Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2=[C:7]([CH:40]=1)[O:8][CH2:9][C:10]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:11]=1/[C:12]/2=[CH:13]\[C:14]1[CH:34]=[CH:33][C:17]2[N:18]([C@H:24]([CH3:32])[CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)/[C:19](=[N:21]/[C:22]#[N:23])/[NH:20][C:16]=2[CH:15]=1.[O:41]1CCOCC1>>[F:2][C:3]1[CH:4]=[CH:5][C:6]2=[C:7]([CH:40]=1)[O:8][CH2:9][C:10]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:11]=1/[C:12]/2=[CH:13]\[C:14]1[CH:34]=[CH:33][C:17]2[N:18]([C@H:24]([CH3:32])[CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)/[C:19](=[N:21]/[C:22]([NH2:23])=[O:41])/[NH:20][C:16]=2[CH:15]=1
Reactant: C[C@H](CN1CCOCC1)n1/c(=N/C#N)[nH]c2cc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)ccc21
Reactant: C1COCCO1
Agent: Cl
Product: C[C@H](CN1CCOCC1)n1/c(=N/C(N)=O)[nH]c2cc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)ccc21
Reaction time: 48 h
Yield: 38 %

Procedure:
Prepare a solution of 4 M hydrogen chloride in dioxane by diluting 12 M hydrochloric acid (10 mL) with dioxane (20 mL). Slowly add this solution to (E)-N—((R)-5-((E)-3,7-difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-1-(1-methyl-2-morpholin-4-yl-ethyl)-1,3-dihydro-benzoimidazol-2-ylidene)-cyanamide (0.005 mol, 3.0 g) at room temperature and stir for 48 hours. Quench the reaction mixture with aqueous 4 N potassium hydroxide solution, extract with dichloromethane and wash with saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduce pressure. Purify on silica gel column using 1% methanol in dichloromethane to obtain the title compound (1.2 g, 38%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) mixture of (E,Z)-N isomers. Major isomer: δ 1.44 (d, 3H), 2.23-2.26 (m, 2H), 2.32-2.33 (m 1H), 2.63 (dd, 1H), 2.77-2.82 (m 1H), 3.29-3.46 (m, 5H), 4.77-4.82 (m, 1H), 5.35-5.44 (br d, 2H), 6.65 (dd, 1H), 6.89 (dt, 3H), 7.13 (s 1H), 7.1 (s, 1H), 7.21-7.28 (m, 2H), 7.31-7.42 (m 1H), 7.55-7.62 (m, 1H), 9.95 (s, 1H). Minor isomer: δ 1.39 (d, 3H, E,Z-isomer), 2.23-2.26 (m, 2H), 2.32-2.33 (m 2H), 2.88-3.0 (m 1H), 3.29-3.46 (m, 5H), 4.80-4.99 (m, 1H), 5.35-5.44 (br d, 2H), 6.65 (dd, 1H), 6.89 (dt, 3H), 7.13 (s 1H), 7.1 (s, 1H), 7.21-7.28 (m, 2H), 7.31-7.42 (m 1H), 7.55-7.62 (m, 1H), 9.95 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:28][CH:27]5[NH:29][CH:24]([CH2:25][CH2:26]5)[CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(N(C(C)C)CC)(C)C.Cl[C:47]([O:49][CH2:50][CH3:51])=[O:48]>C(Cl)Cl.O>[CH2:50]([O:49][C:47]([N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][N:22]([C:20]([C:17]1[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:36])[CH3:1])[N:30]([CH:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=1)=[O:21])[CH2:23]2)=[O:48])[CH3:51]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5)cn3)nc2n1C1CCCC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)N1C2CCC1CN(C(=O)c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C2
Temperature: 23 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
To a solution of 7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.205 mmol, 1.0 eq) and Diisopropylethylamine (0.071 mL, 0.409 mmol, 2.0 eq) in CH2Cl2 (5 mL) was added Ethyl Chloroformate (0.022 mL, 0.225 mmol, 1.1 eq) diluted in 3.0 mL of CH2Cl2. The reaction mixture was stirred at 23° C. for 1 hour then diluted with water. The organic was collected and dried over Na2SO4, filtered, and concentrated. The crude reaction was purified using silica gel chromatography which gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (25 mg) in 21% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22-1.37 (m, 4H) 1.60 (br. s., 2H) 1.69-1.82 (m, 3H) 1.97 (br. s., 3H) 2.04-2.20 (m, 4H) 2.56 (d, J=8.59 Hz, 2H) 3.19 (s, 6H) 3.60 (br. s., 2H) 4.21 (q, J=7.07 Hz, 2H) 4.36 (br. s., 2H) 4.56 (br. s., 1H) 4.83 (t, J=8.59 Hz, 1H) 6.52 (s, 1H) 7.82 (dd, J=8.59, 2.02 Hz, 1H) 8.39 (d, J=2.02 Hz, 1H) 8.59 (d, J=8.59 Hz, 1H) 8.77 (s, 1H). HRMS m/z, (M+H)+: 561.2946.
