Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CSc1ccc(C2=CCC(=O)CC2)cc1
Product: CSc1ccc(C2=CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by the reductive amination of 4-(4-methylsulfanyl-phenyl)-cyclohex-3-enone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: ClC1C=C(OC)C=CC=1OCCOCC[CH:10]([C:15](=[O:18])[CH2:16][CH3:17])[C:11](=[O:14])[CH2:12][CH3:13].[I-].[Li]>>[CH3:17][CH2:16][C:15](=[O:18])[CH2:10][C:11](=[O:14])[CH2:12][CH3:13]
Reactant: CCC(=O)C(CCOCCOc1ccc(OC)cc1Cl)C(=O)CC
Agent: [I-]
Agent: [Li]
Product: CCC(=O)CC(=O)CC

Procedure:
4{2-[2-(2-Chloro-4-methoxyphenoxy)ethoxy]ethyl}-3,5-heptane-dione [I; Ar is 2-Cl-4-CH3OC6H3, Alk is (CH2)2O(CH2)2, R and R' are CH3CH2CO] was prepared from 65.1 g. of the iodide from part (b) and the lithium salt derived from 41.0 g. of 3,5-heptanedione to give 12.1 g. of product, b.p. 168°-172° C. (0.005 mm.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH2:18][CH2:19][CH2:20][Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([OH:11])[CH2:20][CH2:19][CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCCc1ccccc1
Reactant: Br[Mg]CCCc1ccccc1
Solvent: C1CCOC1
Product: OC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a solution of 700 mg (4.7 mmol) of 4-phenyl-1-butanal (119) in 5.0 mL of THF at 0° C. was added 10.0 mL (5.0 mmol) of 3-phenyl-1-propylmagnesium bromide (120) and the resulting mixture was stirred at 0° C. for 0.5 h. The mixture was then quenched by the dropwise addition of saturated NH4Cl and diluted with ether. The phases were separated and the organic layer was washed with water and brine and then dried over MgSO4. Concentration gave 1.12 g of the alcohol 121 as an oil. 1H NMR spectrum was consistent with the structure.
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C([Mg]Br)C.[CH3:12][Si:13]([CH3:20])([CH3:19])[C:14]#[C:15][C:16](=[O:18])[CH3:17].[Cl-].[NH4+]>C(Cl)Cl.C1COCC1>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([C:16]([OH:18])([C:15]#[C:14][Si:13]([CH3:20])([CH3:19])[CH3:12])[CH3:17])=[N:3]1
Reactant: Cn1ccc(I)n1
Reactant: CC(=O)C#C[Si](C)(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1ccc(C(C)(O)C#C[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-iodo-1-methyl-1H-pyrazole (378 mg, 1.82 mmol) in dry DCM (15 mL) at 0° C. under an atmosphere of nitrogen, was introduced ethylmagnesium bromide (2.0 mL of a 1.0M solution in THF, 2.0 mmol). After 30 minutes at 0° C., the reaction mixture was warmed to RT for 15 minutes, then introduced to a solution of 4-(trimethylsilyl)but-3-yn-2-one (0.37 ml, 2.18 mmol) in dry DCM (5 ml) at 0° C. under an atmosphere of nitrogen. The reaction mixture was warmed to RT for 16 hr. Following addition of saturated aqueous ammonium chloride (5 ml), the reaction mixture was extracted with DCM (3×5 mL extractions). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (heptane/EtOAc gradient) furnished the title compound as an orange-brown oil: 1H NMR (500 MHz, CDCl3) delta 0.15 (9H, d, J=3.5 Hz), 1.82 (3H, s), 3.18 (1H, s), 3.86 (3H, s), 6.28 (1H, d, J=2.2 Hz), 7.26 (1H, d, J=2.2 Hz); LC-MS: m/z=+222.95 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH:22]=[CH:21][N:20]=[N:19]1.[I-].[K+].C[O-].[Na+]>CO>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH:9]=[CH:8][C:5]2[O:6][CH:7]=[C:3]([CH2:2][O:33][C:30]3[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][CH2:23][N:18]4[CH:22]=[CH:21][N:20]=[N:19]4)=[CH:28][CH:29]=3)[N:4]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(C=Cc2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1

Procedure:
