH:22].[ClH:21].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:23][C:24]1[C:25]([NH:35][CH3:36])=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([CH3:34])=[CH:29][CH:28]=2
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CNc1nc2ccc(C)cc2cc1CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCc1nc(O)c(Cc2cc3cc(C)ccc3nc2NC)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 5 %

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (250 mg, 1 mmol) in toluene (15 mL) in a 20 mL microwave vial was added a 2 N KOH solution (1 mL, 2 mmol) following by 3-(chloromethyl)-N,6-dimethylquinolin-2-amine hydrochloride MDE 32062 (352 mg, 1.2 mmol). The reaction mixture was stirred at 160° C. for 1.5 h under microwave irradiation then cooled to RT. The volatiles were removed under vacuum and the residue was taken back in a mixture of CH2Cl2:MeOH=9:1 (50 mL). The organic layer was washed with water (3×20 mL), brine (20 mL), dried over Na2SO4, filtered and evaporated to give yellow solid that was purified by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 90:10) to give, after evaporation and drying, 6,7-dimethoxy-4-(6-methyl-2-methylamino-quinolin-3-ylmethyl)-1-propyl-isoquinolin-3-ol (26 mg). This free base was dissolved in MeOH (5 mL) and a 0.19 N HCl solution in MeOH (600 μL, 0.11 mmol) was slowly added. The reaction mixture was stirred at 4° C. for 15 min. After evaporation of the solvent and drying under vacuum pump over P2O5, 6,7-dimethoxy-4-((6-methyl-2-(methylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol hydrochloride 34 was obtained as a yellow solid (28.7 mg, 5% yield).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].O.[NH2:17][NH2:18].[BH4-].[Na+].O>CO>[CH:1]([C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH:12]([NH:17][NH2:18])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)c1noc(C2CCC(=O)CC2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)c1noc(C2CCC(NN)CC2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
A mixture of 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexanone (Intermediate 11; 600 mg, 2.9 mmol) and hydrazine hydrate (160 mg, 3.2 mmol) in methanol (2 mL) was heated at reflux for 3 h. The reaction mixture was cooled to 0° C. and sodium borohydride (220 mg, 5.8 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 4 h and then at room temperature overnight. Water was added and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried (sodium sulfate), filtered, and evaporated to give [4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-hydrazine (280 mg, 43%) which was used directly in the next step without further purification. Mass spectrum M+=224.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][CH:13]2[CH2:15][CH2:14]2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: NC1CC1
Product: CSc1nc(Cl)c(C=O)c(NC2CC2)n1

Procedure:
Prepared as described above in Example 2 starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and cyclopropylamine to give the title compound 4-chloro-6-cyclopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.68 (m, 2H), 0.90 (m, 2H), 2.58 (s, 3H), 3.07 (m, 1H), 9.20 (br s, 1H), 10.28 (s, 1H). LC MS (m/e)=244 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.Cl[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=1>C(O)C>[CH:1]1([CH2:4][NH:5][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1nccc(Cl)n1
Reactant: NCC1CC1
Solvent: CCO
Product: Nc1nccc(NCC2CC2)n1
Temperature: 100 °C

Procedure:
To cyclopropylmethanamine (3.62 g, 50.9 mmol) in ethanol (90 mL) was added solid 4-chloropyrimidin-2-amine (6.00 g, 46.3 mmol). The reaction was stirred at reflux (100° C. oil bath) for 16 h. The reaction was cooled to room temperature and solvent was removed in vacuo. The product 237 obtained in quantitative yield. LCMS-ESI (POS), M/Z, M+1: Found 165.0, Calculated 165.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[CH2:13])[CH:11]=[O:12])([O-:3])=[O:2].[CH:14]([NH:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15].[O-]CC.[Na+]>C(O)C>[CH2:26]([O:25][C:23]([C:17]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH:11]([OH:12])[N:16]1[CH:14]=[O:15])=[O:24])[CH3:27]
Reactant: C=C(C=O)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(NC=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CC(c2ccccc2[N+](=O)[O-])C(O)N1C=O
Reaction time: 1 h

