Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:15][CH2:16][CH3:17])[CH2:9][CH2:8][CH:7]([C:10](OCC)=[O:11])[CH2:6][CH2:5]1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:16]([O:15][C:4]1([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH:7]([CH2:10][OH:11])[CH2:8][CH2:9]1)[CH3:17]
Reactant: CCOC(=O)C1CCC(OCC)(OCC)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC1(OCC)CCC(CO)CC1

Procedure:
Ethyl 4,4-diethoxycyclohexanecarboxylate (6.67 g) synthesized according to a literature procedure (European Journal of Organic Chemistry, 2008, 5, 895) in tetrahydrofuran (60 mL) was treated with 2 M lithium aluminum hydride in tetrahydrofuran (14.5 mL) at 0° C. for 1 hour. Water (3 mL) was slowly added to quench the reaction. The precipitates were filtered off and washed with ethyl acetate. The filtrate was dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:6][N:5]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Br.[Cl-].[Na+]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[O:20]1[CH2:19][CH:18]1[CH2:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[O:8][C:4]([CH3:3])=[N:5][N:6]=1
Reactant: Cc1nnc(-c2ccccc2O)o1
Reactant: BrCC1CO1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1nnc(-c2ccccc2OCC2CO2)o1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
1.6 g of sodium hydride, in the form of a 55% strength suspension in paraffin oil (0.036 mole) are introduced into 70 ml of anhydrous tetrahydrofuran and 6.3 g (0.036 mole) of ortho-(5-methyl-1,3,4-oxadiazol-2-yl)-phenol, dissolved in 50 ml of tetrahydrofuran, are added dropwise. 5 g (0.036 mole) of epibromohydrin are then introduced dropwise, 10 ml of hexamethylphosphorotriamide are added to the reaction mixture, and the whole is stirred for 32 hours at room temperature. Thereafter, the reaction mixture is poured into 500 ml of aqueous sodium chloride solution and repeatedly extracted by shaking with diethyl ether. The combined ether extracts are dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil. This crystallizes on triturating with a toluene/hexane mixture. 5.5 g (66% of theory) of colorless crystals are obtained; melting point 38°-40° C.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[OH-].[K+].[F:8][C:9]([F:22])([F:21])[C:10]1([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[N:12]=[N:11]1.O>C(#N)C>[O:18]1[CH2:2][CH:17]1[C:16]1[CH:19]=[CH:20][C:13]([C:10]2([C:9]([F:8])([F:21])[F:22])[N:11]=[N:12]2)=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(C2(C(F)(F)F)N=N2)cc1
Reactant: C[S+](C)C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: FC(F)(F)C1(c2ccc(C3CO3)cc2)N=N1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 52.7 %

Procedure:
0.95 g of trimethylsulfonium iodide and 0.52 g of potassium hydroxide were dissolved in 4 ml of acetonitrile, and agitated for 10 minutes at 60° C. in a nitrogen gas atmosphere. 1.00 g of 4-(3-trifluoromethyl-3H-diazirine-3-yl)benzaldehyde were added together with 5.3 ml of acetonitrile, then 0.02 g of water were added. This was agitated for one hour at 60° C. in a nitrogen gas atmosphere. After extracting with ethyl ether, the resulting substance was washed twice with water and once with saturated saline solution, then dried with anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the resulting substance was purified by silica gel chromatography (hexane:chloroform=1:2, V/V) to obtain 0.56 g of 3-(4-oxiranylphenyl)-3-trifluoromethyl-3H-diazirine (52% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][O:9][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15])[N:7]=1
Reactant: OCc1cccc(Br)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Temperature: 25 °C

Procedure:
(6-Bromopyridin-2-yl)methanol (5.0 g, 26.6 mmol), DMAP (0.65 g, 5.3 mmol), tert-butyl(chloro)dimethylsilane (4.8 g, 31.9 mmol) and imidazole (2.3 g, 34.0 mmol) was mixed in DCM (100 mL) and stirred at room temperature over night. The reaction mixture was washed with water (3×100 mL), dried over a phase separator and concentrated in vacuo to give the product as an oil. Yield: 8.3 g (103%) 1H NMR (400 MHz, CDCl3) δ 7.55 (t, 1H, J=7.87 Hz), 7.46 (d, 1H, J=7.87 Hz), 7.32 (d, 1H, J=7.87 Hz), 0.94 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: C([O:8][C:9](=[O:40])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:25]=3)[CH:20]=2)=[O:18])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH2:30]([O:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([OH:40])=[O:8])=[CH:11][CH:12]=1)=[O:18])[CH:28]=[CH:27]2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCOc1ccc2cc(C(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)ccc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc2cc(C(=O)Oc3ccc(C(=O)O)cc3)ccc2c1
Yield: 97.5 %