MS: M=250.2 (API+). 1H-NMR(400 MHz, D6-DMSO): δ=3.80(s, 3H, OCH3), 4.69(s, 2H, CH2Cl), 6.98(d, 2H, Ar—H), 7.00(d, 1H, ═CH), 7.49(d, 1H, ═CH), 7.67(d, 2H, Ar—H), 8.13(s, 1H, oxazole). 0.250 g (1.00 mmol) 4-Chloromethyl-2-[2-(4-methoxyphenyl)-vinyl]-oxazole, 0.217 g 1.00 mmol) 4-(4-[1,2,3]Triazol-1-yl-butyl)-phenol, 0.166 g (1.00 mmol) potassium iodide and 0.191 ml (1.00 mmol) of a 30% sodium methylate solution were added to 50.0 ml methanol and heated to reflux for 8 h. After removal of solvent, partitioning of the residue between 50 ml ethyl acetate and 15 ml water, the organic phase was washed with 10 ml water, 10 ml 0.1 N NaOH, 15 ml water twice and dried over sodium sulphate. The solution was concentrated until crystallisation of the product started. After leaving for 1 h at room temperature the precipitate was isolated, washed with diethyl ether and dried at 40° C. in vacuo. 0.16 g (37%) 1, m.p. 148–151° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[O:13]=[C:14]1[CH2:31][CH2:30][C:17]2([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH2:16][CH2:15]1.C(OCC)(=O)C>C(OCC)C.O>[OH:13][C:14]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:31][CH2:30][C:17]2([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH2:18]2)[CH2:16][CH2:15]1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(O)(c1cccnc1)CC2
Temperature: -78 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
3-Bromopyridine (22.47 mmol, 2 eq) was dissolved in diethyl ether (10 ml) and the solution was added dropwise to a solution of n-BuLi (24.7 mmol, 2.2 eq) in diethyl ether (70 ml) at −78° C. The resulting mixture was stirred for 30 min. tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (for the synthesis see above) (11.23 mmol, 1 eq.) was dissolved in diethyl ether (10 ml), the solution was slowly added, and the reaction mixture was then stirred at −78° C. for 1 h. The reaction mixture was warmed to room temperature, ethyl acetate (150 ml) and water (80 ml) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×70 ml) and the combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (2% methanol in methylene chloride). Yield: 19%
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C.[OH-].[NH4+:11]>>[NH2:11][CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2][C:1]([OH:8])=[O:7]
Reactant: [NH4+]
Reactant: CCCCCC(=O)O
Agent: C
Agent: [OH-]
Product: CCCC(N)CC(=O)O
Temperature: 150 °C

Procedure:
A mixture of 2 hexanoic acid (7.0 g, 0.06 mole) and concentrated aqueous ammonium hydroxide (70 ml) is heated for 24 hours in an autoclave at 150° C. The cooled mixture is treated with carbon black and filtered. After evaporation of the solvent, the crude product is recrystallized from ethanol to give the title compound m.p. 203° C. (Compound 1.21, Table 1).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].Cl[C:33]([O:35][CH3:36])=[O:34]>>[CH3:36][O:35][C:33]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH:2]([CH3:3])[CH3:4])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)=[O:34]
Reactant: COC(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Agent: Cl
Product: COC(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n2C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and methyl chloroformate. Light-yellow solid. MS (m/z): 471.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10]O)[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:14])=O>ClCCl>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][Cl:14])[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1cc(CO)sn1
Solvent: ClCCl
Product: CC(C)(C)c1cc(CCl)sn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.61 g of (3-t-butyl-isothiazol-5-yl)methanol was dissolved in 50 ml of dichloromethane, and 3.2 ml of thionyl chloride was added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain 1.12 g of 3-t-butyl-5-(chloromethyl)isothiazole. The crude product was subjected to the next step without purification.
