Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11].Cl[C:32]1[C:41]([C:42]([OH:44])=[O:43])=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([Cl:45])[CH:38]=2)[N:33]=1.C([O-])([O-])=O.[K+].[K+].Cl>CS(C)=O.O>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C@H:9]([NH:8][C:32]3[C:41]([C:42]([OH:44])=[O:43])=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[C:37]([Cl:45])[CH:38]=4)[N:33]=3)[C:10]([OH:12])=[O:11])=[CH:15][CH:16]=2)=[CH:22][CH:23]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ccnc3ccccc23)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccnc3ccccc23)cc1)C(=O)O
Temperature: 100 °C
Reaction time: 13 h
Yield: 41.3 %

Procedure:
A mixture of trifluoroacetic acid salt of (S)-2-amino-3-[4-(quinolin-4-yloxy)-phenyl]-propionic acid (0.296 g, 0.7 mmol), 2,6-dichloroquinoline-3-carboxylic acid (0.16 g, 0.66 mmol) and K2CO3 (0.46 g, 3.3 mmol) in dry DMSO (1 mL) is stirred for 13 h in a closed Pierce reaction vial at 100° C. temperature. After cooling the reaction mixture is diluted with water (25 mL), acidified with 2N aqueous HCl till pH 3, and the precipitated solid is collected on filter. The crude product is washed with water and recrystallized from DMF/EtOH (0.5 mL/0.5 mL) mixture to give the title compound as a yellow solid (0.14 g, 41%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[H][H]>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CCN2CCN(c3ccc([N+](=O)[O-])c(F)c3)CC2)cc1
Agent: [Pd]
Product: Nc1ccc(CCN2CCN(c3ccc(N)c(F)c3)CC2)cc1

Procedure:
1-(3-Fluoro-4-nitrophenyl)-4-(4-nitrophenethyl)piperazine (0.19 g) and 10% palladium on carbon (150 mg) were hydrogenated at 4 atmospheres and 60° until completion of hydrogen uptake. The catalyst was then filtered off, the solvent evaporated, and the residual product (0.06 g) used directly in the next stage.
Reaction SMILES: [CH3:1][C@H:2]([C@@H:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11]CO1)C)[CH2:3][OH:4].[CH2:14](I)CCC.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH2:8]([O:7][CH2:5][C@H:2]([CH3:1])[C@@H:3]([OH:4])[CH3:14])[CH2:13][CH2:12][CH3:11]
Reactant: C[C@H](OC1CCCCO1)[C@@H](C)CO
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC[C@H](C)[C@H](C)O
Reaction time: 2 h
Yield: 59.7 %

Procedure:
In 40 ml of N,N-dimethylformamide were dissolved 5.0 g of the (2S,3S)-2-methyl-3-(2-tetrahydropyranyloxy)butanol obtained in Example 1 i) and 24.5 g of butyl iodide. Thereto was added 1.22 g of oily sodium hydride (about 60%) in small portions with ice-cooling. The mixture was stirred for 2 hours with ice-cooling. The reaction mixture was poured into 300 ml of ethyl acetate and the resulting mixture was stirred. The insoluble materials were removed by filtration. The filtrate was washed with water three times. The organic layer was dried and concentrated. The residue, i.e. crude (2S,3S)-4-butoxy-3-methyl-2-(2-tetrahydropyranyloxy)butane was dissolved in 150 ml of methanol. To the solution was added 6.0 g of a nonaqueous strongly acidic cation exchange resin (Amberlist 15), and the mixture was stirred for 6 hours at room temperature. The cation exchange resin used was removed by filtration and the filtrate was concentrated. The residue was subjected to Kugelrohr distillation under reduced pressure to obtain 2.54 g of (2S, 3S )-4-butoxy-3-methyl-2-butanol.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:37]O)[N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8].CC[N:41](C(C)C)C(C)C.N>CN(C=O)C.CO>[NH2:41][CH2:37][C:4]1[NH:5][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]3[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[C:21]([Cl:27])[CH:20]=3)[C:12]=2[F:28])=[O:8])=[C:2]([Br:1])[N:3]=1
Reactant: C[Si](C)(C)CCOCn1c(CO)nc(Br)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(CN)nc3Br)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
Ms-CI (0.023 ml, 0.30 mmol) was added to a solution of 4-bromo-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-(hydroxymethyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.097 g, 0.15 mmol) and DIEA (0.26 ml, 1.50 mmol) in DMF (1 ml) and the reaction mixture was stirred at room temperature for 1 h. Ammonia (1 ml of a 7M solution in methanol, 7.00 mmol) was added and stirring was continued overnight. Deprotection using similar procedures as that described herein and purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% NH4OH) provided the title compound (0.004 g, 5%) as an off-white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.32 (br. s., 1H), 7.56 (s, 1H), 7.33-7.45 (m, 2H), 7.28 (br. s., 1H), 7.21 (s, 1H), 4.65 (br. s., 2H), 4.19 (s, 2H). ES-LCMS: m/z 511.9, 513.9, 515.9 (M+1).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[S:9](N)(N)(=[O:11])=[O:10]>COCCOCCOC>[NH:7]1[S:9](=[O:11])(=[O:10])[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=2
Reactant: Nc1ccccc1N
Reactant: NS(N)(=O)=O
Solvent: COCCOCCOC
Product: O=S1(=O)Nc2ccccc2N1
Temperature: 25 °C

