Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:41]1([C:44](Cl)=O)[CH2:43][CH2:42]1.[NH4+].[Cl-]>C(Cl)Cl.C1COCC1.CCOCC>[CH2:1]([N:8]([CH2:44][CH:41]1[CH2:43][CH2:42]1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:24][Si:25]([CH2:28][CH3:29])([CH2:30][CH3:31])[CH2:26][CH3:27])([C:20]([F:21])([F:22])[F:23])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NCc2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)OC([C@H]1CC[C@H](N(Cc2ccccc2)CC2CC2)CC1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 930 mg (1.73 mmol) of trans benzyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amine (example 3.1) in 2 mL of CH2Cl2 was treated with 0.6 mL (3.5 mmol) of DIPEA and 0.23 mL (2.56 mmol) of cyclopropylcarbonylchloride. The mixture was stirred at RT overnight and distributed between a saturated aqueous solution of NH4Cl and Et2O. The combined organic phases were dried over Na2SO4, and the solvent was evaporated. The crude material obtained was dissolved in 10 mL of THF, treated with 3.46 mL of a 1M BH3-solution in THF and refluxed for 6 hrs. Distribution between a diluted aqueous solution of NaOH and Et2O, drying of the combined organic phases over Na2SO4 and evaporation of the solvent gave 1 g of crude trans benzyl-cyclopropylmethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amine as a yellow oil, MS: 524 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH3:18])[C:14]4[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: CCC1(CCCCCl)C(=O)Nc2cc(F)ccc21
Reactant: Clc1cccc(N2CCNCC2)c1
Product: CCC1(CCCCN2CCN(c3cccc(Cl)c3)CC2)C(=O)Nc2cc(F)ccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1-(3-chloro-phenyl)-piperazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9](Br)=[CH:10][CH:11]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)C=Cc1ccc(Br)nc1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)C=Cc1ccc(-c2ccc(F)cc2)nc1

Procedure:
A mixture of 2980 mg (12.31 mmol) of 3-(6-bromopyridin-3-yl)acrylic acid methyl ester, 2067 mg (14.77 mmol) of 4-fluorophenylboronic acid, 138.2 mg (0.61 mmol) of palladium(II)acetate, 322.9 mg (1.23 mmol) of triphenylphosphane and 14.7 ml of a 1M sodium carbonate solution in 73 ml of toluene and 20 ml of ethanol was heated under reflux for 1.5 h. After cooling, the mixture was poured onto water and extracted with ethyl acetate. The organic phases were evaporated and residue purified by chromatography (silica gel, n-heptane/ethyl acetate 5:1). Yield: 2.4 g (76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]2[CH2:18][CH2:17][C@@H:16]([CH2:19][OH:20])[C@@H:15]3[C@:10]2([OH:21])[CH2:11][CH2:12][CH2:13][O:14]3)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:25].[NH4+].[Cl-]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@@H:9]2[CH2:18][CH2:17][C@@H:16]([CH2:19][O:20][CH3:25])[C@@H:15]3[C@@:10]2([OH:21])[CH2:11][CH2:12][CH2:13][O:14]3)=[CH:6][CH:7]=1
Reactant: CI
Reactant: OC[C@@H]1CC[C@@H](Nc2ccc(F)cc2)[C@@]2(O)CCCO[C@H]12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H]1CC[C@@H](Nc2ccc(F)cc2)[C@]2(O)CCCO[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dissolved 95 mg (4aS,5R,8S,8aR)-5-[(4-fluorophenyl)amino]-8-(hydroxymethyl)hexahydro-2H-chromen-4a(5H)-ol in 2.1 mL THF then added 39 mg NaH. The reaction was stirred for 1.5 hours at RT, then diluted with an additional 1 mL of THF before adding 50 uL iodomethane. The reaction was stirred overnight at RT, then added to sat. NH4Cl. The mixture was diluted with water and extracted with CH2Cl2. The crude extract was dried over Na2SO4 then filtered, concentrated, then purified on silica gel to provide the title compound. 3H NMR (500 MHz, CDCl3) δ=1.34-1.40 (m, 2H), 1.54-1.62 (m, 2H), 1.72-1.77 (m, 1H), 1.78-1.87 (m, 1H), 2.10-2.16 (m, 1H), 2.22-2.30 (m, 1H), 2.32-2.42 (m, 1H), 3.29 (dd, J1=9.3 Hz, J2=6.6 Hz, 1H), 3.31-3.33 (m, 1H), 3.44-3.50 (m, 2H), 3.53 (bd, J=11.2 Hz), 4.09 (dd, Jz=11.6 Hz, J2=6.5 Hz, 1H), 4.58 (d, J=11.2 Hz) ppm. HRMS (ES) m/z calc'd: 310.1813. found 310.1811.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([NH:10][C:11]([NH:13][CH2:14][CH2:15]O)=[S:12])[C:2]1=2.O.C>Cl>[S:12]1[CH2:15][CH2:14][N:13]=[C:11]1[NH:10][C:9]1[C:2]2[O:1][CH:5]=[CH:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: OCCNC(=S)Nc1cccc2ccoc12
Agent: Cl
Solvent: O
Product: c1cc(NC2=NCCS2)c2occc2c1