Reaction SMILES: FC(F)(F)C(O)=O.CS(O)(=O)=O.C(O[C:16]([C:31]1[CH:35]=[C:34]([N:36]=[C:37]([NH2:44])[N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[O:33][N:32]=1)([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([F:30])[CH:19]=1)[CH3:17])C.[Cl-].[Na+]>C(Cl)Cl>[F:30][C:20]1[CH:19]=[C:18]([C:16]([C:31]2[CH:35]=[C:34]([N:36]=[C:37]([NH2:44])[N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[O:33][N:32]=2)=[CH2:17])[CH:23]=[CH:22][C:21]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(C)(c1ccc(-c2ccccc2)c(F)c1)c1cc(N=C(N)N2CCOCC2)on1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(c1ccc(-c2ccccc2)c(F)c1)c1cc(N=C(N)N2CCOCC2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
Trifluoroacetic acid (4 ml) was added to a solution of the compound (30.0 mg) obtained in Example 53 in methylene chloride (1 ml), and the resulting mixture was stirred at room temperature for 8 hours. After the addition of a saturated aqueous sodium chloride solution, the mixture was subjected to extraction with ethyl acetate, and the organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, thereafter dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography to obtain the desired compound (20 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]2[C:25]=1[O:24][C:23]([C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1)=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:19]([CH3:34])[C:20]([C:32]#[N:33])=[C:21]3[C:25]=2[O:24][C:23]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=[N:22]3)[CH2:4]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(-c3cnccn3)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3cnccn3)nc2c1C#N
Temperature: 95 °C
Reaction time: 0.2 h
Yield: 38.6 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (93.4 μl, 0.736 mmol) and triethylamine (121 μl, 0.866 mmol) were added to a dimethyl sulfoxide (4 ml) solution of 7-fluoro-5-methyl-6-phenyl-2-(pyrazin-2-yl)-1,3-benzoxazole-4-carbonitrile (I-187) (143 mg, 0.433 mmol), followed by stirring in an oil bath at 95° C. for 0.2 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (100 ml), washed with saturated brine (50 ml). After drying over anhydrous sodium sulfate, the solvent was evaporated away, and the resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=9:1), the eluate was recrystallized from isopropanol to obtain the entitled compound (71.0 mg, 38.6%) as a pale yellow acicular crystal.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Cl)[N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[N:25]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2c(O)cccc2n1C(=O)OC(C)(C)C
Reactant: Clc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(Oc3cccc(Cl)n3)cccc2[nH]1
Temperature: 160 °C

Procedure:
159 (500 mg, 1.6 mmol), 2,6-Dichloro-pyridine (360 mg, 24 mmol) are dissolved in 15 ml of dimethylformamide. After addition of potassium carbonate (340 mg, 24 mmol) and a catalytic amount Cu-powder the mixture is heated to 160° C. for 3 hours. The reaction mixture is cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layers are dried over sodium sulphate and evaporated. The crude product is solved in dichloromethane and after evaporation crystallized with cyclohexane.