Procedure:
To a stirred, icebath-cooled mixture of 42.5 g. (0.24 mol) of acrolein of Example 1 and 50.4 g (0.25 mol) of diethyl formamidomalonate in 200 ml. of absolute ethanol was added, over 15 minutes, 4 ml. of a 1M solution of sodium ethoxide in ethanol. The mixture was stirred at 5° for 1 hour as the Michael adduct crystallized out. After the suspension had been stored for 4 hours at -20°, the product was collected by filtration washed with ethanol (-60°) and dried to yield 82.4 g (90%) of offwhite crystals, m.p. 109-111°. The analytical sample was prepared by recrystallization from ethanol: white crystals, m.p. 113-115°.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[Br:11][C:12]1[C:13]([O:24][CH3:25])=[C:14]([C:19]2[NH:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[C:16]([Br:18])[CH:17]=1.C([O-])(=O)C.[Na+]>ClCCCl>[Br:11][C:12]1[C:13]([O:24][CH3:25])=[C:14]([C:19]2[NH:20][C:21]([CH:8]=[O:9])=[CH:22][CH:23]=2)[CH:15]=[C:16]([Br:18])[CH:17]=1
Reactant: CN(C)C=O
Reactant: COc1c(Br)cc(Br)cc1-c1ccc[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1c(Br)cc(Br)cc1-c1ccc(C=O)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Phosphorus oxychloride (0.18 ml, 1.9 mmol) was added to N,N-dimethylformamide (0.15 ml, 1.9 mmol) at 0° C. under argon with constant stirring. The resulting mixture was allowed to warm to room temperature and was then stirred for 1.5 h. 1,2-Dichloroethane (1.5 ml) was added and a solution of 2-(3,5-dibromo-2-methoxyphenyl)-1H-pyrrole (0.30 g, 0.91 mmol) in 1,2-dichloroethane (3 ml) was then added at 0° C. The reaction mixture was stirred at room temperature for 16 h. On cooling, the mixture was poured onto crushed ice and basified with aqueous sodium acetate (50%, 20 ml). The organic phase was separated and the aqueous layer was extracted with ether. The combined organic extracts were washed with aqueous sodium hydrogen carbonate, dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on alumina (Brockmann grade 1) with ether - methanol (0-1% ) gradient elution gave the title compound (D29) as a beige solid (0.18 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C(OCC)(=O)C>[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:3][CH:4]=1)#[N:10]
Reactant: N#CCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CC#N)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
4-Hydroxyphenylacetonitrile (13.3 g, 100 mmol) and potassium carbonate (20.73 g, 150 mmol) were added to dimethylformamide (75 mL). Subsequently, tert-butyl 2-bromoisobutyrate (50.41 mL, 250 mmol) was added thereto, and the mixture was stirred for 24 hours at 80° C. The temperature of the reaction mixture was returned to room temperature, and ethyl acetate was added thereto. Washing was performed sequentially with water and brine, followed by drying over sodium sulfate. The resultant mixture was subjected to concentration under reduced pressure and purification by silica gel column chromatography (n-hexane/ethyl acetate=7/1), whereby the target compound was obtained (18.62 g, 67.62 mmol, 67.6%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:20])[CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[CH:9][CH:8]=1>>[O:20]=[C:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])=[CH:8][CH:9]=1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCC(=O)Cl
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: CCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 43.3 %

Procedure:
In a manner similar to that described in Example 3, propionyl chloride (0.029 g, 0.00032 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.027 g of 4-oxo-4-[4-(propionylamino)-phenyl]-butyric acid as an off-white solid; MS-(AP+) MH+250.
Reaction SMILES: [F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]([N:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[CH2:12][NH2:13])=[CH:7][N:6]=1)([F:4])[CH3:3].[Cl:22][C:23]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].C1COCC1.CCN(C(C)C)C(C)C>>[Cl:22][C:23]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:13][CH2:12][CH:11]([C:8]1[CH:7]=[N:6][C:5]([C:2]([F:1])([F:4])[CH3:3])=[N:10][CH:9]=1)[N:14]1[CH2:19][CH2:18][C:17]([F:20])([F:21])[CH2:16][CH2:15]1)=[O:26]
Reactant: CC(F)(F)c1ncc(C(CN)N2CCC(F)(F)CC2)cn1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)c1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(F)(F)CC2)cn1
Yield: 47.4 %