Procedure:
To 37.6 g (0.07 mol) of the 4-(6-decyloxy-2-naphthoyloxy)benzoic acid benzyl ester obtained in the first stage was added 3.76 g of 5% palladium/carbon, and further added 188 g of THF. Then, hydrogen gas was blown into the mixture. The resultant mixture was stirred overnight and filtered to obtain 30.6 g of 4-(6-decyloxy-2-naphthoyloxy)benzoic acid.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17]Cl)(OC(C)(C)C)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:45])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH:35]2[C:44]3[N:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:38][CH2:37][CH2:36]2)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[CH2:37]1[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[N:43][C:44]=2[CH:35]([N:34]([CH2:17][C:9]2[NH:8][C:12]3[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:26]([NH:25][C:20]3[N:19]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:45])=[CH:28][CH:29]=2)[CH2:36]1
Reactant: O=C(Nc1ccccn1)c1ccc(CNC2CCCc3cccnc32)cc1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccn1)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 47.6 %

Procedure:
N-BOC-chloromethylbenzimidazole (115 mg, 0.43 mmol), N-Pyridin-2-yl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzamide (AMD9362) (155 mg, 0.43 mmol), and K2CO3 (179 mg, 1.29 mmol) were heated to reflux in CH3CN (3 mL) for 24 hours under N2. The reaction mixture was diluted with 200 mL ethyl acetate, and washed with sat. NaHCO3, brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, followed by radial chromatography on silica gel (2 mm plate, 3:3:94 CH3OH—NH3 H2O—CH2Cl2), afforded AMD9370 (100 mg, 47%) as white foam. 1H NMR (CDCl3) δ 1.68-1.75 (m, 1H), 1.97-2.08 (m, 2H), 2.26-2.32 (m, 1H), 2.71-2.84 (m, 1H), 2.86-2.91 (m, 1H), 3.84 (s, 2H), 3.95 (d, 1H, J=16.5 Hz), 4.08-4.14 (m, 1H), 4.22 (d, 1H, J=16.0 Hz), 7.03-7.07 (m, 1H), 7.16-7.22 (m, 3H), 7.45 (d, 1H, J=6.9 Hz), 7.52-7.61 (m, 3H), 7.65 (d, 1H, J=7.5 Hz), 7.73 (ddd, 1H, J=1.8, 7.2, 8.7 Hz), 7.80 (d, 2H, J=8.1 Hz), 8.27-8.29 (m, 1H), 8.33 (d 1H, J=8.4 Hz), 8.44 (br, s, 1H), 8.72-8.80 (m, 1H); 13C NMR (CDCl3) δ 21.72, 23.30, 29.56, 49.29, 54.16, 60.83, 111.39, 114.52, 120.17, 122.29, 122.81, 127.72, 129.28, 133.58, 135.17, 137.76, 138.77, 144.61, 147.38, 148.21, 152.00, 156.13, 157.54, 165.99; ES-MS m/z 489.2 (M+H); Anal. Calcd. for (C30 H28N6O)•0.6(H2O)•0.7(CHCl3): C, 63.25; H, 5.17; N, 14.42. Found: C, 63.56; H, 5.25; N, 14.31.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1>O1CCCC1>[Br:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:34]/[C:33]2[CH:36]=[CH:37][C:30]([Br:29])=[CH:31][CH:32]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Brc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Brc1ccc(/C=C/c2cccc(Br)c2)cc1
Reaction time: 0.05 h