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@H:5]([CH3:9])[C:6]([OH:8])=[O:7].Cl.[CH3:17]O>>[F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@H:5]([CH3:9])[C:6]([O:8][CH3:17])=[O:7]
Reactant: C[C@@H](Nc1ccc(F)c(F)c1F)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H](C)Nc1ccc(F)c(F)c1F

Procedure:
(2R)-2-(2,3,4-trifluoroanilino)propionic acid (1.1 g; 98% ee) was dissolved in methanol (10 ml) and hydrochloric acid (5 mol/l; 1 ml) was added thereto at room temperature. The liquid reaction mixture was heated under reflux for 6 hours and then the solvent was evaporated. To the obtained residue was added chloroform (10 ml). Next, the organic layer was washed with a saturated aqueous solution of sodium chloride and water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane=1:4) to give the title compound (1.17 g) as an oily substance. The optical purity of the product was 99% ee. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 5.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([N:10]=[C:11]=[S:12])[CH:7]=[CH:6][C:5]=1[F:13])=[C:2]=[S:3].[CH:14]([NH:17][CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>C(#N)C>[F:13][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11]([N:17]([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[S:12])=[CH:9][C:4]=1[NH:1][C:2]([N:17]([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[S:3]
Reactant: Fc1ccc(N=C=S)cc1N=C=S
Reactant: CC(C)NC(C)C
Solvent: CC#N
Product: CC(C)N(C(=S)Nc1ccc(F)c(NC(=S)N(C(C)C)C(C)C)c1)C(C)C

Procedure:
To a solution of 4.2 g. of 2,4-diisothiocyanatofluorobenzene in 100 ml. of acetonitrile is added 4.1 g. of diisopropylamine and the mixture is refluxed for 3 hours. The solvent is removed in vacuo and the residue is crystallized from acetonitrile to yield 5.1 g. of the title compound, melting point 133°-135° C.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])/[C:7](=[N:13]/[C:14](=[O:24])[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])/[S:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>C(Cl)Cl>[CH3:32][S:33]([O:12][CH:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:6]/[C:7]/1=[N:13]\[C:14]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])=[O:24])[CH3:11])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C(C)O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A mixture of the product of Example 163 (220 mg, 0.6 mmol) in CH2Cl2 (20 mL) and triethylamine (181 mg, 1.8 mmol) was cooled to 0° C., and treated dropwise with methanesulfonyl chloride (102 mg, 0.9 mmol). The reaction was stirred at 0° C. for 30 min., poured into water, and the mixture was extracted with CH2Cl2 (2×). The organics were combined, dried over MgSO4, filtered and concentrated to afford the title compound (234 mg, 88%). MS (DCI/NH3) m/z 383 (M−Ms+15)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[N:17]=[C:16](S(C)(=O)=O)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:34]([OH:37])([CH3:36])[CH3:35].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[N:17]=[C:16]([O:37][CH:34]([CH3:36])[CH3:35])[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNc2cc(-c3ccc(OC)c(OC)c3)nc(S(C)(=O)=O)n2)cc1OC
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCNc2cc(-c3ccc(OC)c(OC)c3)nc(OC(C)C)n2)cc1OC
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of [2-(3,4-dimethoxy-phenyl)-ethyl]-[6-(3,4-dimethoxy-phenyl)-2-methanesulfonyl-pyrimidin-4-yl]-anine [200 mg, 0.42 mmol, Intermediate (33)], and isopropyl alcohol (1 mL) in N,N′-dimethylformamide (2 mL) at 0° C. is treated with sodium hydride (60%, 102 mg, 12.7 mmol). After 1 hour at 20° C., the mixture is concentrated, and extracted twice with EtOAc (50 mL). The combined extracts are washed twice with water, dried over magnesium sulfate, filtered, and concentrated. The residue is subjected to chromatography on silica gel eluting with 60% EtOAc in heptane to afford [2-(3,4-dimethoxy-phenyl)-ethyl]-[6-(3,4-dimethoxy-phenyl)-2-isopropoxy-pyrimidin-4-yl]-amine [0.15 g, 79%, Example 17(a)] LCMS: RT=2.57 minutes, MS: 454 (M+H). 1H NMR (300 MHz, CDCl3) □7.64 (1H, d, J=2.1 Hz), 7.55 (1H, dd, J=8.4, 2.4 Hz), 6.91 (1H, d, J=8.4 Hz), 6.86-6.76 (3H, m), 6.3 (1H, s), 5.43-5.34 (1H, m), 4.83 (1H, brs), 3.99 (3H, s), 3.95 (3H, s), 3.89 (3H, s), 3.75-3.65 (2H, m), 2.91 (2H, t, J=6.9 Hz) 1.45 (6H, d, J=6 Hz). IC50=6728 nM