Reaction SMILES: [C:1]1([CH3:19])[C:2]([NH:13][C:14](OCC)=[O:15])=[CH:3][C:4]([NH:7][C:8](OCC)=[O:9])=[CH:5][CH:6]=1.CCCCC(COC(C1C(C(OCC(CCCC)CC)=O)=CC=CC=1)=O)CC>>[CH3:19][C:1]1[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][C:2]=1[N:13]=[C:14]=[O:15]
Reactant: CCOC(=O)Nc1ccc(C)c(NC(=O)OCC)c1
Agent: CCCCC(CC)COC(=O)c1ccccc1C(=O)OCC(CC)CCCC
Product: Cc1ccc(N=C=O)cc1N=C=O
Temperature: 250 °C

Procedure:
A mixture of 10 g of diethyl toluene- 2,4-dicarbamate and 50 g of di-2-ethylhexyl phthalate was heated in a cylindrical reactor at 250° C. for 1 hour. Nitrogen at 32 liters per hour was passed through a fritted disc at the bottom of the reactor. A yield of toluene-2,4-diisocyanate of 57.6 mol percent together with 28.6 mol percent of the monocarbamate and 2.5 mol percent of unconverted dicarbamate was obtained. This run demonstrated that ester type solvents also can be employed in the process of this invention with excellent results.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:29])[O:4][N:3]=1.B(F)(F)F.S(C)C.O>C(Cl)Cl.CO>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: CCNC(=O)n1c(-c2c(C)noc2C)c(-c2ccc(OC)cc2)c2ccccc21
Agent: FB(F)F
Solvent: CSC
Solvent: CO
Solvent: ClCCl
Product: CCNC(=O)n1c(-c2c(C)noc2C)c(-c2ccc(O)cc2)c2ccccc21
Temperature: 1 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
2-(3,5-dimethylisoxazol-4-yl)-N-ethyl-3-(4-methoxyphenyl)-1H-indole-1-carboxamide (8 mg, 0.02 mmol) was dissolved in 8 ml DCM and the mixture was cooled in an ice bath. BF3.SMe2 (0.40 ml) was added drop wise and the mixture was stirred at 0-2° C. for 16 h. A few drops MeOH were added followed by water. The layers were separated and the organic layer was concentrated. The crude product was purified by preparative HPLC. 3.4 mg 2-(3,5-dimethylisoxazol-4-yl)-N-ethyl-3-(4-hydroxyphenyl)-1H-indole-1-carboxamide was obtained. ES/MS m/z: 376.1 (pos. M+H), 374.2 (neg. M−H); 1H NMR (acetone-d6, 500 MHz): 7.90 (m, 1H), 7.63 (m, 1H), 7.33 (m, 1H), 7.23 (m, 1H), 7.14 (m, 2H), 6.88 (m, 2H), 3.38 (m, 2H), 2.04 (s, 3H), 2.03 (s, 3H) and 1.16 (t, 3H, J=7.3 Hz).
