Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH:12]=[CH2:13])=[CH:5][N:6]=[CH:7]2.O=[C:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(OCC)(=O)C.CO>[CH:12]([C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][CH:19]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18]2)[CH:7]=[N:6][CH:5]=1)=[CH2:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: C=Cc1cncc2cccc(N)c12
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: C=Cc1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 19 h
Yield: 64.1 %

Procedure:
A solution of Intermediate 1 (251 mg), and tert-butyl 3-oxo-1-pyrrolidinecarboxylate (563 mg, AstaTech) in dichloromethane (85 ml) was added with titanium tetraisopropoxide (905 μl, Aldrich) at room temperature, and stirred at room temperature for 19 hours. The reaction mixture was added with methanol (6 ml), and sodium borohydride (249 mg, Kanto Chemicals), and stirred at room temperature for 3.5 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (20 ml), and ethyl acetate (20 ml), and then the precipitates were removed by filtration. Then, the organic layer was separated, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the title compound (321 mg).
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.C([Li])CCC.[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].Cl>C(OCC)C.CCCCCC.O>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18](=[NH:3])[NH2:19]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: N#Cc1ccccc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: N=C(N)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a solution of hexamethyldisilazane (19.4 g, 120 mmol) in diethyl ether (200 ml) was added dropwise a 1.6 N solution (75.0 ml, 120 mmol) of n-butyllithium in hexane under ice-cooling. Thereto 2-fluorobenzonitrile (7.01 g, 57.9 mmol) was added, followed by stirring at room temperature for 2 hours. Thereto 3 N hydrochloric acid (80 ml) was added dropwise under ice-cooling, and the reaction mixture was stirred at room temperature for 0.5 hour. Water (200 ml) was added thereto, and the ether layer was removed. The aqueous layer was basified with an aqueous 3 N sodium hydroxide solution, and then extracted with chloroform. The extracts were dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 5.17 g (64.7%) of the desired product as a solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([Cl:18])[CH:11]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([Cl:18])[C:11]=1[C:5](=[O:7])[CH3:6]
Reactant: COc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(Cl)c(C(C)=O)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
A mixture of aluminum chloride (4.50 g, 33.9 mmol) and acetyl chloride (2.40 mL, 33.9 mmol) in CH2Cl2 (20.0 mL) was stirred at 0° C. for 30 min. The reaction mixture was slowly added with 1,3-dichloro-5-methoxybenzene (10-1, 2.00 g, 11.3 mmol) in CH2Cl2 (10.0 mL), and the resultant solution was stirred at room temperature for additional 2.0 h. The solution was basified with saturated aqueous NaHCO3. The organic layer was separated, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 1-(2,6-dichloro-4-methoxyphenyl)ethanone (10-2, 1.0 g, 4.6 mmol) as yellow oil in 40% yield: 1H NMR (CDCl3, 500 MHz) δ 7.01 (d, J=1.6 Hz, 2 H), 6.82 (d, J=1.6 Hz, 2 H), 3.83 (s, 3 H), 2.49 (s, 3 H).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:16]3[CH2:32]C(O)C[CH:15]3[C:14]=2[CH:13]=1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:16]3[CH2:32][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH:15]3[C:14]=2[CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(O)CC32)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(OC(C)=O)CC32)cc1
Yield: 82.7 %

Procedure:
Add acetic anhydride (53 mg, 0.52 mmol) to a solution of alcohol 25 (200 mg, 0.52 mmol), Et3N (0.14 mL, 1.03 mmol), and DMAP (6 mg, 0.052 mmol) in CH2Cl2 (5 mL) and stir the reaction at room temperature for 1 hour. Dilute the solution with EtOAc and wash with H2O, saturated aqueous sodium bicarbonate and brine. Dry (Na2SO4), filter and concentrate the solution in vacuo. Purify the product by flash chromatography (10 g SiO2, 40 mL/min, 0-40% EtOAc/Hexanes over 20 minutes and then 40% EtOAc/Hexanes for 13 minutes) to afford acetate 42 (183 mg, 0.43 mmol, 83%) as a yellow oil. HRMS(FAB+) calcd for C24H28O7: 428.1835; found: 428.1833 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].N1(C2C=C[C:26]([CH:27]=[O:28])=CC=2)C=CC=N1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[CH:26][CH:27]=[O:28])=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cn2)cc1
Product: O=CC=Cc1ccc(-c2ccc([N+](=O)[O-])cn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(5-nitro-2-pyridinyl)benzaldehyde (prepared as described in Reference Example 19) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 255 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH:9]1([NH:1][C@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC[C@@H](N)C(=O)OC
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC[C@@H](NC1CCCC1)C(=O)OC
Reaction time: 1.5 h
Yield: 32.6 %