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[I:11].S(=O)(=O)(O)O.[CH3:17]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][C:3]=1[I:11]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)c(I)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)c(I)c1

Procedure:
A solution of 4-chloro-3-iodobenzoic acid (500 mg, 1.77 mmol, 1.00 equiv), methanol (20 mL), and concentrated sulfuric acid (0.35 g, 2.00 equiv) was heated to reflux overnight in an oil bath. The resulting mixture was concentrated in vacuo and diluted with 50 mL of ethyl acetate. The organic layer was washed with 3×20 mL of water and 3×20 mL of saturated aqueous sodium carbonate. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo, resulting in 0.52 g (99%) of methyl 4-chloro-3-iodobenzoate as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9](OCC)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cccc(CCCOC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCCc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a THF solution (0.2 M) of ethyl 3-(3-methoxypropyl)benzoate from the previous step (1 eq.) was added lithium aluminum hydride (1.0 M THF solution, 5 eq.) at 0° C. over a period of 20 min. The resulting suspension was stirred at 0° C. for 1 h and then at RT for 1 h. The reaction was quenched, at 0° C., with the dropwise addition of H2O and then 1 N aq. NaOH. The biphasic mixture was allowed to stir at RT for 10 min, poured into H2O and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded a cloudy oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 7:3 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[N:5]1.[F:9][C:10]([F:19])([F:18])[CH2:11][CH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:4]1([CH2:3][C:13]([CH2:12][CH2:11][C:10]([F:9])([F:18])[F:19])([C:14]#[N:15])[C:16]#[N:17])[CH:8]=[CH:7][CH:6]=[N:5]1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCn1cccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cccn1
Yield: 29.9 %

Procedure:
0.76 g of 1-(chloromethyl)-1H-pyrazole hydrochloride and 0.81 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 10 ml of N,N-dimethylformamide. 1.38 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 5 hours. Water was added to the reaction mixture, and then extracted with methyl-t-butyl ether (may be referred as MTBE, hereinafter) . The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to obtain 0.36 g of (1H-pyrazole-1-yl methyl) (3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (1), hereinafter) shown by below formula.
Reaction SMILES: [O-2].[Mg+2].[Br:3][CH2:4][CH2:5][CH2:6]Br.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][C:14]=1[NH2:15].Cl>CC(N(C)C)=O>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][C:14]=1[NH:15][CH2:6][CH2:5][CH2:4][Br:3]
Reactant: BrCCCBr
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Agent: Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(=O)N(C)C
Product: COC(=O)Cc1ccc(NCCCBr)c(Cl)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Magnesium oxide (10 grams, 250 mmoles), was added to a solution of 1,3-dibromopropane (139 grams, 70 mL, 700 mmoles) in dimethylacetamide (150 mL). A solution of methyl 3-chloro-4-aminophenylacetate.HCl (23.6 grams, 100 mmoles) in dimethylacetmide (200 mL) was added dropwise over 30 minutes and the mixture stirred at 80° C. for 6 hours. The cooled mixture was partitioned with methylene chloride and water. The aqueous phase was extracted with methylene choride and the combined organic phases washed with brine, dried over magnesium sulfate and concentrated in vacuo to an oil. The crude product was chromatographed on a silica gel column eluting with hexane:ethyl acetate (9:1). The product was further purified by a second silica gel chromatography in methylene chloride:hexane (2:3) to give the title compound as an oil. NMR, (CDCl3): δ 2.15 (qnt, 2H); 3.35 (q, 2H); 3.47 (s,2H); 3.49 (t, 2H); 3.67 (s, 3H); 6.63 (d, 1H); 7.03 (dd, 1H); 7.17 (d, 1H).