Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[CH2:7]([O:9][C:10]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH3:28])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][C:11]=1[C:12]#[N:13])[CH3:8]>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH2:26]2)(=[O:20])=[O:19])=[CH:14][C:11]=1[C:12]([NH2:6])=[NH:13])[CH3:8]
Reactant: [NH4+]
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1C#N
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=N)N
Temperature: 25 °C
Yield: 28.6 %

Procedure:
Trimethylaluminium (10 mL, 2 Molar solution in hexanes) was added dropwise to a slurry of ammonium chloride (1.07 g, 0.02 Mol) in toluene (15 mL) at 0° C. The mixture was stirred without cooling until gas evolution stopped. 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)benzonitrile (the compound of Preparation 7) (3.23 g, 0.01 Mol) was then added and was washed in with toluene (5 mL) before the reaction was stirred at 80° C. for 40 h. After cooling to room temperature silica gel (15 g) and dichloromethane (100 mL) were added. The mixture was then filtered and the solids were washed with dichloromethane/methanol mixtures. The combined filtrate and washings were evaporated and the residue was chromatographed over silica gel using dichloromethane methanol mixtures to afford 1.08 g, 28.6% of the title compound. M/Z=found 341 (M+H). 1H NMR (CD3OD) 1.28 (t, 3H) 1.49 (t, 3H) 2.97 (q, 2H) 3.14 (br, s, 4H) 3.33(br, s, 4H) 4.32 (q, 2H) 7.45(d, 1H) 7.96 (d, 1H) 8.05 (dd, 1H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>>[N:5]1[CH:6]=[CH:7][C:2]([C:1]([Cl:12])=[O:9])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccncc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccncc1
Temperature: 70 °C

Procedure:
Isonicotinic acid (1.27 g, 10.36 mMole) was added to thionyl chloride (30 mL) and the mixture heated to 70° C. After 1 hour the solution was cooled, concentrated under reduced pressure and co-evaporated with ethyl acetate (2×30 mL). The residue was used as such in the following step.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)(=[O:5])=[O:4])[CH3:2].[C:16]([OH:20])(=[O:19])[CH:17]=[CH2:18].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH2:1]([S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:18][CH2:17][C:16]([OH:20])=[O:19])(=[O:5])=[O:4])[CH3:2]
Reactant: C=CC(=O)O
Reactant: CCS(=O)(=O)Nc1ccc2[nH]ccc2c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCS(=O)(=O)Nc1ccc2[nH]cc(CCC(=O)O)c2c1
Yield: 99.4 %

Procedure:
A solution of 5-ethanesulfonylamino-1H-indole (8.0 g, 36 mmol), acrylic acid (5.15 g, 71 mmol), and acetic anhydride (7.3 g, 71 mmol) in 35 mL of acetic acid was heated at 90° C. for 20 h. The volatile materials were removed under high vacuum at 90° C. The remaining residue was dissolved in 1N NaOH and subsequently acidified to pH 1 with concentrated HCl. The aqueous solution was then extracted with five portions of ethyl acetate. The organic extracts were combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to yield 3-(5-ethanesulfonylamino-1H-indol-3-yl)propanoic acid (10.6 g of crude material). NMR and mass spectral analysis indicated the presence of the desired product. No attempt was made to purify this material; it was immediately subjected to reduction as described below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9](Br)[CH:8]=[N:7][C:6]=12.[CH3:12][N:13]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[N:14]1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:16]3[CH:15]=[N:14][N:13]([CH3:12])[CH:17]=3)[CH:8]=[N:7][C:6]=12
Reactant: Brc1cnc2c(Br)cnn2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3c(Br)cnn3c2)cn1
Temperature: 85 °C