Procedure:
The crude compound methyl (2R)-2-aminobutanoate 1j (11.24 g, 0.10 mol) and cyclopentanone (8.24 g, 0.10 mol) were dissolved in 150 mL of dichloromethane, stirred for 1.5 hours followed by the addition of sodium acetate (8.04 g, 0.10 mol) and sodium triacetoxyborohydride (30.52 g, 0.14 mol), and stirred for 3 hours. The reaction solution was poured into 150 mL 10% sodium bicarbonate solution, extracted with dichloromethane (100 mL×3). The combined organic phase was washed with saturated sodium chloride solution (100 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl (2R)-2-(cyclopentylamino)butanoate 1k (6.04 g, yield: 34.0%) as a light liquid.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:6]([OH:8])=O)[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]([CH3:30])([CH3:29])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:4][C@H:5]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:6]([NH:28][C:25]2[CH:26]=[CH:27][N:23]([CH2:22][C:21]([O:20][CH3:19])([CH3:29])[CH3:30])[N:24]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(O)[C@H](CC1CC1)N1Cc2ccccc2C1=O
Reactant: COC(C)(C)Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CC2)N2Cc3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
To a solution of (S)-3-cyclopropyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (85 mg, 0.35 mmol) and 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 94, 64 mg, 0.38 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.18 g, 0.42 mmol) in methylene chloride (8 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) dropwise and the resulting solution stirred at room temperature for 4 h. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (25 mL), a saturated sodium bicarbonate solution (25 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-40 g column, 50-70% ethyl acetate/hexanes) to give (S)-3-cyclopropyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (46 mg, 34%) as an off white solid: [α]30D=−38.1°, (c=0.21, chloroform); HR-ES(+) m/e calcd for C22H28N4O3 [M+H]+ 397.2234, observed 397.2235; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.03-1.69 (m, 9H), 2.00-2.28 (m, 1H), 3.15 (s, 4H), 3.99 (s, 2H), 4.36-5.39 (m, 4H), 6.42 (d, J=1.81 Hz, 1H), 7.25-7.88 (m, 6H), 10.80 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([CH3:6])[C:3]([OH:5])=[O:4].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[F:1][C:2]([F:7])([CH3:6])[C:3]([O:5][C:3](=[O:4])[C:2]([F:7])([F:1])[CH3:6])=[O:4]
Reactant: CC(F)(F)C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CC(F)(F)C(=O)OC(=O)C(C)(F)F
Reaction time: 48 h

Procedure:
To a solution of 2,2-difluoropropanoic acid (330 mg, 2.97 mmol) in DCM (5 mL) was added P2O5 (3.3 g, 29.7 mmol) at room temperature and the mixture was stirred for 2 days to give 2,2-difluoropropanoic anhydride. To a suspension of Intermediate A-2a (170 mg, 0.59 mmol) in TEA (5 mL) was added dropwise the 2,2-difluoropropanoic anhydride in DCM at 0˜10° C. The mixture was stirred at room temperature for 2 h. The volatiles were evaporated and the residue was purified by prep-TLC (PE:EA=1:1) to afford methyl 4-(2-(1,1-difluoroethyl)-7-hydroxy-4-oxo-4H-chromen-3-yl)benzoate as brown oil (45 mg, 21%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.CO[CH2:12][CH2:13]OC>C([O-])([O-])=O.[K+].[K+].C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:9][C:4]1[N:3]=[C:2]([CH:12]=[CH2:13])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(Cl)nc(Cl)c1
Reactant: COCCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: C=Cc1cc(C)cc(Cl)n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 2,6-dichloro-4-methyl-pyridine (2.34 g, 14.4 mmol) and 2,4,6-trivinyl-cyclotriboroxane pyridine complex (1.75 g, 7.26 mmol) in DME (27 mL), 2 M aq. K2CO3 solution (10 mL) is added. The mixture is degassed and put under argon before Pd(PPh3)4 (300 mg, 0.26 mmol) is added. The mixture is stirred at 80° C. for 3 h before it is cooled to rt, diluted with diethyl ether and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1. The thus obtained product is dissolved in EA, repeatedly washed with 5% aq. citric acid solution, dried over MgSO4, filtered and evaporated to give 6-chloro-4-methyl-2-vinyl-pyridine (1.24 g) as a colourless oil; LC-MS: tR=0.90 min, [M+1]+=154.03.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](I)[CH:13]=1)(=[O:3])[CH3:2].CS(C)=O.[C:31]1([S:37]([O-:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CNCCNC>C(OCC)(=O)C.O>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(I)c1
Reactant: O=S([O-])c1ccccc1
Agent: CNCCNC
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(S(=O)(=O)c2ccccc2)c1
Temperature: 130 °C
Yield: 43 %