Procedure:
A solution of 1,2-phenylenediamine (91 mg, 0.84 mmol) and sulfamide (81 mg, 0.84 mmol) in diglyme (2.5 ml) is stirred at 155° C. for 1.5 h. After cooling to RT, the reaction solution is poured into ice-water (15 ml) and the product is extracted with ethyl acetate. The solvent is distilled off under reduced pressure and the red residue is purified by flash chromatography (1:1 ethyl acetate/toluene).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH2:21][CH2:22][N:23]([C:26]([N:28]6[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]6)=[O:27])[CH2:24][CH:25]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[CH2:35][CH:36]1[CH2:39][CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:19]=[C:18]([C:20]5[CH2:21][CH2:22][N:23]([C:26]([N:28]6[CH2:29][CH2:30][N:31]([CH2:35][CH:36]7[CH2:39][CH2:38][CH2:37]7)[CH2:32][CH2:33]6)=[O:27])[CH2:24][CH:25]=5)[NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1)N1CCNCC1
Reactant: BrCC1CCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1)N1CCN(CC2CCC2)CC1

Procedure:
The reaction mixture derived from the preparation of {4-[4-(benzothiazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridin-1-yl}-piperazin-1-ylmethanone (EXAMPLE 154) was reacted with (bromomethyl)cyclobutane (90 mg, 5 eq.) in the presence of DIPEA at 60° C. for 72 h before the mixture was purified by HPLC, giving the title compound as yellow powder. 1H NMR (400 MHz, DMSO-d6): δ=11.78 (s, 1H), 9.52 (s, 1H), 9.16 (s, 1H), 8.84 (d, 1H, J=2.0 Hz), 8.26 (s, 1H), 8.14 (s, 1H), 7.97 (d, 1H, J=8.9 Hz), 7.91 (s, 1H), 7.80 (dd, 1H, J=2.0 Hz & 8.9 Hz), 6.82 (d, 1H, J=1.7 Hz), 6.57 (br s, 1H), 3.94 (s, 2H), 3.46 (m, 4H), 3.36 (m, 4H), 3.18 (m, 4H), 2.54 (br s, 2H), 2.46 (m, 1H), 2.34 (m, 3H), 2.03 (m, 1H), 1.84 (m, 1H), 1.65 (m, 1H). LC/MS: m/z 529.17 (15) [MH+], tR=1.94 (ZQ2000, polar—5 min).
Reaction SMILES: C1(C)C=CC=CC=1.F[C:9]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=1[CH:11]=[O:12].Cl.[CH3:22][NH:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH3:22][N:23]([CH3:24])[C:9]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=1[CH:11]=[O:12]
Reactant: CNC
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(C(F)(F)F)cc1C=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To toluene (5 ml) are added 2-fluoro-5-trifluoromethyl-benzaldehyde (650 mg) and dimethylamine hydrochloride (2.76 g), followed by addition of potassium carbonate (1.4 g), and the mixture is stirred at 120° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=49:1→4:1) to give 2-dimethylamino-5-trifluoromethyl-benzaldehyde (529 mg). MS (m/z): 218 [M+H]+
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].[C:25]1(C)[C:26]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.O.[CH3:37]N(C=O)C>>[C:29]1([CH3:37])[CH:30]=[CH:25][C:26]([S:31]([N:12]2[CH:13]=[CH:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:11]2[C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)(=[O:32])=[O:33])=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)c1ccc(-c2[nH]ccc2-c2ccc(F)cc2)cc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc(-c3ccc(F)cc3)c2-c2ccc(S(C)(=O)=O)cc2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 2-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-1H-pyrrole (31.6 g, 0.1 mole) in 200 ml dry N,N'-dimethylformamide was cooled in an ice bath and treated with sodium hydride (2.4 g, 0.1 mole). The mixture was stirred for one hour and reacted with toluenesulfonyl chloride (19.0 g, 0.1 mole). The mixture was stirred at room temperature and poured into one liter of cold water with vigorous stirring. The resulting precipitate was collected by filtration, washed with water and dried. The off white solid was triturated with 150 ml chloroform, washed with other and dried. The product was collected in 100% yield (46.9 g); m.p. 228.5°-229°.