Procedure:
2-(2-(1,1-Difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamine (34 mg, 0.044 mmol, 40% pure) and 2,3-dichlorobenzoyl chloride (65 mg, 0.31 mmol), was dissolved in anhydrous THF (4400 mg, 5 ml, 61.0 mmol), DIPEA (111 mg, 0.15 ml, 0.859 mmol) was added and stirred over night. The solution was concentrated and purified by column chromatography on silica gel (petroleum ether: EtOAc=1:0 to 0:1) followed by HPLC, to afford 2,3-dichloro-N-(2-(2-(1,1-difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide (10 mg, 47% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]([N:16](C)[C:17](=O)OC(C)(C)C)[CH2:7]1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]([NH:16][CH3:17])[CH2:7]1.[C:31]([OH:33])([C:30]([F:35])([F:34])[F:29])=[O:32]
Reactant: CN(C(=O)OC(C)(C)C)C1Cc2ccccc2N(Cc2ccc(Cl)c(Cl)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1Cc2ccccc2N(Cc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydroquinolin-3-yl(methyl)carbamate (0.760 g, 1.8 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (6 mL). The mixture was stirred at room temperature for 1 hour. Solvent was removed under reduced pressure and the residue triturated with hexane and dried under vacuum to give 1-(3,4-dichlorobenzyl)-N-methyl-1,2,3,4-tetrahydroquinolin-3-amine as its solid TFA salt (580 mg). 1H NMR (DMSO) 400 MHz δ 7.57 (m, 2H), 7.28 (dd, J=2.0 Hz and 19.2 Hz, 1H), 7.01 (m, 2H), 6.63 (t, J=7.2 Hz, 1H), 6.54 (d, J=7.6 Hz, 1H), 4.50 (q, J=17.2 Hz, 2H), 3.68 (br, 1H), 3.58 (d, J=12 Hz, 1H), 3.39 (m, 1H), 3.20 (dd, J=5.2 Hz and 16.8 Hz, 1H), 2.89 (dd, J=5.6 Hz, and 16.4 Hz, 1H), 2.63 (t, J=5.2 Hz, 3H). LCMS m/e 321 (M+H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:18]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(OCCCOc2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccccc1)c1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1

Procedure:
1,3-Diphenoxypropane (22.8 g), benzoyl chloride (31 g) and anhydrous aluminum chloride (33 g) are reacted in 1,2-dichloroethane (300 ml) for eighteen hours at 70° to yield 33.4 g (77% of theory) of colorless crystals mp 146°-8°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:13]
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc2cc(Br)ccc2c1Cl
Product: Oc1ccc2cc(-c3ccccc3)ccc2c1Cl

Procedure:
The title compound was prepared by reacting 6-bromo-1-chloro-naphthalen-2-ol (300 mg, 1.17 mmol) with phenylboronic acid (170.7 mg, 1.40 mmol) according to method A to yield 240 mg (81%) of white solid: mp 135–137° C.; 1H NMR (DMDO-d6): δ 7.33 (1H, d, J=8.85 Hz), 7.39 (1H, td, J=7.25 Hz, J=0.75 Hz), 7.51 (2H, t, J=7.59 Hz), 7.80 (2H, d, J=7.63 Hz), 7.88 (1H, d, J=8.96 Hz), 7.93 (1H, dd, J=8.85 Hz, J=1.19 Hz), 8.10(1H, d, J=8.84 Hz), 8.20 (1H, s), 10.53 (1H, s); MS (ESI) m/z 253/255 (M−H)−.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[C:26]1([NH:32]N)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1ccccc1
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Yield: 64 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and phenylhydrazine according to the method described for Example 1 in 64% yield. MS: M=399.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@H:7]2[O:11][C@@H:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:9]3[C@H:8]2[OH:17])[CH2:4][O:3]1.C(OC(=O)C)(=O)C.[BH4-].[Na+]>CS(C)=O>[CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@H:7]2[O:11][C@@H:10]3[O:12][C:13]([CH3:16])([CH3:15])[O:14][C@@H:9]3[C@@H:8]2[OH:17])[CH2:4][O:3]1
Reactant: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@@H](O)[C@H]2O1