Procedure:
3,6-Dibromopyrazolo[1,5-a]pyrimidine (2.0 g, 7.22 mmol) was mixed with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.51 g, 7.22 mmol). Dioxane (36 mL) and 1M Na2CO3 (10.8 mL) were added. The mixture was evacuated and flushed with nitrogen under stirring, then Pd(Ph3P)4 (0.42 g, 0.36 mmol) was added in a counter flow of nitrogen. The reaction mixture was heated to 85° C. under stirring for 16 h, cooled, and poured into a 5-fold excess of water. The product was extracted thrice with CH2Cl2. The organic layer was washed with brine, dried with MgSO4, filtered, and evaporated. The residue was purified by column chromatography (1-5% methanol/DCM) to give 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine as a yellow solid: LC/MS [M+H]=277.9.
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[CH3:8][CH:9]([C:13](=[O:15])[CH3:14])[C:10](=[O:12])[CH3:11].IC>O>[CH3:8][C:9]([CH3:4])([C:13](=[O:15])[CH3:14])[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)C(C)C(C)=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(=O)C(C)(C)C(C)=O
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To 0.1 mol sodium hydride was added 100 ml anhydrous tetrahydrofuran, and slowly added dropwise 0.12 mol 3-methyl-2,4-pentandione at room temperature. Upon completion, the mixture was stirred for 0.5 hours, then 0.12 mol iodomethane was slowly added dropwise. After stirred at room temperature for 10 hours, 20 ml water was added to dissolve solid. The mixture was extracted with ethyl acetate. The solvent was removed. Distillation was carried out under reduced pressure, and cut fraction 82-84° C./1 kPa was collected. The yield was 98%.
Reaction SMILES: [OH:1][C@H:2]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:23]1[CH:24]=[C:25]([C:29]#[N:30])[CH:26]=[N:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[OH:1][C@H:2]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([CH:24]=2)[C:29]#[N:30])=[CH:7][CH:6]=1
Reactant: OB(O)c1ccc(OC[C@H](O)CCc2cccnc2)cc1
Reactant: N#Cc1cncc(Br)c1
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: [Na+]
Product: N#Cc1cncc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 90 °C
Yield: 55.4 %

Procedure:
Prepared according to the method described in Example 21b) from (2R)-4-(2-hydroxy-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.15 g, Example 28a)), 5-bromopyridine-3-carbonitrile (0.19 g), 2M aqueous sodium carbonate (0.60 ml) and tetrakis(triphenylphosphine)palladium(0) (0.014 g) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.10 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[F:17][C:18]1[N:23]=[C:22]2[C:24]([CH3:28])=[CH:25][N:26]([NH2:27])[C:21]2=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:17][C:18]1[N:23]=[C:22]2[C:24]([CH3:28])=[CH:25][N:26]([NH:27][C:14]([C:10]3[C:11]([CH3:13])=[N:12][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][CH:9]=3)=[O:16])[C:21]2=[CH:20][CH:19]=1
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: Cc1cn(N)c2ccc(F)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C)c2nc(F)ccc21
Yield: 57.8 %