Procedure:
3 g of N-benzo[b]furan-7-yl-N'-2-hydroxyethylthiourea in 12 ml of concentrated hydrochloric acid are heated for 10 minutes on a steam bath. The mixture is treated with 60 ml of water, treated with active charcoal and filtered. The colourless filtrate is made basic with conc. aqueous sodium hydroxide solution. The resultant precipitate is filtered off. After recrystallisation from methanol/ether, the title compound is obtained in free base form. M.Pt. 143°-145°.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd].[C]>[CH3:19][C:14]1([CH3:20])[CH2:13][CH:12]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[O:15]1
Reactant: [H][H]
Reactant: CN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O

Procedure:
7.3 g of N-[6-benzyloxy-2,2-dimethylchroman-4-yl]-N-methylmethanesulfonamide were dissolved in 100 ml of THF/methanol (1:1) and hydrogenated in a shaking duck using Pd/carbon. After absorpt ion of hydrogen was complete, the catalyst was filtered off with suction, the filtrate was concentrated and the residue was crystallized using dhsopropyl ether/petroleum ether, 5.2 g, m.p. 159-161° C.
Reaction SMILES: F[C:2]1[C:7]2[N:8](CC3C=CC4NC5C=CC=CC=5CCC=4C=3)[C:9]([CH2:11][CH2:12]C)=[N:10][C:6]=2[C:5]([CH3:30])=[CH:4][CH:3]=1.FC1C2NC(CCC)=[N:37]C=2C(C)=CC=1>>[CH2:11]([C:9]1[NH:8][C:7]2=[N:37][C:3]([CH3:2])=[CH:4][C:5]([CH3:30])=[C:6]2[N:10]=1)[CH3:12]
Reactant: CCCc1nc2c(C)ccc(F)c2[nH]1
Reactant: CCCc1nc2c(C)ccc(F)c2n1Cc1ccc2c(c1)CCc1ccccc1N2
Product: CCc1nc2c(C)cc(C)nc2[nH]1

Procedure:
[step 1] 2-(7-Fluoro-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (370 mg, 92%) was obtained in the same manner as in step 1 of Example 1, using 4-fluoro-7-methyl-2-propylbenzimidazole (478 mg, 1.10 mmol), obtained in Reference Example 4, instead of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [CH:1]1([CH:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH2:5][CH2:6][OH:7])[CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.FC(F)(F)C1C=CC(C(C)C=O)=CC=1>C(Cl)Cl>[CH:1]1([CH:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)[CH2:5][CH:6]=[O:7])[CH2:3][CH2:2]1
Reactant: OCCC(c1ccc(C(F)(F)F)cc1)C1CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(C=O)c1ccc(C(F)(F)F)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCC(c1ccc(C(F)(F)F)cc1)C1CC1

