Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45][C:46](=[O:48])[CH3:47])=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:41](=[O:42])[C:40]1[CH:44]=[C:36]([CH2:35][C:29]2[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=2[CH3:49])[CH:37]=[CH:38][C:39]=1[O:45][C:46](=[O:48])[CH3:47]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccccn1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccccn3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.1 %

Procedure:
2-Aminopyridine (0.282 g, 3.000 mmol), triethylamine (0.304 g, 3.000 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.507 g, 3.000 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.374 g, 1.000 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.140 g, 0.311 mmol, 31%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([O:14]CC)=O)=[N:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:1]1([C:7]2[C:8]([C:12]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:14])=[N:9][NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1n[nH]cc1-c1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1n[nH]cc1-c1ccccc1

Procedure:
5.0 g (23.12 mmol) of ethyl 4-phenyl-3-pyrazolecarboxylate were heated to 120° under reduced pressure for 2 hours with 7.4 g (46.19 mmol) of t-butyl (2-aminoethyl)carbamate, whereby the ethanol formed was distilled off continuously. The reaction mixture was then taken up in methylene chloride and chromatographed on 150 g of silica gel with 9:1, 8:2 and 7:3 mixture of methylene chloride and ethyl acetate as the eluting agent. The fractions which were pure according to the thin-layer chromatogram were combined and evaporated, ant the residue was crystallized from ethyl acetate/hexane, whereby there were obtained 5.1 g (66.8%) to t-butyl [2-(4-phenylpyrazole-3-carboxamido)ethyl]carbamate as white crystals, melting point 71°/162°-163° (still containing 0.05 mol of hexane).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:13])=[C:9]([CH2:11][OH:12])[N:10]=1.Cl[C:15]1[N:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:13])=[C:9]([CH2:11][O:12][C:15]2[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=2)[N:10]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1oc(-c2ccco2)nc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of [2-(2-furyl)-5-methyl-4-oxazolyl]methanol (5.18 g), 6-chloro-3-cyanopyridine (4.00 g) and N,N-dimethylformamide (100 ml) was added sodium hydride (60% in oil, 1.27 g) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and 6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]nicotinonitrile was obtained as colorless crystals (6.97 g, yield 86%) from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 105–106° C.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][C@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH:24]2[CH2:26][CH2:25]2)[C:18](=[O:27])[CH2:17]3)[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH:24]2[CH2:26][CH2:25]2)[C:18](=[O:27])[CH2:17]3)[CH2:9]1
Reactant: COC(=O)Cl
Reactant: NC[C@@H]1CN(c2cc(F)c3c(c2)CC(=O)N3C2CC2)C(=O)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC[C@H]1CN(c2cc(F)c3c(c2)CC(=O)N3C2CC2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.055 ml, 0.715 mmol) is added dropwise to (R)-5-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-1-cyclopropyl-7-fluoro-1,3-dihydro-indol-2-one (Example 50, Step 5, 0.200 g, 0.476 mmol) and diisopropylethylamine (0.349 ml, 1.90 mmol) in dichloromethane (5 ml) at 0° C. The reaction is stirred at 0° C. for 30 minutes and then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated. The residue is purified by PTLC (5% MeOH/DCM) to give the title compound as a yellow solid. HPLC r.t. 4.05 min; 1H NMR (300 MHz, CDCl3) 7.23 (m, 1H), 7.18 (m, 1H), 5.12 (t, 1H), 4.77 (m, 1H), 4.02 (t, J=8.7 Hz, 1H), 3.79 (dd, J=6.6, 9 Hz, 1H), 3.69 (s, 3H), 3.51 (m, 2H), 2.85 (m, 1H), 0.97 (m, 2H); MS for C17H18FN3O5 m/z 364.0 (M+H)+.
Reaction SMILES: C([NH:11][C@@H:12]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[C@H:26]1[O:55][C@H:54]([CH2:56][O:57]CC2C=CC=CC=2)[C@@H:45]([O:46]CC2C=CC=CC=2)[C@H:36]([O:37]CC2C=CC=CC=2)[C@@H:27]1[O:28]CC1C=CC=CC=1)[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[H][H]>C(O)C.[OH-].[Pd+2].[OH-].[C]>[NH2:11][C@@H:12]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[C@H:26]1[O:55][C@H:54]([CH2:56][OH:57])[C@@H:45]([OH:46])[C@H:36]([OH:37])[C@@H:27]1[OH:28])[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: O=C(N[C@@H](Cc1c([C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N[C@@H](Cc1c([C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[nH]c2ccccc12)C(=O)O
Yield: 59.6 %