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].C=O.[C:7]([O:11][C:12]([NH:14][CH:15]([CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[C:7]([O:11][C:12]([NH:14][CH:15]([CH2:20][N:21]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[CH3:1])[C:16]([O:18][CH3:19])=[O:17])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)C(CNCc1ccc(Cl)c(Cl)c1)NC(=O)OC(C)(C)C
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)C(CN(C)Cc1ccc(Cl)c(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
Sodium cyanoborohydride (121 mg) was added to a solution of formaldehyde (570 mg), methyl 2-(tert-butoxycarbonylamino)-3-(3,4-dichlorobenzylamino)propionate (720 mg) and acetic acid (0.1 ml) in acetonitrile and the mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydrogen carbonate (10 ml) was added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colourless oil (722 mg). NMR δH (360 MHz, CDCl3) 1.45 (9H, s), 2.21 (3H, s), 2.73 (2H, d, J=7.0 Hz), 3.46 (2H, m), 3.75 (3H, s) 4.37 (1H, m), 5.19 (1H, br s), 7.10 (1H, dd, J=11.0 and 1.0 Hz), 7.36 (2H, m).
Reaction SMILES: Br[C:2]1C(Cl)=NC(Cl)=N[CH:7]=1.[Br:10][C:11]1[C:12]([NH:18][CH:19]([CH:29]([CH3:31])C)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Br:10][C:11]1[C:12]([NH:18][C:19]2([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:29][CH2:31][CH2:7][CH2:2]2)=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Product: CC(C)(C)OC(=O)NCC1(Nc2nc(Cl)ncc2Br)CCCC1

Procedure:
tert-butyl N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate L using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, DMSO-d) δ ppm 1.34 (s, 9H) 1.50-1.58 (m, 2H) 1.63-1.78 (m, 4H) 1.96-2.06 (m, 2H) 3.25 (d, J=6.15 Hz, 2H) 6.71 (s, 1H) 7.18 (t, J=6.29 Hz, 1H) 8.20 (s, 1H). LCMS (ESI) 405 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[Cl:17][CH2:18][CH2:19][CH2:20]I.[H-].[Na+].C(OCC)(=O)C>O1CCCC1>[Cl:17][CH2:18][CH2:19][CH2:20][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:13]([F:14])([F:15])[F:16])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1ccc(Cl)cc1C(F)(F)F
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of methyl (4-chloro-2-trifluoromethylphenyl)acetate (5.5 g) and 3-chloro-1-iodopropane (4.6 mL) in tetrahydrofuran (15 mL) was added dropwise to a suspension of sodium hydride (containing 60% in mineral oil, 955 mg) in tetrahydrofuran (50 mL) under ice-cooling. The reaction solution was stirred at the same temperature for 10 minutes and then at room temperature for three hours and 20 minutes. Ice water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The aqueous layer was reextracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Wakogel™ C-200; elution solvent:heptane:ethyl acetate=19:1) to obtain 5.30 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=O.[CH3:5][CH:6](N1CCOCC1)[CH:7]=[CH:8][CH3:9].[Cl-].[NH4+:17]>C(Cl)Cl>[CH3:4][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:5])[C:1]=1[NH2:17]
Reactant: [NH4+]
Reactant: C=CC=O
Reactant: CC=CC(C)N1CCOCC1
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cccc(C)c1N
Temperature: 50 °C
Reaction time: 15 h
Yield: 36.9 %