Procedure:
This compound was prepared in a manner analogous to that of Example 1, Step D, using 2.5 grams (0.01 mole) of 3-cyclopropyl-3-(4-trifluoromethylphenyl)propan-1-ol and 8.6 grams (0.04 mole) of pyridinium chlorochromate in 50 ml of methylene chloride. The yield of 3-cyclopropyl-3-pressure (4-trifluoromethylphenyl)propionaldehyde was 1.4 grams.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCCI
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCCn1nc(-c2ccc(OC)cc2)c2cccc(C(F)(F)F)c21
Yield: 37.5 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (0.146 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopentane (0.130 mL, 1.0 mmol) to give the title compound (0.068 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][N:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:21][C:22]([O:24]C)=[O:23].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][N:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: COC(=O)Cc1ccc2nc(-c3nccc4ccccc34)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc2nc(-c3nccc4ccccc34)oc2c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To methyl (7-fluoro-2-(1-isoquinolinyl)-6-benzoxazolyl)acetate (155 mg, 0.46 mmol) were added THF (3 ml) and 0.5N NaOH (3.0 ml, 1.50 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured in ice-1N HCl to acidify the mixture therewith. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (7-fluoro-2-(1-isoquinolinyl)-6-benzoxazolyl)acetic acid (116 mg, 78%) as a brown solid.
Reaction SMILES: [C:1]([CH2:6][C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH2:2][CH2:3][CH3:4].[F:14]F>C(#N)C>[C:1]([CH:6]([F:14])[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)CC(=O)C(=O)OCC
Reactant: FF
Solvent: CC#N
Product: CCCC(=O)C(F)C(=O)C(=O)OCC

Procedure:
In the same manner as in Example 1, ethyl 3-butyrylpyruvate (9.53 g; 0.0512 mol) is dissolved in acetonitrile (94 g) and reacted with fluorine at -5° C. By distilling off the solvent under reduced pressure, there is obtained a crude product (5.5 g), which is rectified to give ethyl 3-butyryl-3-fluoropyruvate. Boiling point, 72°-78° C./2 mmHg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]1=[O:26])[CH:7]=[CH:6]2)#[N:2].C(O)(C(F)(F)F)=O>>[O:26]=[C:14]1[CH2:15][NH:16][CH2:17][CH2:18][N:13]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C#N)ccc3n2)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2nc(N3CCNCC3=O)ccc2c1
Reaction time: 0.33 h

Procedure:
tert-Butyl 4-(6-cyanoquinolin-2-yl)-3-oxopiperazine-1-carboxylate (0.15 g, 0.79 mmol) was treated with TFA (2 mL) and stirred for 20 minutes. Analysis of the reaction mixture by LC indicated the reaction had gone to completion. The solution was concentrated in vacuo and crude was azetroped (3×) with dichloroethane to furnish the title product. LC/MS (IE, m/z): [M+1]+=253.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=2)[N:15]=1.[C:28](=[O:30])=[O:29]>C1COCC1>[Cl:13][C:14]1[C:23]([C:28]([OH:30])=[O:29])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]([F:26])([F:25])[F:27])[CH:20]=2)[N:15]=1
Reactant: O=C=O
Reactant: FC(F)(F)c1ccc2nc(Cl)ccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc2cc(C(F)(F)F)ccc2nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 1.54 ml (11.0 mmol) diisopropylamine in THF (38 ml) was cooled to 0° C. 6.9 ml (1.6 M in hexane, 11.0 mmol) n-BuLi were added dropwise at this temperature and then the mixture was stirred for 30 min at −78° C. Then a solution of 2.31 g (10.0 mmol) 2-chloro-6-(trifluoromethyl)quinoline in THF (12 ml) was added dropwise at −78° C. and the mixture was stirred for a further 30 min at −78° C. Then the reaction solution was poured onto finely dispersed dry ice. After heating to RT the mixture was concentrated to small volume under vacuum and the residue was taken up with water. It was made alkaline with a 1N aqueous NaOH solution and then washed with ether. Then it was acidified with a 10% aqueous hydrochloric acid and extracted with EE. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 198 mg (0.7 mmol, 72%) 2-chloro-6-(trifluoromethyl)quinoline-3-carboxylic acid were obtained as residue.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]([CH3:27])([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:12][CH:11]=1)[CH:7]=[CH2:8])C.[OH-].[Na+].CO>O>[CH3:27][C:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:12][CH:11]=1)([CH:7]=[CH2:8])[CH2:5][C:4]([OH:28])=[O:3]
Reactant: C=CC(C)(CC(=O)OCC)Cc1ccc(OCCCNc2ccccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CC(C)(CC(=O)O)Cc1ccc(OCCCNc2ccccn2)cc1
Yield: 62.3 %