Reaction SMILES: [C:1]([C:5]1[N:6]([CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[C:9]([F:31])[CH:8]=2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:34][CH2:33][CH2:32][N:6]1[C:7]2[C:12](=[CH:11][C:10]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:18][CH2:19]3)=[O:16])=[C:9]([F:31])[CH:8]=2)[CH:13]=[C:5]1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1CCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of tert-butyl 2-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6-fluoro-1H-indol-1-yl)ethylcarbamate (137.5 mg, 0.24 mmol) in dichloromethane (1.8 mL) was added trifluoroacetic acid (444 μL, 5.8 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane and washed with saturated aqueous NaHCO3 solution (3 mL) and brine (3 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to yield N-(1-(2-aminoethyl)-2-tert-butyl-6-fluoro-1H -indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as a white solid (93.7 mg, 82%). ESI-MS m/z calc. 473.19, found 474.5 (M+1)+. Retention time 1.61 minutes.
Reaction SMILES: [I:1][C:2]1[C:20]([C:21]([O:23]CC)=[O:22])=[C:5]2[CH2:6][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:8]3[CH2:12][O:11][CH2:10][C@@H:9]3[N:4]2[N:3]=1.[OH-].[Na+]>C1COCC1.O>[C:16]([O:15][C:13]([N:7]1[C@@H:8]2[CH2:12][O:11][CH2:10][C@@H:9]2[N:4]2[N:3]=[C:2]([I:1])[C:20]([C:21]([OH:23])=[O:22])=[C:5]2[CH2:6]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1c(I)nn2c1CN(C(=O)OC(C)(C)C)[C@@H]1COC[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2[C@H]2COC[C@H]21
Temperature: 70 °C
Yield: 60.1 %

Procedure:
To a stirred solution of Intermediate 352D (0.85 g, 1.835 mmol) in THF (5 mL) was added a solution of NaOH (0.220 g, 5.50 mmol) in water (4 mL) and the reaction mixture was heated to 70° C. for 16 h. The reaction mixture was concentrated and the pH of the residue was adjusted to 4-5 using an aqueous solution of citric acid. The formed precipitate was filtered, washed with n-hexanes and dried to afford Intermediate 352E (0.48 g, 51%) as an off-white solid. MS(ES): −m/z=434 [M−H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 12.80-12.67 (m, 1H), 5.30 (d, J=18.5 Hz, 2H), 4.87 (dd, J=3.4, 6.8 Hz, 1H), 4.46-4.32 (m, 1H), 4.12-4.04 (m, 1H), 3.98-3.90 (m, 1H), 3.89-3.82 (m, 1H), 3.80-3.69 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:22]=[C:23]([S:28]([CH2:31][CH2:32][CH2:33][OH:34])(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:21]2[CH:22]=[C:23]([S:28]([CH2:31][CH2:32][CH2:33][OH:34])(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=2[CH3:27])[CH:11]=1)#[N:16]
Reactant: Cc1ccc(S(=O)(=O)CCCO)cc1Br
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)CCCO)cc1C#Cc1cc(C#N)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 3-[(3-bromo-4-methylphenyl)sulfonyl]propan-1-ol (Intermediate 68), the title compound was obtained as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[N:5]=[C:4]([S:23][CH3:24])[N:3]=1.C(N(C(C)C)C(C)C)C.[CH2:34]([CH2:36][NH2:37])[OH:35]>O1CCOCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:6]3[C:7]([C:8]#[N:9])=[C:2]([NH:37][CH2:36][CH2:34][OH:35])[N:3]=[C:4]([S:23][CH3:24])[N:5]=3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: NCCO
Reactant: CSc1nc(Cl)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CSc1nc(NCCO)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Yield: 83.6 %

Procedure:
A dispersion of 200 mg (0.55 mmol) of 4-chloro-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methylsulfanyl-pyrimidine-5-carbonitrile and 84 mg (0.6 mmol) of N-ethyl-diisopropylamine in 4 ml of dioxane was treated at 65° C. with 37 mg (0.6 mmol) of ethanolamine during 18 h. For the working-up, the reaction mixture was evaporated, and, thereafter, the residue obtained was directly chromatographed on silica gel using a 5:1 mixture of toluene and ethyl acetate as the eluent yielding 177 mg (0.46 mmol, 83% of theory) of the 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-(2-hydroxy-ethylamino)-2-methylsulfanyl-pyrimidine-5-carbonitrile as a yellowish oil which crystallized on standing. MS: [M+H]+=388.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Se].O.[C]=O.[O:13]1CCC[CH2:14]1>C(N(CC)CC)C>[N:7]1[C:14](=[O:13])[N:8]=[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=12
Reactant: C1CCOC1
Reactant: Nc1ccccc1N
Agent: [C]=O
Agent: [Se]
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1N=c2ccccc2=N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