Procedure:
8.4 g (0.15 mol) of acrolein is added dropwise to a solution of 23.3 g (0.15 mol) of N-(3-penten-2-yl)-morpholine in 100 ml of methylene chloride. After addition of the acrolein the mixture is stirred for 15 hours at 25° C. and subsequently for further 15 hours at 50° C. Then 12.0 g (0.225 Mol) of ammonium chloride are added and the solvent is distilled off. The residue is transferred into an autoclave and after addition of 400 ml of concentrate aqueous ammonia and 10.0 g of palladium coal (5%) the whole is heated under a nitrogen pressure of 50 bar for 15 hours at 280°-290° C. Then the catalyst is filtered off and washed with ether. The filtrate is extracted several times with ether. The extracts are combined and dried over magnesium sulphate and the ether is distilled off. The residue (14.2 g; 79% of theory) is distilled at a pressure of 15 torr. There is obtained 6.7 g (37% of theory) of 2,6-dimethylaniline, b.p. 15 : 94°-98° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:45])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[N:39]=2)[CH:33]=1)=O)(C)(C)C>>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:45])[CH2:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[N:39]=4)[CH:33]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Product: Cc1nccc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (160 mg, 0.5 mmol) and 3-[3-(2-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K42) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (152 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[C:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.C(=S)=S.O=[C:22]([CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:23]>O>[CH3:9][C:17]1([CH3:16])[C:6]2[CH:5]=[C:17]3[C:9]([C:10]4[CH:11]=[C:12]5[C:22]([CH3:23])=[CH:24][C:25]([CH3:27])([CH3:26])[C:13]5=[CH:14][C:15]=4[CH2:16]3)=[CH:8][C:7]=2[C:6]([CH3:7])=[CH:5]1
Reactant: CC(=O)C=C(C)C
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: CC1=CC(C)(C)c2cc3c(cc21)-c1cc2c(cc1C3)C(C)(C)C=C2C
Reaction time: 0.25 h

Procedure:
To a 300-ml three-neck flask, 25.8 g of anhydrous aluminum chloride, 5.18 g of fluorene, and 200 ml of carbon disulfide were charged under nitrogen atmosphere. 6.18 g of mesityl oxide was added dropwise thereto over 15 minutes in a water bath, and the mixture was stirred for 10 hours under reflux. After standing to cool, 100 ml of water was added thereto, and the organic layer was separated. The aqueous layer was extracted with 300 ml of hexane, and the separated organic layer was combined, and washed with water and a saturated aqueous solution of sodium chloride. After the solution was dried over magnesium sulfate, the solvent was distilled off, and the obtained product was purified by column chromatography, and recrystallized with a mixed solvent of ethanol/hexane. The yield was 1.14 g. Identification was performed by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.II.O>C(O)(=O)C.[Fe]>[Br:1][C:8]1[CH:9]=[C:4]([F:3])[CH:5]=[CH:6][C:7]=1[CH3:10].[Br:1][C:5]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[F:3]
Reactant: Cc1ccc(F)cc1
Reactant: BrBr
Agent: [Fe]
Agent: II
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(F)c(Br)c1
Product: Cc1ccc(F)cc1Br
Reaction time: 3 h