Procedure:
A solution of the product of STEP 7 (0.26 g), 1 N sodium hydroxide in water (2 ml), and methanol (4 ml) was stirred overnight. Solvent was removed. The crude product was purified on a reverse phase HPLC using acetonitrile/water (0.5% TFA) gradient to give colorless oil (0.150 g). Anal. MS (APCI): m/z=355 (MH+), 1H NMR (500 MHz, CD3OD): δ1.09 (3H, s), 2.16 (2H, m), 2.25 (2H, q), 2.70 (2H, s), 3.59 (2H, t), 4.08 (2H, t), 4.85 (1H, d), 4.98 (1H, d), 5.92 (1H, dd), 6.81 (2H, d), 6.84 (1H, t), 7.07 (3H, m), 7.79 (1H, d), 7.86 (1H. t). Calcd. for C21H26N2O3+1.1 TFA: C, 58.07; H, 5.69; N, 5.84, Found: C, 57.87; H, 5.77; N, 5.70.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[C:20](C1NC=CN=1)(C1NC=CN=1)=O.C(OC(=O)CC(O)=O)C.O.FC(F)(F)C(O)=O>C1COCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](=[O:15])[CH3:20]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)O)c1Cl
Agent: CCOC(=O)CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Yield: 77.5 %

Procedure:
2-[(2,6-Dichloro-3-methylphenyl)amino]benzoic acid (8.4 g, 28.5 mmol) and carbonyl diimidazole (6.9 g, 42.7 mmol) are stirred in 300 ml THF under argon for two hours. Malonic acid monoethyl ester, magnesium salt (24.0 g, 85.4 mmol) is added and the reaction mixture is warmed to reflux for 15 hours. The solvent is evaporated, and the residue partitioned between ethyl acetate and 1N HCl. The pH of the aqueous layer is adjusted to pH=1 with concentrated HCl. The aqueous layer is extracted with ethyl acetate. The organic layer is washed with 1N HCl, and with saturated sodium bicarbonate, and then dried over magnesium sulfate and evaporated. The solid remaining is taken up in ethyl acetate and adsorbed onto a silica gel pad. The pad is washed with chloroform. Evaporation of the chloroform gives crude β-keto ester which is treated with 30% water/trifluoroacetic acid at reflux for two hours. The trifluoroacetic acid is evaporated, and the residue is taken up in diethyl ether. The ether solution is washed with 100 ml of saturated sodium bicarbonate three times. It is dried over magnesium sulfate, and evaporated. The remaining solid is taken up in methylene chloride and adsorbed onto a silica gel pad. This pad is washed with methylene chloride. Evaporation of the solvent gives a yellow solid. Recrystallization from methylene chloride/hexane gives 6.5 g (42%) of 1-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]ethanone; mp 130° -132° C.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C@H:3]([N:29]1[CH2:33][CH2:32][C@H:31]([NH:34]C(=O)OC(C)(C)C)[CH2:30]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][C@H:24]([CH3:28])[CH2:25][O:26][CH3:27])=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[ClH:44]>ClCCl>[ClH:44].[ClH:44].[F:42][C:2]([F:1])([F:43])[C@H:3]([N:29]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][C@H:24]([CH3:28])[CH2:25][O:26][CH3:27])=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: COC[C@@H](C)Oc1ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Agent: Cl
Solvent: ClCCl
Product: COC[C@@H](C)Oc1ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 162.8 %