Procedure:
To a solution of (2S*)-2-[N-(carbobenzyloxy)amino]-3-[2-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)indole-3-yl]propionic acid [compound (XII-2) wherein R1 to R4 are benzyl and Ar is phenyl](90.5 mg (0.11 mmol)) in ethanol (25 ml) was added 20% palladium hydroxide-carbon catalyst (75 mg) and the mixture was stirred at about 60° C. for about 11 hours under atmospheric pressure in the presence of hydrogen. The reacted solution was filtrated on Celite and the filtrate was concentrated. The residue was fractionated by high performance liquid chromatography [column: YMC-Pack ODS-AM SH-365-10AM, 500×30 mm, S-10, 120Å; temperature: room temperature; migrating layer: 5% acetonitrile-water; flow rate: 40 ml/min.; detection: 278 nm (UV)] and then freeze-dried to give 24 mg (yield 62%) of (2S*)-2-amino-3-[2-(α-D-mannopyranosyl)indole-3-yl]propionic acid [compound (XIII-2)].
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])=[C:14]([F:34])[CH:13]=1>>[CH3:32][C:31]1[C:26]([N:23]2[CH2:24][CH2:25][N:20]([C:18]([C:15]3[CH:16]=[CH:17][C:12]([N:5]4[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]4(=[O:10])=[O:9])=[CH:13][C:14]=3[F:34])=[O:19])[CH2:21][CH2:22]2)=[N:27][CH:28]=[C:29]([CH3:33])[CH:30]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CC(C)[C@@H]1CCS(=O)(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C(C)C)CCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 16.4 %

Procedure:
Using (S)-3-isopropylisothiazolidine 1,1-dioxide (400 mg) described in Preparation Example 6 and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (392 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 4, the title compound (78 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[NH:10][C:9]2[N:8]=[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:6]=[CH:5][C:4]=2[CH:3]=1.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:7]2[N:8]=[C:9]3[C:4]([CH:3]=[C:2]([CH3:1])[C:11](=[O:12])[NH:10]3)=[CH:5][CH:6]=2)[CH2:29][CH2:28]1
Reactant: Cc1cc2ccc(OCCCC=O)nc2[nH]c1=O
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]c1=O
Reaction time: 0.08 h
Yield: 19.4 %

Procedure:
To a solution of crude 4-(6-methyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.65 g, 2.24 mmol, 1.0 equiv) in anhydrous methanol (40 mL) cooled to 0° C. was added 2,3-dichlorophenylpiperazine (1.2 g, 4.0 mmol, 2.0 equiv). The mixture was stirred for 5 min and NaBH(OAc)3 (2.3 g, 11.2 mmol, 5.0 equiv) was added. The reaction mixture was brought to room temperature and stirred overnight. The reaction was quenched with water and was concentrated to remove methanol completely. The resultant pale green residue was dissolved in ethyl acetate and washed with 0.5 N HCl (1×10 mL), saturated NaHCO3 solution (1×10 mL) and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, 2% MeOH/CH2Cl2) to afford the title compound as a white foamy solid (0.2 g, 30%). MS: ES+ 461.03, 463.03 (Exact Mass: 460.14).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=C(C#N)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[OH-:13].[K+].[CH2:15]([OH:17])[CH3:16]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:16]([C:15]([OH:13])=[O:17])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: N#Cc1cc(Cl)c2[nH]ncc2c1
Reactant: [OH-]
Reactant: CCO
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(Cl)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-1H-indazole-5-carbonitrile (250 mg, 1.41 mmol) in ethanol/water (3:1 ration, 15 mL) was added potassium hydroxide (395 mg, 7.04 mmol) and the mixture was heated at reflux. After 3 houra, the majority of the ethanol was allowed to distill off, additional potassium hydroxide (614 mg) was added and heating was continued for overnight. The reaction mixture was cooled to room temperature, washed with Et2O (3×20 mL) and the organic extract was acidified with 1 N HCl. The resultant precipitate was isolated by vacuum filtration, washed with water (about 15 mL) and heptane (about 15 mL), dried at room temperature/0.5 mmHg to provide the title compound (221 mg, 79.7%).
Reaction SMILES: Cl.CON(C)[C:5](=[O:14])[C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[N:8][C:7]=1[NH2:13].[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>C1COCC1.CCOCC>[NH2:13][C:7]1[C:6]([C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])=[CH:11][C:10]([Br:12])=[CH:9][N:8]=1
Reactant: CON(C)C(=O)c1cc(Br)cnc1N
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Nc1ncc(Br)cc1C(=O)c1ccccc1
Temperature: -50 °C