Procedure:
A solution of 2-pyridin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (1.36 mmol), 5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.36 mmol), DIPEA (158 mg, 4.07 mmol) and HATU (1.63 mmol) in anhydrous DMF (8 mL) is stirred at 90° C. for 15 hours. DMF is evaporated in vacuo. The residue is dissolved in EtOAc (40 mL), washed with water (3×15 mL) and brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue is recrystallized from EtOAc to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (285 mg) as a solid. MS: 363 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.35 (s, 3H), 2.87 (s, 3H), 6.92 (d, H), 7.51 (s, H), 7.60 (t, H), 7.97 (t, H), 8.05 (t, H), 8.65 (d, H), 8.78 (d, H), 9.23 (s, H).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[N:17]=[CH:18][N:19]([CH3:30])[C:20]=2[S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[C:6]1[CH3:31].CO.[OH-].[Na+]>O1CCCC1>[C:24]1([S:21]([C:20]2[N:19]([CH3:30])[CH:18]=[N:17][C:16]=2[CH2:15][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)[N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]=2[CH3:31])(=[O:23])=[O:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)Cn1c(C)c(Cc2ncn(C)c2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cc2ncn(C)c2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A mixture of [3-(5-benzenesulfonyl-1-methyl-1H-imidazol-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.027 g), methanol (3.0 mL) and 1.0 M aqueous sodium hydroxide solution (0.12 mL) was stirred at room temperature for 1 hour. The mixture was treated with tetrahydrofuran (1.0 mL) and 1.0 M aqueous sodium hydroxide solution (0.24 mL), and stirred at room temperature for 4 hours and then at 40° C. for 30 minutes. The mixture was concentrated under reduced pressure and acidified by the addition of 1.0 M aqueous hydrochloric acid solution. The resulting precipitate was collected by filtration, washed with water and dried to afford the title compound as a white solid (0.024 g).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4](OC)=[O:5].C1C(=O)[N:17](Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1>[I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:5])[NH:17][CH2:12]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cccc1I
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: O=C1NCc2cccc(I)c21
Temperature: 90 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
Methyl 2-iodo-6-methylbenzoate (I58) (2.00 g, 7.245 mmol) and NBS (1.418 g, 7.969 mmol) were stirred in chlorobenzene (50 mL) and benzoyl peroxide (75% w/w, 0.234 g, 0.724 mmol) was added. The reaction was stirred at 90° C. for 18 hours, cooled to room temperature, filtered and the precipitate was washed with cyclohexane (4×10 mL). The combined filtrates were evaporated, and the resulting brown oil was diluted with THF (50 mL). Aqueous ammonia solution (20 mL) was added, and the mixture was stirred vigorously for 17 hours. The mixture was diluted with water (20 mL) and the THF was removed in vacuo. DCM (150 mL) was added, the layers were separated and the aqueous layer was extracted with DCM (2×100 mL), the combined organics were washed with brine (100 mL), dried (MgSO4) and filtered. Silica gel was added and the volatiles were removed in vacuo to give the crude material absorbed onto silica gel. The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% methanol in EtOAc) to give the title compound (I59) (0.757 g, 40% yield) as a beige solid; 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J=7.8, 0.7 Hz, 1H), 7.46 (dd, J=7.5, 0.8 Hz, 1H), 7.26-7.21 (m, 1H), 7.10 (br s, 1H), 4.37 (d, J=0.6 Hz, 2H). LCMS Method C: rt 5.06 min; m/z 260.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:22][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[OH:21])[C:7]=2[C:6]=1[CH3:23])=[O:4].Br[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]([C:5]1[S:22][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:7]=2[C:6]=1[CH3:23])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Reactant: BrC1CCCC1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCCC3)c2c1C

Procedure:
Prepared analogously to example 243.2 from 4-(4-fluoro-2-hydroxy-phenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (67 mg) and bromocyclopentane (60 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([O:21]CC3C=CC=CC=3)=[CH:16][C:15]=2[O:29]CC2C=CC=CC=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([OH:21])=[CH:16][C:15]=2[OH:29])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(F)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(F)c(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 29 h
Yield: 147.8 %

Procedure:
A mixture of 860 mg (0.42 mmol, 1 eq) of 4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid tert-butyl ester at 35% in 10 ml of ethyl acetate, in the presence of 200 mg of palladium-on-charcoal at 10%, is stirred at ambient temperature under a hydrogen pressure of 5 bar for 17 hours. 5 ml of methanol are added and the reaction medium is stirred at ambient temperature under a hydrogen pressure of 5 bar for 29 hours. The reaction medium is filtered through filter paper and the filtrate is evaporated off. The residue is chromatographed on silica gel, elution being carried out with 60/40 heptane/ethyl acetate. 192 mg of 4-(5-fluoro-2,4-dihydroxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester are obtained. Yield=100%.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][C:23]([NH2:30])=[N:24][C:25]=2Cl)[C@H:9]([O:11][Si](C(C)(C)C)(C)C)[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=[O:34]>O>[NH2:30][C:23]1[NH:24][C:25](=[O:34])[C:26]2[N:27]=[CH:28][N:20]([CH2:19][C@H:8]([C@H:9]([OH:11])[CH3:10])[CH2:7][OH:6])[C:21]=2[N:22]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1cnc2c(Cl)nc(N)nc21
Solvent: O
Product: C[C@@H](O)[C@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21
Reaction time: 48 h
Yield: 70 %