Procedure:
To a solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(7-((R)-1-methoxypropan-2-yloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.11 g, 0.18 mmol) in dichloromethane (1 mL) was added hydrochloric acid (5-6M in 2-propanol; 9.2 mL, 0.18 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed under reduced pressure, and the resulting solid was suspended in acetonitrile (3 mL) and stirred at ambient temperature for 5 minutes. The solid formed was collected by vacuum filtration to give the title compound (0.084 g, 77%). LCMS APCI (+) m/z 501 (M+H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[N:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH:29]1([Mg]Br)[CH2:31][CH2:30]1>O1CCCC1>[CH:29]1([N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=2)[CH2:31][CH2:30]1
Reactant: COC(=O)c1ccc(N=Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C2CC2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a 0° C. solution of methyl 6-((4′-(trifluoromethyl)biphenyl-4-yl)methyleneamino)nicotinate (600 mg, 1.56 mmol) in tetrahydrofuran (10 mL) was added cyclopropylmagnesium bromide (5 mL, 2N in THF, 8 mmol). The reaction was stirred at 0° C. for 1 hr, then warmed to room temperature and left stirring for 12 h. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (3×15 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. Purification by preparative TLC (5:1 petroleum ether:ethyl acetate) gave methyl 6-(cyclopropyl(4′-(trifluoromethyl)biphenyl-4-yl)methylamino)nicotinate (130 mg).
Reaction SMILES: Br[C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([CH:21]3[CH2:23][CH2:22]3)[CH:14]=2)[C:6]1=[O:24].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([N:7]2[C:8](=[O:12])[C:9]([CH3:11])([CH3:10])[N:5]([CH2:4][C:3]3[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=3[NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=3)[C:6]2=[O:24])=[CH:14][C:15]=1[CH:21]1[CH2:23][CH2:22]1)#[N:18]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C3CC3)c2)C(=O)N1Cc1ccc(F)cc1Br
Reactant: COC(=O)c1ccc(N)cc1
Product: COC(=O)c1ccc(Nc2cc(F)ccc2CN2C(=O)N(c3ccc(C#N)c(C4CC4)c3)C(=O)C2(C)C)cc1

Procedure:
The further reaction of 158.2 with methyl 4-aminobenzoate was effected under conditions as described above for the preparation of example 1, stage 3. 158 with the molecular weight of 526.20 (C30H27F4N4O4) was obtained; retention time Rt=2.19 min. [B]; MS (ESI): 527.28 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:2][C:3]#[N:4])=[C:8]([CH:13]2[O:14][CH2:15][CH2:16][O:17]2)[CH:7]=1
Reactant: Oc1ccc(Cl)cc1C1OCCO1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1ccc(Cl)cc1C1OCCO1
Temperature: 100 °C

Procedure:
At room temperature, 2-chloroacetonitrile (12 g, 0.16 mol) was added into a mixture of 4-chloro-2-[1,3]dioxolan-2-yl-phenol (24.6 g, 0.123 mol) and K2CO3 (34 g, 0.246 mol) in DMF (150 mL). After the reaction mixture was heated at 100° C. for 3 h and cooled to room temperature, water was added. The aqueous phase was extracted with EtOAc twice, washed with saturated K2CO3 solution, water, and dried over anhydrous Na2SO4 to give crude (4-Chloro-2-[1,3]dioxolan-2-yl-phenoxy)-acetonitrile. The crude product was used for next step without further purification.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:34])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].N(C(OC(C)C)=O)=NC(OC(C)C)=O.CO.O>ClCCl.C(OCC)(=O)C>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH3:34])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(CCO)C(=O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCn2c(CC3(c4ccccn4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (443) (90 mg, 0.195 mmol), in dichloromethane (10 mL), TPP (178.64 mg, 0.682 mmol) and diisopropyl azodicarboxylate (0.115 mL, 0.584 mmol) were added and stirring was continued for 1 h at room temperature while silica thin layer chromatography was performed (3% methanol in ethyl acetate; Rf=0.2). After completion of the reaction, water (5 mL) was added and the mixture was extracted with dichloromethane (2×30 mL). The organic part was dried and concentrated. The resulting crude product was purified by normal silica gel (100-200 mesh) column chromatography using 60-70% ethyl acetate in hexane as gradient polarity mobile phase to get 9-benzyloxy-2-methyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (444) (71 mg, 82%) as a white solid.