Procedure:
In a preferred embodiment of the method according to the invention, 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose is reacted with a mixture of DMSO and acetic anhydride in a molar ratio of 1:3 to 1:9 at 20-25° C., for around 12-48 h, typically for around 24 h, followed by reaction with sodium borohydride at 20-25° C., for around 0.5-2 h, typically for around 1 h, in order to yield 1,2:5,6-di-O-isopropylidene-α-D-allofuranose. The two reactions are performed sequentially, i.e. without isolation or purification of the intermediate product, i.e. the ulose.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:36])[C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19](=[O:35])[C@H:20]([CH:32]([CH3:34])[CH3:33])[NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])(C)(C)C>C(Cl)Cl>[CH2:25]([O:24][C:22]([NH:21][C@H:20]([C:19]([N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[C:13]([OH:36])=[O:12])=[O:35])[CH:32]([CH3:34])[CH3:33])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Trifluoroacetic acid (200 ml) was added to a mixture of N-benzyloxycarbonyl-L-valyl-L-proline tert-butyl ester (80.0 g) in methylene chloride ((300 ml) at 0° C. over approximately 30 minutes. After stirring at 0° C. for one hour, the reaction mixture was allowed to rise to ambient temperature and stirred an additional 3 hours. The reaction mixture was then concentrated under vacuum and reconcentrated four times from toluene to remove residual trifluoroacetic acid. The resulting viscous oil was dried under vacuum for 16 hours. The crude product was purified on by chromatography on silica gel, using methylene chloride as eluant, to give N-benzyloxycarbonyl-L-valyl-L-proline (A) (63.6 g) as a pale yellow viscous oil; NHR (d6 -DMSO): 0.92(2d,6H), 1.65-2.05(2 m,4H), 2.25(m,1H), 3.60(m,1H), 3.80(m,1H), 4.05(dd,1H), 4.25(m,1H), 5.02(2d,2H), 7.35(m,5H), 7.50(d,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:24][CH2:25][C:26]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38](Br)[CH:39]=1)(=[O:33])=[O:32])([CH2:28][OH:29])[CH3:27]>>[OH:24][CH2:25][C:26]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([C:23]#[C:22][C:21]2[CH:20]=[N:19][N:12]3[C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)=[N:10][C:11]=23)[CH:39]=1)(=[O:33])=[O:32])([CH2:28][OH:29])[CH3:27]
Reactant: CC(CO)(CO)NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: CC(CO)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (Example B.4) (81 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (24 mg, 16%). MS (ISN) 598.2 [(M−H)−].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCC1CCCCN1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCC1CCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of piperidine-2-methanol (12; 6 g, 52.09 mmol) in dimethylformamide (DMF, 50 mL) were added successively K2CO3 (10.78 g, 78.14 mmol) and benzyl bromide (6.85 mL, 57.30 mmol) at 0° C. and the mixture stirred at rt for 16 hours. The reaction mixture was then filtered and the filtrate was concentrated. The residue was dissolved in EtOAc and the organic layer was washed with water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography on 230-400 mesh silica gel eluting with 30% EtOAc-hexane to provide compound 13.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH2:21][C:22]([F:25])([F:24])[F:23])[N:19]=[C:18]([CH3:26])[N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([CH:34]2[CH2:38][CH2:37][CH2:36][NH:35]2)[CH2:30][CH2:29]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:26][C:18]1[N:17]=[C:16]([C:10]2[N:11]=[C:12]3[C:13]4[CH:14]=[N:15][C:2]([N:35]5[CH2:36][CH2:37][CH2:38][CH:34]5[CH:31]5[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]5)=[CH:3][C:4]=4[O:5][CH2:6][CH2:7][N:8]3[CH:9]=2)[N:20]([CH2:21][C:22]([F:25])([F:24])[F:23])[N:19]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Reactant: CN1CCC(C2CCCN2)CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CCCC4C4CCN(C)CC4)cc2OCC3)n(CC(F)(F)F)n1
Temperature: 110 °C
Reaction time: 3 h
Yield: 11.9 %

Procedure:
A mixture of 12-chloro-4-[3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (50.0 mg, 0.130 mmol), 1-methyl-4-(pyrrolidin-2-yl)piperidine (30.0 mg, 0.178 mmol), Pd(P-t-Bu3)2 (6.00 mg, 0.0120 mmol), and NaOt-Bu (40.0 mg, 0.412 mmol) in toluene (20.0 mL) in a seal tube was stirred at 110° C. for 3 h. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-40% gradient of CH3CN in 0.5% NH4HCO3 to afford 253 (8 mg, 12% yield) as white solid. LCMS (ESI): RT=4.70 min, m/z: 517.3 [M+H+]. 1H-NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.66 (s, 1H), 5.85 (s, 1H), 5.70 (dd, J=8.5 Hz, J=23.5 Hz, 2H), 4.46-4.43 (m, 4H), 4.06 (s, 1H), 3.38 (s, 1H), 3.26 (s, 1H), 2.09 (s, 3H), 1.95 (s, 9H), 1.84-1.72 (m, 2H), 1.52-1.34 (m, 3H), 1.19-1.12 (m, 2H)