o-Phenylenediamine 1.35 g (12.5 m moles), selenium powder 0.99 g (12.5 m moles), water 1.6 ml (89 m moles), triethylamine 5 g (50 m moles) and tetrahydrofuran 100 ml were placed in a 200-ml capacity autoclave, and the atmosphere therein was replaced by carbon monoxide of 20 Kg/cm2. The contents in the autoclave were heated to 80° C. and held at the temperature for 3 hours with stirring. Thereafter the reaction mixture was cooled to room temperature, and carbon monoxide was removed from the autoclave. The reaction mixture was taken out of the autoclave and worked up in the same manner as in EXAMPLE 1 to provide benzimidazolone 1.66 g (99.0% yield) of 95.6% purity.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[S:8][C:7](=[O:13])[C:6]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:5]2[OH:21]>[OH-].[Na+].O.[Pd]>[OH:21][C:5]1[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[CH:2][CH:3]=2)[S:8][C:7](=[O:13])[C:6]=1[C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15]
Reactant: Cc1cc(Cl)cc2c(O)c(C(=O)NCC(=O)O)c(=O)sc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc2c(O)c(C(=O)NCC(=O)O)c(=O)sc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
[(6-Chloro-4-hydroxy-8-methyl-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (95 mg, 0.29 mmol) was dissolved in 1N sodium hydroxide (1.16 mL) and water (1.84 mL). 10% Palladium on carbon (9.5 mg) was added and the solution was vacuum purged and treated with hydrogen gas (1 atm). The reaction stirred overnight (18 h) at ambient temperature and the crude mixture was filtered through Celite® and the filter cake was washed with 1N sodium hydroxide. The aqueous phase was acidified to pH 3 with 1N hydrochloric acid and the product was collected by filtration to give [(4-hydroxy-8-methyl-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (75 mg, 88%). MS ESI(+) m/e: 392.22 (M−1).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([O:28][CH2:29][CH3:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[O:26][CH3:27].[Li+].[OH-]>>[CH2:29]([O:28][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[O:26][CH3:27])[C:3]([OH:31])=[O:2])[CH3:30]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1OC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1OC)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-[2-methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-[2-methoxy-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid as colorless solid.
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:4][CH2:3]1.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([F:15])[CH:8]=1.[Cl-].[NH4+]>O1CCCC1>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([CH:2]2[CH2:4][CH2:3]2)=[O:12])=[C:9]([F:15])[CH:8]=1
Reactant: BrC1CC1
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To magnesium (265 mg), tetrahydrofuran (2 mL) was added, and cyclopropyl bromide (1.1 mL) was added slowly at room temperature, and then the reaction mixture was stirred at room temperature for 1 hour. To a solution of 4-bromo-2-fluorobenzaldehyde (2.0 g) in tetrahydrofuran (20 mL) was added the solution of the obtained Grignard reagent in tetrahydrofuran at 0° C., and then the reaction mixture was stirred at room temperature for 2 days. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (2.19 g) as a brown oil.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:19][CH:20]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:21]([F:24])([F:23])[F:22])[C:8]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[N:9]2)=[CH:4][CH:3]=1.O.C[C:33]([N:35](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn].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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:33]([C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:19][CH:20]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:21]([F:24])([F:22])[F:23])[C:8]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:14])=[O:15])=[N:9]2)=[CH:4][CH:3]=1)#[N:35]
Reactant: CCCS(=O)(=O)Nc1nc2cc(I)ccc2nc1OC(c1cccnc1)C(F)(F)F
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCCS(=O)(=O)Nc1nc2cc(C#N)ccc2nc1OC(c1cccnc1)C(F)(F)F