Procedure:
A solution of 160 g of bromine in 60 ml of glacial acetic acid was added all at once to a solution of 110 g of 4-fluorotoluene in 40 ml of glacial acetic acid, to which 1.1 g of iron powder and 1.1 g of iodine had been added. The initially exothermic reaction was kept at 25° C. to 27° C., first by cooling with water and then with warm water. The mixture was subsequently stirred at the above temperature for 3 hours, the glacial acetic acid and unreacted 4-fluorotoluene were then distilled off in vacuo and a mixture consisting of 3-bromo-4-fluorotoluene (57%), 2-bromo-4-fluorotoluene (41.9%) and dibromo-4-fluorotoluene (1.1%) was subsequently distilled off under 20 mbars and between 65° C. and 85° C. 8 g of residue remained. The monobrominated isomers were separated by distillation on a column. 21.5 g of 2-bromo-4-fluorotoluene (boiling point: 176°-8° C. (normal pressure)) and 28.5 g of 3-bromo-4-fluorotoluene (boiling point 184°-5° C. (normal pressure)) were obtained.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[CH:32]=[CH:31][C:10]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:9]([F:33])[CH:8]=1)=[O:6])[CH3:3].[CH:34]([C:36]1[N:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]2)=[CH:38][CH:37]=1)=O>>[CH2:2]([O:4][C:5]([C:7]1[CH:32]=[CH:31][C:10]([CH:11]=[CH:34][C:36]2[N:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]3)=[CH:38][CH:37]=2)=[C:9]([F:33])[CH:8]=1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Reactant: CCOC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1
Agent: [Br-]
Product: CCOC(=O)c1ccc(C=Cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c(F)c1
Yield: 98.8 %

Procedure:
By a method similar to Production Example 108, step 4, [4-(ethoxycarbonyl)-2-fluorobenzyl](triphenyl)phosphonium bromide (2.513 g, 4.802 mmol) and tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (1.166 g, 4.002 mmol) were condensed to give tert-butyl 4-(6-{2-[4-(ethoxycarbonyl)-2-fluorophenyl]vinyl}pyridin-3-yl)piperazine-1-carboxylate (1.802 g, yield 98.9%, E/Z mixture) as a pale-brown solid.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:16])=O>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([Cl:16])=[O:8])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Product: CC(=O)SCC(CC(C)C)C(=O)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[(Acetylthio)methyl]-4-methylpentanoic acid (6.0 g) is combined with thionyl chloride (5 ml). The reaction mixture is allowed to exotherm to 45° C. It is stirred at room temperature for about 16 hours and the acid chloride product is then vacuum distilled yielding 5.1 g, boiling point 80°-90° C. at 10 mm of Hg.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[C:34]([F:41])=[C:33]([F:42])[C:32]=1[CH2:43]I>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@H:15]([CH2:43][C:32]1[C:31]([Cl:30])=[CH:36][C:35]([C:37]([F:40])([F:38])[F:39])=[C:34]([F:41])[C:33]=1[F:42])[CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: Fc1c(C(F)(F)F)cc(Cl)c(CI)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](Cc1c(Cl)cc(C(F)(F)F)c(F)c1F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
Cool a solution of (R)-4-Benzyl-3-pent-4-enoyl-oxazolidin-2-one (0.94 g, 3.6 mmol) in THF (10 mL) to −78° C. Treat this solution dropwise with 10M LiHMDS in THF (4 mL, 4.0 mmol) and stir at −78° C. for 30 minutes. Treat the solution with 1-Chloro-3,4-difluoro-2-iodomethyl-5-trifluoromethyl-benzene (1.35 g, 3.8 mmol) and allowed to slowly warm to room temperature. The reaction stirs 4 hr at room temperature. Quench the reaction with 1N HCl (aqueous) and extracted with Et2O. Wash the organic with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 0.725 g (41%) of desired product. MS (m/e): 488 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([OH:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:19][CH3:22])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred, 0° C. solution of methyl 4-benzyloxy-2-hydroxybenzoate (12g, 46 mmol) from step 1 above in DMF (150 mL) was added NaH (2.76 g of a 60% suspension in mineral oil, 69 mmol) and methyl iodide (7.2 mL, 116 mmol). The solution was warmed to ambient temperature and stirred for 18 h. The reaction mixture was poured onto ice and the resulting solution was extracted with ether (3×200 mL). The organic phase was dried (MgSO4), filtered and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 4:1 hexanes:EtOAc as eluant. Methyl 4-benzyloxy-2-methoxybenzoate was obtained as a white powder.