Procedure:
A solution of 36 (1.8 g, 3.6 mmol) in a mixture of TFA (60 ml) and water (20 ml) was kept at room temperature for 2 days until almost no starting material was found by HPLC analysis. The reaction was concentrated, co-evaporated with water (3×100 ml) and re-dissolved in ˜5 ml of acetonitrile. Ethyl ether (˜50 ml) was added to precipitate 0.84 g of 37 as a TFA salt. The salt was dissolved in ˜7 ml of ethanol, treated with 0.5 ml of triethylamine and allowed to crystallize at −20° C. for 2 hrs. The crystals were collected by filtration, washed with ethyl ether and dried in vacuo to afford 0.64 g (70%) of 37 as a white solid. 1H NMR (DMSO-d6): δ 10.55 (s, 1H), 7.63 (s, 1H), 6.46 (s, 2H), 4.63 (d, J=5 Hz, 1H), 4.55 (t, J=5 Hz, 1H), 3.97 (d, J=7.5 Hz, 2H), 3.64 (m, 1H), 3.41 (m, 2H), 1.92 (m, 1H), 1.10 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:6][CH:7]([C:13]#[N:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:22]([O:25][CH:26](OCC)[O:27][CH2:28][CH3:29])(=O)[CH3:23]>>[C:8]([C:7]([CH:26]([O:27][CH2:28][CH3:29])[O:25][CH2:22][CH3:23])([CH2:6][C:5]1[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:13]#[N:14])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(OCC)OC(C)=O
Reactant: CCOC(=O)C(C#N)Cc1cc(OC)c(OC)c(OC)c1
Product: CCOC(=O)C(C#N)(Cc1cc(OC)c(OC)c(OC)c1)C(OCC)OCC
Temperature: 95 °C
Yield: 72.7 %

Procedure:
Ethyl 3,4,5-trimethoxybenzylcyanoacetate (5 g) was mixed with diethoxymethyl acetate (15 g) and heated at 95° C. overnight. The mixture was cooled and crystallized by addition of ether-hexane (1:1, 25 ml). The product was filtered and drier under reduced pressure giving 4.9 g (73%) of white solid, m.p. 95°-97° C.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][N:7]=[C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH3:9])C.O.[OH-].[Li+]>O1CCCC1.O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[N:7][O:6][CH2:5][C:4]([OH:17])=[O:3])[CH3:9])=[CH:11][CH:12]=1
Reactant: CCOC(=O)CON=C(C)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=NOCC(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Yield: 37.8 %

Procedure:
To a solution of ethyl({[1-(4-fluorophenyl)ethylidene]amino}oxy)acetate (8.7 g) in a mixture of 50 ml of tetrahydrofuran and 10 ml of water was added, at 20° C., lithium hydroxide monohydrate (2.3 g) and the mixture was stirred at this temperature for 18 hours. Subsequently, the mixture was stirred into ice-cold 10% hydrochloric acid and extracted twice with ethyl acetate (50 ml each time). The combined organic phases were dried over sodium sulphate and concentrated. Purification by column chromatography on silica gel with a solvent gradient from 0:100 methanol/dichloromethane to 60:0 methanol/dichloromethane gave ({[1-(4-fluorophenyl)ethylidene]amino}oxy)acetic acid (2.9 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH2:10]
Reactant: COc1ccc(C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A suspension of 1-methyl-4-(methyloxy)-2-nitrobenzene (20.0 g, 119.8 mmol) and Pd/C (10%, 3 g) in methanol (100 mL) was stirred under H2 atmosphere at room temperature overnight. The mixture was filtered through a pad of celite and the filtrate was evaporated under vacuum to afford the title compound as a solid (16.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>ClCCl>[C:2]1([NH:1][C:20]([C:16]2[O:15][CH:19]=[CH:18][CH:17]=2)=[O:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1ccco1
Temperature: -10 °C