Temperature: 120 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Compound 77 (41.0 mg, 0.074 mmol) obtained in Example 74 was dissolved in DMA (1.60 mL). To the solution were added zinc cyanide (21.8 mg, 1.11 mmol), zinc (1.17 mg, 0.018 mmol), tris(dibenzylideneacetone)dipalladium (2.72 mg, 0.003 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (2.67 mg, 0.005 mmol), and the mixture was stirred at 120° C. for 1 hour. Water was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. Washing with saturated brine and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 2/3) to give Compound 78 (14.0 mg, 42% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH3:25][C:24]1[C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccnc1COc1ccn(CCc2ccc(CBr)cc2)c(=O)c1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: Cc1cccnc1COc1ccn(CCc2ccc(CN3CCCC3)cc2)c(=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 100 mg (0.24 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(3-methyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 14.1b) in 1.5 mL DMF is added 79 μL (0.97 mmol) pyrrolidine at RT. The reaction mixture is stirred for 2 h at RT and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][C:13](=[O:16])[C:12]=2[CH:17]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C1(C)C=CC=CC=1>C(OCC)(=O)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>[F:18][C:19]1[CH:24]=[C:23]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH2:14][C:13](=[O:16])[C:12]=3[CH:17]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C1COc2ccc(Br)cc21
Reactant: OB(O)c1cccc(F)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: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1COc2ccc(-c3cccc(F)c3)cc21
Temperature: 80 °C
Yield: 98.9 %

Procedure:
Cesium carbonate (612 mg, 1.88 mmol) was added to a solution of 5-bromobenzofuran-3(2H)-one (200 mg, 0.939 mmol), (3-fluorophenyl)boronic acid (263 mg, 1.88 mmol) and toluene (20 mL) in a 50 mL Schlenk tube. A nitrogen atmosphere was established by evacuating and refilling with nitrogen (3×), then tetrakis(triphenylphosphine)palladium (0) (11 mg, 0.01 mmol) was added to the reaction. The flask was sealed and heated in a 80° C. oil bath overnight. The resulting mixture was cooled to room temperature. The reaction was then diluted with ethyl acetate and filtered through celite. Ethyl acetate (30 mL) was used to wash the flask and the combined organic filtrate was concentrated. The resulting crude residue was purified on a Teledyne-Isco Combiflash machine (40 g column, hexanes→100% ethyl acetate/hexanes, gradient), to afford 212 mg (99%) of 5-(3-fluorophenyl)benzofuran-3(2H)-one.
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[N:10]=1)(=O)=O.CN1C(=O)CCC1.[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH2:40])[CH3:36].O>CCOC(C)=O>[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH:40][C:5]1[N:6]=[C:7]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[N:10]=1)[CH3:36]
Reactant: CCN(CC)CCN
Reactant: CS(=O)(=O)c1nc(-c2ccccc2)c2ccc(=O)n(-c3ccccc3)c2n1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCN(CC)CCNc1nc(-c2ccccc2)c2ccc(=O)n(-c3ccccc3)c2n1
Reaction time: 1 h
Yield: 101.6 %

Procedure:
A solution of the product of Example 46 (18.8 mg, 0.05 mmol), NMP (5 mL) and N,N-diethylethylenediamine (28 mg, 0.25 mmol, 5 eq) was heated to 50°. After 1 h, H2O (20 mL) was added and then EtOAc (20 mL). The layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4) filtered and the solvent was evaporated in vacuo. The yellow residue was purified by Flash chromatography to afford 2-(2-diethylamino-ethylamino)-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one (21 mg, 89% yield). 1H-NMR (CDCl3) δ 0.74-0.98 (m, 6H), 2.28-2.56 (m, 8H), 2.98 (br s, 1H), 6.32 (d, 1H, J=9.8 Hz), 7.26 (m, 2H), 7.09-7.88 (m, 1111), LC MS (m/e)=414 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH2:28][O:29][C:25]=3[CH:24]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.O1C2C=CC(NCC3CCCCC3)=CC=2OC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([N:15]([CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:13](=[O:14])[NH:12][C:10]3[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=3)=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCCC2)c2ccc3c(c2)OCO3)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: c1cc2c(cc1NCC1CCCCC1)OCO2
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCCC2)c2ccc3c(c2)OCO3)s1

Procedure:
The title compound was prepared via [2-(3-benzo[1,3]dioxol-5-yl-3-cyclohexylmethyl-ureido)thiazol-5-ylsulfanyl]-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using benzo[1,3]dioxol-5-yl-cyclohexylmethyl-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester