Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=O)[NH:19][CH:20]=[N:21]2)=[C:16]([O:25][CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([Cl:3])=[N:19][CH:20]=[N:21]2)=[C:16]([O:25][CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2nc[nH]c(=O)c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2ncnc(Cl)c12
Temperature: 50 °C

Procedure:
Phosphorous oxychloride (520 μl) was added dropwise to a mixture of tert-butyl (2R)-2-({[7-(benzyloxy)-4-oxo-3,4-dihydroquinazolin-5-yl]oxy}methyl)pyrrolidine-1-carboxylate (500 mg) and N,N-diisopropylethylamine (52 μl) in DCM (10 ml) and the reaction mixture was heated at 50° C. for 62 hours. The reaction mixture was concentrated in vacuo and then water and saturated aqueous sodium carbonate (cooled to 4° C.) was added. The aqueous mixture was then extracted with DCM and the organic layer was dried (MgSO4) and concentrated in vacuo to leave tert-butyl (2R)-2-({[7-(benzyloxy)-4-chloroquinazolin-5-yl]oxy}methyl)pyrrolidine-1-carboxylate as a brown oil, which was used without further purification.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[C:10]([C:19]([OH:21])=[O:20])=[N:11][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:13][CH:14]=1>C1C=CC=CC=1.CO>[CH3:1][O:20][C:19]([C:10]1[C:9]([Br:8])=[CH:14][N:13]=[C:12]([C:15]([CH3:16])([CH3:17])[CH3:18])[N:11]=1)=[O:21]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)c1ncc(Br)c(C(=O)O)n1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1nc(C(C)(C)C)ncc1Br
Reaction time: 48 h
Yield: 80.6 %

Procedure:
A 2.0 M hexanes solution of trimethylsilyldiazomethane (11.8 mL, 23.62 mMol) was added dropwise to a stirring solution of 5-bromo-2-tert-butyl-pyrimidine-4-carboxylic acid (6.12 g, 23.62 mMol) in 9:1 benzene/methanol (100 mL), and the reaction was stirred for 2 days. TLC analysis showed that the reaction was complete, so the mixture was concentrated in-vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with water (3×20 mL), dried over sodium sulfate, then concentrated in-vacuo. Purified over silica gel, eluting with 10% ethyl acetate/hexanes, to yield 5.2 g of a colorless oil as product. MS (ES+)=273, 275 (M+H)+. Yield=81%.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[NH2:19][CH:20]([CH:30]([CH3:32])[CH3:31])[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>C(O)C>[Br:1][C:2]1[C:3]([NH:19][CH:20]([CH:30]([CH3:32])[CH3:31])[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)C(N)CNC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-bromo-2,4-dichloro-pyrimidine 7.11 g (0.0312 mole) in ethanol (100 mL) was added diisopropylethyl amine 5.45 mL (1.0 eq) and tert-butyl N-(2-amino-3-methyl-butyl)carbamate 6.31 g (0.0312 mole). The reaction mixture was stirred at room temperature for 20 hrs. After concentration under vacuum, ethyl acetate and water was added. The organic layer was separated, dried with magnesium sulfate and then concentrated under vacuum. The crude product was purified by column chromatography using hexane/ethyl acetate (0-30%) over silica gel to afford tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, DMSO-d6) δ ppm 0.77-0.85 (d, J=6.5 Hz, 3H) 0.87 (d, J=6.73 Hz, 3H) 1.31-1.39 (m, 9H) 1.82-1.93 (m, 1H) 2.94 (d, J=5.56 Hz, 1H) 3.08-3.22 (m, 2H) 3.98 (d, J=8.20 Hz, 1H) 6.96 (d, J=8.78 Hz, 1H) 8.21 (s, 1H). LCMS (ESI) 393 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>O1CCCC1>[CH2:3]([O:5][C:6](=[O:16])[CH:7]=[CH:22][C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1)[CH3:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
Sodium hydride (2.11 g, 48.4 mmol) was suspended in anhydrous tetrahydrofuran (60 ml), and diethylphosphonoacetic acid ethyl ester (10.84 g, 48.4 mmol) was added dropwise thereto in an ice bath followed by stirring for 10 minutes. To this mixture solution, a solution of 4-fluorobenzaldehyde (5.00 g, 40.3 mmol) in anhydrous tetrahydrofuran (60 ml) was added dropwise at the same temperature. The reaction solution was stirred for 3 hours, and poured into ice-cold water (150 ml), and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated in vacuo, and then the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=10:1-3:1) to give 4-fluorocinnamic acid ethyl ester (6.69 g, 86% yield) as a colorless oil.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:14])=[O:15])[CH2:10][N:9]1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)c1ccccc1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K1 was coupled with benzoic acid in analogy to experiment A1 to give (2S,4R)-1-benzoyl-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as an amorphous solid. MS: 432.2 [M+H]+.
Reaction SMILES: Cl.C(O)(=O)C.[OH:6][N:7]=[C:8]([C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1)[C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:26][N:25]1[C:21]([C:8]2[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=3)[O:6][N:7]=2)=[CH:22][CH:23]=[N:24]1
Reactant: Cn1nccc1C(C#Cc1ccc(C(F)(F)F)cc1)=NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1nccc1-c1cc(-c2ccc(C(F)(F)F)cc2)on1
Yield: 75.6 %