Procedure:
0.495 g (1 mM) of 5-iodo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 4 ml of DMSO, 0.025 g (0.05 mM) of benzene/copper trifluoro-methanesulfonate complex, 0.196 g (1.2 mM) of phenyl sulfinate and 0.0088 g (0.1 mM) of N,N′-dimethylethylenediamine are mixed under an argon atmosphere in a reactor adapted for microwaves. The mixture is heated at 130° C. for 3 hours by microwaves. Water is added to the cooled reaction mixture and extraction is carried out with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel using a toluene/acetone mixture (9/1; v/v) as the eluent to give the expected product in the form of a white solid with a yield of 43%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11](NC(C3CC3)=O)[CH:10]=2)[C:5](=[O:21])[N:4]2[C:22]([C:27]3C=CC=C(F)C=3)([CH3:26])[NH:23][C:24](=[O:25])[C:3]=12.[Cu][C:35]#[N:36].[C-]#N.[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][C:22]1([CH3:27])[N:4]2[C:5](=[O:21])[C:6]([NH:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][N:14]=3)=[CH:7][C:2]([C:35]#[N:36])=[C:3]2[C:24](=[O:25])[NH:23]1
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Reactant: N#C[Cu]
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1(C)NC(=O)c2c(C#N)cc(Nc3ccncn3)c(=O)n21
Temperature: 150 °C

Procedure:
To a vial was added 8-chloro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-c]pyridine-1,5-dione (1, 1000 mg, 3.27 mmol), copper(I) cyanide (293 mg, 3.27 mmol) and sodium cyanide (160 mg, 3.27 mmol) in 1,4-dioxane (10 mL) at room temperature under argon. The reaction was purged with argon for 5-10 min, followed by addition of tricyclohexylphosphine (92 mg, 0.33 mmol) and tris(dibenzylideneacetone)dipalladium(0) (299 mg, 0.33 mmol) under argon. The vial was then sealed and heated at 150° C. for 48 h. After completion the reaction was quenched with sat solution of potassium permanganate and extracted the crude compound with 10% methanol in dichloromethane. The organic layer was concentrated to dryness and crude was purified by flash column chromatography (silica gel 100-200 mesh) using 2% methanol in dichloromethane. The desired fractions were concentrated to dryness under vacuum to obtain 3,3-dimethyl-1,5-dioxo-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-8-carbonitrile (Cpd. No. 181) as off white solid. Yield: 0.2 g, 20%; MS (ESI) m/z 297.36 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.69 (s, 1H), 8.90 (s, 1H), 8.85 (s, 1H), 8.44 (d, J=5.84 Hz, 1H), 7.44 (d, J=5.36 Hz, 1H), 1.82 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(=O)CC>[CH3:23][O:22][C:20](=[O:21])[CH2:19][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1cccc(C(F)(F)F)c1