Procedure:
N-phenyl furamide was prepared by adding to a mixture of aniline (23.3 g; 250 mmol) and triethylamine (25.3 g; 250 mmol) in dichloromethane slowly 32.6 g (250 mmol) of 2-furoyl chloride, while maintaining the temperature at -10° C. The product obtained was washed with diluted hydrochloric acid and water, dried with magnesium sulphate and evaporated. The product so obtained was than triturated with hexane and filtered. 39.3 g (84% yield of product was recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]C(C)(C)C)=[O:36].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(Cl)cc5)n4)cc3)c(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2ccc(Cl)cc2)n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
Enantiomer 2 of tert-butyl 6-chloro-7-(4-(6-(4-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (10 mg, 0.017 mmol) was diluted with dichloromethane (100 μL) followed by the addition of trifluoroacetic acid (100 μL). After stirring for 2 hours, the reaction was concentrated to yield Enantiomer 2 of 6-chloro-7-(4-(6-(4-chlorophenyl)pyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (9.0 mg, 0.017 mmol, 99% yield). MS (apci, positive) m/z=535.1. 1H NMR (400 MHz, CDCl3) δ 9.03 (br s, 1H), 8.35 (d, 1H), 7.96 (d, 2H), 7.90-7.85 (m, 4H), 7.48-7.42 (m, 4H), 7.05 (d, 2H), 6.60 (s, 1H), 4.29-4.23 (m, 2H), 3.82 (t, 1H), 2.36 (dd, 1H), 2.19-2.10 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH3:17])[CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)=[O:20].C1(O)C=CC=CC=1>ClCCl>[F:37][C:35]([F:36])([F:38])[C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:19]([N:13]3[CH2:12][CH2:11][CH:10]([CH2:9][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:16][CH3:17])[CH2:15][CH2:14]3)=[O:20])=[CH:23][CH:24]=2)=[N:30][CH:31]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CCN(Cc1ccccc1)CC1CCNCC1
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: CCN(Cc1ccccc1)CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1
Reaction time: 8 h

Procedure:
Benzyl-ethyl-piperidin-4-ylmethyl-amine (1.42 mmol) was dissolved in dichloromethane. 4-(5-Trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate (1.42 mmol, 0.451 g) (prepared from the corresponding phenol by conventional methods) was added at room temperature. The reaction mixture was stirred overnight and evaporated to dryness. The crude product was subjected to column chromatography, ethyl acetate/heptane (1:3)→Triethylamine/ethyl acetate 1:9). The fractions containing the title product, was evaporated to dryness and HCl (g) in ethyl acetate was added and stirred for 16 hours. The solution was evaporated to dryness and dryed in vacoum for 16 h. to give the title product. (58%, light yellow crystals). HPLC-MS m/z=514.1 (M+1), Rt: 3.27 min.
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[CH:14]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:20][CH:21]=3)[CH2:16]2)[N:12]=[C:11]([NH2:32])[N:10]=1.[NH:33]1[CH2:38][CH2:37][CH:36]([NH:39]C(=O)OC(C)(C)C)[CH2:35][CH2:34]1>>[NH2:39][CH:36]1[CH2:37][CH2:38][N:33]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([C:26]5[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(N2CCC(N)CC2)nc(N)n1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 118 starting from 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and tert-butyl piperidin-4-ylcarbamate (Aldrich, Cat. No. 540935). LCMS (M+H)+: m/z=419.2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.O.[Pd]>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=[O:19])=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1cccc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 70 °C
Yield: 98.6 %

Procedure:
The Suzuki coupling was carried out according to the method of Dyer et al. (2001) Tetrahedron Letters 42:1765-1767. Commercially available 4-(trifluoromethyl)phenylboronic acid (15 g, 78.7 mmol) and 3-bromobenzoic acid (15.1 g, 75 mmol) were suspended in i-PrOH:water (1:4, 72 mL). 10% Pd/C (1.5 g) was added followed by aqueous Na2CO3 (39 mL, 20% by wt.). The resulting mixture was heated at 70° C. for 4 hours. The precipitate was filtered and rinsed with 20% aqueous Na2CO3 solution. The filtrate was diluted with water and acidified to pH=2. The white solid was filtered and dried in vacuo to afford 2.1 (19.69 g).