Procedure:
1.00 g (3.38 mmol) of N-methoxy-N-methyl-2-amino-5-bromonicotinamide hydrochloride was suspended in 50 ml of anhydrous THF under nitrogen. The suspension was cooled to −50° C. and 13.5 ml of a 1.0 M solution of phenylmagnesium bromide in ether was added rapidly to afford an orange solution. The mixture was stirred, and slowly warmed to room temperature. The resulting yellow-orange solution was distributed between 75 ml of a 10% aqueous citric acid solution and 200 ml of ethyl acetate. The organic phase was separated and washed with 75 ml of a 10% aqueous citric acid solution and 75 ml of saturated aqueous sodium bicarbonate solution. The organic phase was then dried over sodium sulfate and evaporated to afford 985 mg of a yellow crystalline solid. 1H-NMR (d6-DMSO) δ: 8.34 [1H] d, 7.72 [2H] s, 7.70 [1H] d, 7.65 [1H] t(m), 7.63 [2H] d(m), 7.56 [2H] t(m). MS: m/z 277 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[N:36][CH:35]=[CH:34][N:33]=1)CCC.CN(C=[O:50])C>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>[C:21]([OH:25])(=[O:50])[CH3:20].[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:19]1[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:32]2[CH:37]=[N:36][CH:35]=[CH:34][N:33]=2)[CH:3]=1
Reactant: CN(C)C=O
Reactant: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)ccn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)O
Product: COc1cc(C2(c3cccc(-c4cnccn4)c3)N=C(N)c3c(F)cccc32)ccn1
Yield: 48.5 %

Procedure:
1-(3-Bromophenyl)-4-fluoro-1-(2-methoxypyridin-4-yl)-1H-isoindol-3-amine (0.150 g, 0.36 mmol), 2-(tributylstannyl)pyrazine (0.120 mL, 0.38 mmol), tetrakis(triphenylphosphine)palladium(0) (0.042 g, 0.04 mmol) and DMF (4 mL) were put in microwave vial and irradiated in a microwave reactor at 150° C. for 20 min. The resulting product mixture was filtered and purified by preparative-HPLC to give the title compound 0.083 g, (48.5% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[S:8][C:6]=2[N:7]=1.[OH-].[Na+].[CH3:38]N(C=O)C>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)[C:5]2[N:10]=[C:9]([CH:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH3:38])[S:8][C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(Cc3ccc(Cl)cc3)sc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(c1ccc(Cl)cc1)c1nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a suspension of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(4-chlorophenylmethyl)thiazolo[5,4-d]pyrimidine (53 mg, 0.1 mmol) in DMF (2 ml) was added 1N NaOH (150 μl, 0.15 mmol) and Mel (7 μl, 0.11 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/80), yielding the pure title compound (40 mg, 74%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:20][N:21](C=O)C>C(OCC)(=O)C.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.[C-]#N.[Zn+2].[C-]#N>[C:20]([C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:21]
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCOCCc1cccc(C#N)c1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
Pd(Ph3P)4 (0.53 g) was added in one portion to tert-butyl 3-(3-bromophenethoxy)propanoate [Preparation 3, Step i)] (3.00 g), and zinc cyanide (1.68 g) in DMF (35 mL) under nitrogen. The resulting mixture was stirred at 130° C. for 30 min. The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through Celite. Isohexane (100 mL) was added and the mixture was washed with water (4×20 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0-20% ethyl acetate in isohexane to afford the subtitled compound (2.30 g). 1H NMR (300 MHz, CDCl3) δ 7.54-7.43 (m, 3H), 7.41-7.34 (m, 1H), 3.67 (t, J=6.3 Hz, 2H), 3.66 (t, J=6.6 Hz, 2H), 2.89 (t, J=6.5 Hz, 2H), 2.47 (t, J=6.3 Hz, 2H), 1.43 (s, 9H).
Reaction SMILES: [NH:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([N:21]1[CH2:26][C:25]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)([CH2:27][CH2:28][CH2:29]OS(C)(=O)=O)[CH2:24][O:23][C:22]1=[O:43])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:50](OC(=O)C)(=[O:52])[CH3:51].Cl>CN(C=O)C.CCOCC.O>[ClH:41].[CH2:14]([N:21]1[CH2:26][C:25]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)([CH2:27][CH2:28][CH2:29][N:11]2[CH2:12][CH2:13][CH:8]([N:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:50](=[O:52])[CH3:51])[CH2:9][CH2:10]2)[CH2:24][O:23][C:22]1=[O:43])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(Cc2ccccc2)C1
Reactant: c1ccc(NC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(=O)N(c1ccccc1)C1CCN(CCCC2(c3ccc(Cl)c(Cl)c3)COC(=O)N(Cc3ccccc3)C2)CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 1.76 g of 4-anilinopiperidine, 2 g of the compound obtained in step C of EXAMPLE 8 and 0.75 g of potassium carbonate in 10 ml of DMF is heated at 50° C. for 1 hour 30 minutes. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed three times with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained is taken up with 10 ml of acetic anhydride and the reaction mixture is stirred for 48 hours at RT. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed twice with 20% aqueous ammonia solution, twice with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The product obtained is taken up with a saturated solution of gaseous HCl in ether and the solvent is evaporated off under vacuum to give 1.4 g of the expected product after crystallization from AcOEt. M.p.=195° C.
Reaction SMILES: CC(C1C=CC=CC=1N)CC(C)C.CC(C)CC(C1C=CC=CC=1N)=C.CC(C1C=CC=CC=1N)=CC(C)C.[CH3:40][CH:41]([CH3:64])[CH2:42][C:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:52]([C:54]1[C:55]([C:60]([F:63])([F:62])[F:61])=[N:56][N:57]([CH3:59])[CH:58]=1)=[O:53])=[CH2:44]>>[CH3:44][C:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:52]([C:54]1[C:55]([C:60]([F:62])([F:63])[F:61])=[N:56][N:57]([CH3:59])[CH:58]=1)=[O:53])=[CH:42][CH:41]([CH3:64])[CH3:40]
Reactant: C=C(CC(C)C)c1ccccc1NC(=O)c1cn(C)nc1C(F)(F)F
Agent: C=C(CC(C)C)c1ccccc1N
Agent: CC(=CC(C)C)c1ccccc1N
Agent: CC(C)CC(C)c1ccccc1N
Product: CC(=CC(C)C)c1ccccc1NC(=O)c1cn(C)nc1C(F)(F)F
Yield: 68 %

Procedure:
The same procedures as described in Example 2(1) were carried out except that 2-(1,3-dimethylbutyl)aniline was replaced by a 1:1 mixture of 2-(4-methyl-1-pentene-2-yl)aniline and 2-(1,3-dimethyl-1-butenyl) aniline. A mixture of N-[2-(4-methyl-1-pentene-2-yl)phenyl ]-3-trifluoromethyl-1-methylpyrazole-4-carboxamide and N-[2-(1,3-dimethyl-1-butenyl)phenyl ]-3-trifluoromethyl-1-methylpyrazole-4-carboxamide was obtained as a yellow crystal. Yield was 68%. Melting point was 66-74° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[O:33]([CH2:40][C:41](Cl)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:41](=[O:42])[CH2:40][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:20][CH2:19]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Reactant: O=C(Cl)COc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(N2CCN(C(=O)COc3ccccc3)CC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.1 %

Procedure:
To a solution of 5-amino-2-(4-fluorophenyl)-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) in DMF (2 ml) was added diisopropylethylamine (0.33 mmol, 55 μL) followed by phenoxyacetyl chloride (0.17 mmol). The reaction was stirred at room temperature for 4 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 0.5% CH3OH in CH2Cl2), yielding the pure title compound (30 mg) which was characterized by its mass spectrum: MS m/z (%): 465 ([M+H]+, 100).
Reaction SMILES: [K].N#N.C(=[C:7]([CH:9]([CH2:11][OH:12])[OH:10])[OH:8])(C)C.CS(O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O>C1C=CC=CC=1>[CH2:33]([O:12][CH2:11][CH:9]([CH2:7][OH:8])[OH:10])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: CC(C)=C(O)C(O)CO
Reactant: CCCCCCCCCCCCCCCCOS(C)(=O)=O
Agent: N#N
Agent: [K]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(O)CO
Temperature: 0 °C
Yield: 74.9 %

Procedure:
Potassium metal (1.5 g, 38.36 mmol) and anhydrous benzene (180 ml) were placed in a 500 ml three-neck round-bottomed flask equipped with a reflux condenser, dropping funnel, stir bar, and N2 atmosphere. The reaction mixture was refluxed. When the potassium metal had melted, isopropylidene glycerol (6 ml, 48.25 mmol) was added dropwise and the reaction continued to reflux an additional 2.5 hours. A solution of hexadecyl methane sulfonate (10.0 g 32.25 mmol) in anhydrous benzene (80 ml) was added dropwise and the reaction refluxed overnight. The heat was removed and the reaction mixture was cooled to 0° C. Water was added and the benzene layer was removed, washed with H2O, dried (MgSO4) and filtered. This residue was treated as in METHOD A for the hydrolysis of the acetal group to provide compound 35, rac-1-O-hexadecylglycerol (7.65 g 75%, based on mesylate 34).