Procedure:
A mixture of 3-trifluoromethyl-phenol (5.000 g; 30.843 mmol), potassium carbonate (5.328 g; 38.554 mmol), and methyl bromoacetate (3.54 ml; 38.554 mmol) in butanone (210 ml) was heated at reflux for 3 h. Filtration, concentration to dryness under reduced pressure, and purification by FC (heptane/EA, 4/1) afforded (3-trifluoromethyl-phenoxy)-acetic acid methyl ester as a pale yellow oil (7.220 g; 99%). LC-MS: tR=0.95 min.; [M+H]+: no ionisation.
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:22]1[CH2:27][CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH2:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:22]1[CH2:23][CH:24]=[C:25]([C:2]2[C:3]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncccc2Br)CC1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncccc2C2=CCOCC2)CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution tert-butyl 4-((3-bromopyridin-2-yl)oxy)piperidine-1-carboxylate (see PREPARATION P20.4; 4 g, 11.2 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.58 g, 12.4 mmol) and Na2CO3 (2.38 g, 22.4 mmol) in 1,4-dioxane (60 mL) and H2O (6 mL) was added Pd(dppf)Cl2 (410 mg, 0.56 mmol) then the reaction mixture was stirred at 110° C. under N2 for overnight. The reaction mixture was filtered through CELITE® and washed with CH2Cl2. The organic layer was concentrated and the crude product was purified by silica gel column to give the desired compound (3.5 g, 8.7 mmol, yield 70%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:25]2[C:30]([CH3:31])=[C:29]([O:32]C)[C:28]([CH3:34])=[C:27]([CH3:35])[C:26]=2[O:36]C)([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:25]3[C:30]([CH3:31])=[C:29]([OH:32])[C:28]([CH3:34])=[C:27]([CH3:35])[C:26]=3[O:36]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)c(C)c(OC)c(C(O)(c2ccc(C(C)C)cc2)C2CCN(Cc3ccccc3)CC2)c1C
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCN(Cc3ccccc3)CC1)O2
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To a solution of (1-benzyl-4-piperidyl)(2,5-dimethoxy-3,4,6-trimethylphenyl)(4-isopropylphenyl)methanol (6.41 g, 12.8 mmol) in acetic acid (50 mL) was added 48% hydrobromic acid (60 mL), and the mixture was heated under reflux for 15 hours in an argon atmosphere. The reaction mixture was cooled to room temperature, made basic with 8N sodium hydroxide solution, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (4.44 g, yield 76%).
Reaction SMILES: CS([C:4]1[N:9]=[C:8]2[N:10]([CH3:36])[C:11](=[O:35])[N:12]([C:15]3[CH:16]=[C:17]([NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)[CH:18]=[CH:19][C:20]=3[CH3:21])[C:13](=[O:14])[C:7]2=[CH:6][N:5]=1)=O.[CH3:37][NH2:38]>C1COCC1>[CH3:21][C:20]1[CH:19]=[CH:18][C:17]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=2)=[CH:16][C:15]=1[N:12]1[C:13](=[O:14])[C:7]2[C:8](=[N:9][C:4]([NH:38][CH3:37])=[N:5][CH:6]=2)[N:10]([CH3:36])[C:11]1=[O:35]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-n1c(=O)c2cnc(S(C)=O)nc2n(C)c1=O
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2c(=O)n(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3C)c(=O)n(C)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
N-[3-(7-Methanesulfinyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methyl-phenyl]-3-trifluoromethyl-benzamide (30 mg, 58 μmol) is dissolved in 2 M methylamine solution (1 mL) in THF and the mixture is stirred for 1 h at 60° C. The reaction mixture is concentrated, dissolved in DMSO, and purified by preparative LCMS to give N-[4-Methyl-3-(1-methyl-7-methylamino-2,4-dioxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-3-trifluoromethyl-benzamide (20 mg, 71%); 1H NMR 400 MHz (DMSO-d6) δ 10.70 (s, 1H), 8.95 (s, 0.33H), 8.85 (s, 0.66H), 8.39 (m, 3H), 8.11 (d, 1H), 7.93 (t, 1H), 7.84 (m, 2H), 7.49 (d, 1H), 3.65 (d, 2H), 3.58 (s, 1H), 3.08 (m, 3H), 2.17 (s, 3H); MS m/z 485.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:20]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])=[N:19][CH:18]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Reactant: NC1CC1
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)NC2CC2)s1
Yield: 43 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (40 mg, 43%) which was obtained as a light yellow solid after recrystallization from heptane/ethyl acetate. MS: m/e=371.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([CH:19]([OH:26])[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:26])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:27]([F:30])([F:28])[F:29]
Reactant: O=S(=O)(Nc1cc(Cl)cnc1C(O)c1ccncc1)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: O=C(c1ccncc1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(hydroxy-pyridin-4-yl-methyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (15 mg, 0.03 mmol) and PCC (15 mg) was stirred at room temperature for 2 h. It was then treated with small amount of silica gel and filtered. The filtrate was concentrated under reduced pressure to provide the crude ketone. 1H NMR (400 MHz, CDCl3) δ 10.90 (br s, 1H), 8.78 (dd, J=4.4, 1.6 Hz, 2H), 8.35 (d, J=2.0 Hz, 1H), 8.19-8.17 (m, 2H), 7.98 (dd, J=8.4, 2.0 Hz, 1H), 7.65-7.61 (m, 3H). MS m/z: 476.0 (M+H).