Procedure:
Concentrated hydrochloric acid (0.50 mL) was added to an acetic acid (5.0 mL) solution of N-hydroxy-1-(1-methyl-1H-pyrazol-5-yl)-3-[4-(trifluoromethyl)phenyl]prop-2-yn-1-imine (303 mg) at a room temperature, and the obtained solution was then heated to reflux for 30 minutes. Thereafter, water was added to the reaction solution, and the obtained solution was then neutralized with potassium carbonate, followed by extraction with chloroform. The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=3:2), so as to obtain the title compound (229 mg) in the form of a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:28](I)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: CCCCCCCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(CC)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (8.90 g) synthesized in Example 265-1 and heptyl iodide (5.92 g) were dissolved in N,N-dimethylformamide (100 mL), potassium tert-butoxide (2.94 g) was added thereto, and the mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:1) to give the title compound (6.20 g) as a colorless oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.C(N(CC)CC)C.C(O)C.[C:25]([O:28][CH2:29][CH3:30])(=[O:27])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:29]([O:28][C:25]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2)=[O:27])[CH3:30]
Reactant: CCOC(C)=O
Reactant: O=C(O)C1CCc2cc(I)ccc2O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)CCC(C(=O)O)O2
Temperature: 60 °C
Reaction time: 60 h

Procedure:
A 2-neck round bottom flask fit with a reflux condenser was charged the compound from Example 28 (1.05 g, 3.45 mmol) and palladium (II) acetate (23 mg, 0.10 mmol). The flask was placed under an atmosphere of carbon monoxide (1 atm). Triethylamine (1.20 mL, 8.63 mmol) and absolute ethanol (2.0 mL) were added via syringe. The dark reaction mixture was heated to 60° C. and stirred for 60 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The resulting dark solution was washed sequentially with 7% aqueous hydrochloric acid, water, and saturated aquesous sodium chloride. The organic layer was dried (MgSO4), and concentrated to an orange oil which crystallized on standing to a pale solid (0.675 g, 81%). 1H NMR (300 MHz, DMSO-d6) δ 13.03 (s, 1H), 7.68 (m, 2H), 6.90 (m, 1H), 4.89 (m, 1H), 4.25 (q, J=7.36 Hz, 2H), 2.82 (m, 1H), 2.66 (m, 1H), 1.28 (t, J=6.98 Hz, 3H); MS (CI) m/z 251 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:32])[C:16](=[O:31])[C:17]([C:29]#[N:30])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>CC(=O)OCC>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:32])[C:16](=[O:31])[C:17]([C:29]#[N:30])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1
Reactant: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(C#N)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1c(N2CCC(N)CC2)nc(-c2ccc(C#N)c(F)c2)c(C#N)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
To a mixture of {1-[5-cyano-4-(4-cyano-3-fluoro-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (150 mg, 0.33 mmol) in EA (5 mL) was added a 5 N HCl solution in EA (5 mL), and the mixture was stirred at RT for 2 h. The solvent was concentrated in vacuo to give 120 mg the title product as HCl salt (94%). 1H NMR (400 MHz, CD3OD): δ 1.67-1.72 (m, 2H), 2.02-2.06 (m, 2H), 3.13-3.16 (m, 2H), 3.34-3.38 (m, 1H), 3.42 (s, 3H), 3.98-4.02 (m, 2H), 7.82-7.90 (m, 3H). [M+H] Calc'd for C18H17FN6O, 353. Found, 353.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1.[Na].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1OCCOC1>[CH2:10]([O:1][CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCBr
Reactant: CC1(CO)COC1
Agent: [Na]
Solvent: C1COCCO1
Product: CCCCCCCCOCC1(C)COC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.9 %