Procedure:
A solution of 38.0 g of (3-bromo-benzyl)-triphenylphosphonium bromide, known from the literature, in 250 ml of tetrahydrofuran was treated at -10° C. with 8.75 g of potassium tert.-butylate and stirred for 3 minutes. A solution of 14.8 g of 4-bromobenzaldehyde was added dropwise to the yellow-orange suspension within 15 minutes. After stirring for 60 minutes the reaction mixture was concentrated. The residue was treated with ice-water and extracted with ethyl acetate/ether. The organic phases were washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residue was chromatographed over silica gel with hexane and hexane/ether 99:1 and gave (E)-3,4'-dibromostilbene as colourless crystals, MS: m/z 338 (M+), as well as (Z)-3,4'-dibromostilbene as a colourless oil, MS: m/z 338 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH3:10]OC(OC)OC.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:9][C:3]1[C:2]2[N:1]=[CH:10][NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(OC)OC
Reactant: Cc1cccc(N)c1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2,3-diaminotoluene (1.00 g, 8.2 mmol) in CH2Cl2 (82 mL) was added trimethylorthoformate (4.5 mL, 41 mmol) and trifluoroacetic acid (0.32 mL, 4.1 mmol) and the mixture stirred at room temperature for 24 h after which the reaction mixture was diluted with CH2Cl2 (200 mL), and washed consecutively with saturated aqueous NaHCO3 (40 mL) and H2O (40 mL). The aqueous layers were reextracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried over MgSO4 and concentrated to a rusty brown solid (1.07 g, 97%). 1H NMR (300 MHz, CDCl3) δ 8.08 (s, 1H), 7.49 (d, 1H, J=8.1 Hz), 7.23–7.18 (m, 1H), 7.10 (d, 1H, J=7.5 Hz), 2.64 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1.CN1CCOCC1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>C(Cl)Cl>[C:21](=[O:22])([O:23][C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=1)[O:12][CH2:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6][CH2:7]1
Reactant: COCCN1CCC(CO)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COCCN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of (1-(2-methoxyethyl)piperidin-4-yl)methanol (3.65 g, 21.1 mmol) and NMM (2.5 mL, 22.8 mmol) in DCM (100 mL) at 0° C. was added p-nitrophenyl chloroformate. The reaction mixture was stirred at room temperature overnight and then washed sequentially with sat aq NaHCO3 solution (5×100 mL), dried (MgSO4) and concentrated in vacuo. The resulting orange oil was recrystallised from EtOAc and heptane to give (1-(2-methoxyethyl)piperidin-4-yl)methyl 4-nitrophenyl carbonate (3.65 g, 51%) as an orange solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[NH:38][CH:37]=[CH:36]2.[CH3:44][N:45]1[CH:49]2[CH2:50][CH:51](O)[CH2:52][CH:46]1[CH2:47][CH2:48]2>C(N(CC)CC)C.ClCCl>[CH3:44][N:45]1[CH:49]2[CH2:48][CH2:47][CH:46]1[CH2:52][CH:51]([O:32][C:33]1[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[NH:38][CH:37]=[CH:36]3)[CH2:50]2
Reactant: CN1C2CCC1CC(O)C2
Reactant: O=c1[nH]ccc2cc(O)ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C2CCC1CC(Oc1ccc3c(=O)[nH]ccc3c1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
8 mL of dry dichloromethane were added to 814 mg (1.73 mmol) of polystyrene bound triphenyl phosphine. At 0° C. 234 μL (1.48 mmol) of diethyl azodicarboxylate were added. 200 mg (1.24 mmol) of 6-hydroxy-2H-isoquinolinone (66), 210 mg (1.49 mmol) of tropine and 261 μL of triethylamine were added and the reaction mixture was allowed to warm to room temperature and stirred overnight. Another 279 mg of PS-triphenyl phosphine, 43 mg of tropine, 26 μL of diethyl azodicarboxylate and 2 mL of dry dichloeomethane were added and stirring was continued overnight. The solids were filtered off and washed with THF. The mixture was evaporated and purified by flash chromatography to give 158 mg of 6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-2H-isoquinolin-1-one (53). Rt=0.79 min (Method B). Detected mass: 279.2 (M+H+).
Reaction SMILES: C[C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][C:3]=1[Br:9].[H-].[Na+].[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]>C1COCC1.CN(C=O)C>[Br:9][C:3]1[N:4]=[C:5]([CH2:7][N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[S:6][CH:2]=1
Reactant: O=C1CCCN1
Reactant: Cc1sc(CBr)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CCCN1Cc1nc(Br)cs1
Yield: 79 %

Procedure:
A solution of methyl 4-bromo-2-(bromomethyl)thiazole (prepared according to the procedure reported in US 2010/298388), (0.50 g, 1.94 mmol) in THF (5 ml) was added to a solution of sodium hydride (0.12 g 60% in paraffin oil, 2.92 mmol) and pyrrolidin-2-one (0.20 g, 2.33 mmol) in DMF (5 ml) at 0° C. under stirring. The reaction mixture was stirred at room temperature for 30 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (5 ml). The mixture was then extracted with ethyl acetate (2×50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product; the crud product was further purified by flash column chromatography using 60% ethyl acetate in hexanes as an eluent to obtain the title compound (0.40 g, 79%). MS: m/z 262 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=O)=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[CH:6][N+:7]=1[O-].P(Cl)(Cl)([Cl:24])=O.O.[OH-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:19]#[N:21])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[C:6]([Cl:24])[N:7]=1
Reactant: CC(C)n1cc(-c2c[n+]([O-])c(N)c(C(N)=O)n2)ccc1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(-c2nc(C#N)c(N)nc2Cl)ccc1=O
Temperature: -30 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 4-oxide (29.1 g) was dissolved in DMF (290 ml). The solution was cooled to −30° C. To the cooled solution was added phosphoryl chloride (46.3 g) dropwise at −30˜−40° C. After addition of phosphoryl chloride, the temperature of the reaction mixture was raised to 40-45° C. The mixture was stirred at 40-45° C. for 1 hour. To the reaction mixture was added water (1160 ml). The suspension was stirred at 30-35° C. for 15 hours. The pH of the suspension was adjusted to 7 with 12% aq. NaOH (400 ml). The suspension was cooled to 0-5° C. and stirred at the same temperature for 2 hours. The precipitate was collected by filtration and washed with water, and dried in vacuo at 40-50° C., to give 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarbonitrile (17.2 g).
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]([CH3:24])[C:22]#[N:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]([CH3:24])[C:22]([NH2:2])=[NH:23])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [NH4+]
Reactant: CC(C#N)c1ccccc1OCc1ccccc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C(=N)N)c1ccccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 149.3 %

Procedure:
To a mixture of ammonium chloride (4.49 g) in toluene (25.5 ml) at 5° C. was added trimethylaluminium (2M solution in toluene, 42 ml. The mixture was stirred for 2 hours. 2-(2-benzyloxyphenyl)-propionitrile (10 g) in toluene (50 ml) was added and the mixture heated at 80° C. for 18 hours. The cooled mixture was poured into a slurry of silica gel in chloroform, stirred for 5 minutes and filtered. The silica gel was washed with methanol and the combined organic solutions evaporated to give 2-(2-benzyloxyphenyl)propionamidine (16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([CH3:18])[C:8]([CH2:12]OS(C)(=O)=O)=[N:9]2)=[CH:4][C:3]=1[CH2:20][N:21]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1)[CH2:22][C:23]#[CH:24].[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>ClCCl.C(OCC)(=O)C>[CH2:38]([N:40]([CH2:12][C:8]1[N:7]([CH3:18])[C:6](=[O:19])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([CH2:20][N:21]([C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:27][CH:26]=3)[CH2:22][C:23]#[CH:24])[CH:4]=2)[N:9]=1)[CH2:41][CH3:42])[CH3:39]
Reactant: C#CCN(Cc1cc2c(=O)n(C)c(COS(C)(=O)=O)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CCNCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C#CCN(Cc1cc2c(=O)n(C)c(CN(CC)CC)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred under argon solution of tert-butyl 4-[N-[7-chloro-2-methanesulphonyloxymethyl-3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.230 g, 0.42 mmol) in anhydrous dichloromethane (10 ml) was added diethyl amine (0.306 g, 4.2 mmol). The yellow solution was then stirred at room temperature for 18 hours. The solution was then diluted with ethyl acetate (250 ml) and washed with 5% aqueous sodium carbonate solution (2×100 ml), brine (100 ml), and concentrated in vacuo. Purification by column chromatography, on gradient elution with methanol in dichloromethane (0 to 2%) afforded a white crispy solid which was triturated diethyl ether/hexanes (v/v, 1:2). The white solid was collected by filtration, washed with hexanes and dried in vacuo over P2O5 (0.202 g, 92%), mp 112-113° C.; 1H-NMR (DMSO-d6) 0.95 (t, J=6.9 Hz, 6H, 2×CH2CH3), 1.49 (s, 9H, But), 2.56 (q obscured, J=6.85 Hz, 4H, 2×CH2CH3), 3.62 (s, 3H, N3-Me), 3.70 (s, 2H, 2-CH2), 4.40 (s, 2H, CH2C≡C), 4.79 (s, 2H, 6-CH2), 6.78 (d, J=8.9 Hz, 2H, 3′,5′-ArH), 7.72 (d, J=8.9 Hz, 2′,6′-ArH), 7.81, 7.86 (2×s, 2H, 5-H, 8-H); MS (FAB, m/z) 523, 525 [(M+H)+, 100%, 40% respectively; Cl isotopic pattern].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH:18]([F:20])[F:19])[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>C(O)C>[C:7]([C:11]1[N:16]=[C:15]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:14]=[C:13]([CH:18]([F:19])[F:20])[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1nc(Cl)cc(C(F)F)n1
Solvent: CCO
Product: CC(C)(C)c1nc(C(F)F)cc(N2CCNCC2)n1
Temperature: 78 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
6.3 g of piperazine (73.5 mmol) were dissolved in 50 ml of ethanol. 2.31 g of 2-tert-butyl-4-chloro-6-difluoromethyl-pyrimidine (10.5 mmol) were added and the mixture was stirred for 3 h at 78° C. The solvent was evaporated and the residue was added slowly to 100 ml of water. After cooling, the pH was adjusted to 12 with 2 N aqueous sodium hydroxide, and aqueos layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated to yield 2.34 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27].C(N(C(C)C)C(C)C)C>CS(C)=O>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Reactant: Nc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(Nc4ccccn4)n3)cc2s1
Temperature: 180 °C
Yield: 9.2 %

Procedure:
A mixture of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.100 g, 0.3 mmol), pyridin-2-amine (0.03 g, 0.3 mmol), N-ethyl-N-isopropylpropan-2-amine (0.1 g, 1.0 mmol) in DMSO (1 g, 13 mmol) was heated under microwave (CEM) at 180° C. and 200 W (Powermax® off). Then, the mixture was diluted with 1 ml of DMSO and purified by HPLC to give a light yellow solid (10 mg). MS (ESI pos. ion) Found m/z: 363, (M+H)+.
Reaction SMILES: [CH2:1](C(CO)(CO)CC)[OH:2].C[CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=O)[CH3:12]>>[CH2:20]([CH:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:11][CH3:12])[CH2:1][OH:2])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCC(CO)(CO)CO
Reactant: CC(C)CCCCCCCCCCCCC(=O)O
Product: CCCCCCCCC(CO)CCCCCC

Procedure:
The ester oil of claim 1 being the monoisopalmitic acid-di-n-C8-10 alkanoic acid ester of trimethylolpropane, said isopalmitic acid being obtained by the oxidation of 2-hexyldecanol formed from n-octanol by the Guerbet synthesis.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[C:29]([N:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37])(=[O:31])[CH3:30]>>[C:29]([N:32]1[CH2:36][CH2:35][N:34]([C:2]2[CH:3]=[CH:4][C:5]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=2)[C:33]1=[O:37])(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3NS(C)(=O)=O)CC2)c(C)c1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(NS(C)(=O)=O)c2)C1=O
Yield: 13 %

Procedure:
Using N-{5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (806 mg) described in Preparation Example 226 and 1-acetylimidazolidin-2-one (221 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (115 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:24][O:25][CH3:26])[N:3]=1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]4[C:19]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)[N:5]=[C:4]([CH2:24][O:25][CH3:26])[N:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COCc1nc(Cl)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCc1nc(-c2cccc(Cl)c2)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1

Procedure:
Combine 4-chloro-2-methoxymethyl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (388 mg, 1 mmol), 3-chlorophenylboronic acid (157 mg, 1 mmol), Pd(P(Ph)3)4 (100 mg, 0.09 mmol), 2M aqueous sodium carbonate (1 mL), and 1,2-dimethoxyethane (5 mL) under nitrogen. Reflux for 16 hours. Evaporate and add water (5 mL), and extract with EtOAc. Dry the organic layer with sodium sulfate and purify by liquid chromatography, to obtain 4-(3-chloro-phenyl)-2-methoxymethyl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine as a white solid.