Procedure:
Into a 5 liter, three-neck flask, fitted with a stirrer, reflux condenser, and nitrogen inlet tube, were placed 245 g (2.4 mole) of 3-hydroxymethyl-3-methyloxetane and 3000 ml of P-dioxane. To this solution 47 g (2 mole) of solid sodium metal was added, and the pot temperature was raised to reflux. Heat was maintained until all of the sodium had dissolved. 400 g (2 mole) of 1-bromooctane was added, and the reflux was resumed for 3 days. The mixture was cooled to room temperature, and the solid sodium bromide was filtered off using celite. The solvent was removed by evaporation and the product was distilled at 80° C. and 0.3-mm pressure. Redistillation from calcium hydride gave 231 g of polymerizable monomer, representing a 58 percent yield.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:6](=[O+:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[C:4]([OH:16])[CH:3]=1.[C-:17]#[N:18].[K+]>CN(C)C=O>[C:17]([CH:14]1[C:15]2[C:2]([OH:1])=[CH:3][C:4]([OH:16])=[CH:5][C:6]=2[O:7][C:8]2[C:13]1=[CH:12][CH:11]=[CH:10][CH:9]=2)#[N:18]
Reactant: [C-]#N
Reactant: Oc1cc(O)c2cc3ccccc3[o+]c2c1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1c2ccccc2Oc2cc(O)cc(O)c21
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of 15.5 g (50.0 mmol) of 1,3-dihydroxy-xanthenium bisulfam [R. K. M. Pillai et al, J. Org. Chem. 51, 717 (1986)] and 4.90 g (75.0 mmol) of potassium cyanide in 150 ml of dimethylformamide is kept at 130° C. for 2 hours. The solvent is then concentrated on a vacuum rotary evaporator and the residue is taken up in ethyl acetate. The ethyl acetate phase is washed with water, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Chromatography of the residue over silica gel using the mobile phase system hexane/ethyl acetate=3:1 and crystallization of the pure fractions from ethyl acetate gives 10.0 g (83%) of 9-cyano-1,3-dihydroxy-xanthene, melting point 211°-215° C. (compound (107), Table 1).
Reaction SMILES: Cl.[Cl:2][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][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH3:19][S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:32][C@@H:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])=[C:27]([CH:31]=1)[C:28](O)=[O:29])(=[O:22])=[O:21].C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:28]([C:27]3[CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=[CH:25][C:26]=3[O:32][C@@H:33]([CH3:38])[C:34]([F:36])([F:37])[F:35])=[O:29])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride (Example 1.20b) and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example 2.7) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: CC(C)([O-])C.[K+].C(O[C:10]([C:12]1[C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=[C:14]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[N:13]=1)=O)C.[NH2:28][C:29]([CH3:36])([CH:33]([CH3:35])[CH3:34])[C:30]([NH2:32])=[O:31]>C1(C)C=CC=CC=1>[S:25]1[CH:26]=[CH:27][C:23]([C:14]2[N:13]=[C:12]([C:10]3[NH:28][C:29]([CH:33]([CH3:35])[CH3:34])([CH3:36])[C:30](=[O:31])[N:32]=3)[C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[CH:24]1
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: CCOC(=O)c1ccc(-c2ccsc2)nc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)C1(C)NC(c2nc(-c3ccsc3)ccc2C(=O)O)=NC1=O
Temperature: 80 °C
Yield: 85.7 %

Procedure:
12 g of potassium tert.-butoxide are added to a solution of 14 g of 6-(thiophen-3-yl)-pyridine-2,3-dicarboxylic acid diethyl ester and 6 g of 2-amino-2,3-dimethyl- butyramide in 100 ml of dry toluene while stirring and the solution is heated at 80° C. for 5 hours. The reaction solution is then poured onto ice, the phases are separated and the aqueous phase is acidified with 10 ml of glacial acetic acid. After some time the above acid crystallises out and is filtered off with suction and dried. In this manner 13.5 g of 6-(thiophen-3-yl)-2-(5-isopropyl-5-methyl-4-oxo-imidazol-2-yl)-pyridine-3-carboxylic acid having a melting point of 253°-257° C. are obtained.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[H+].[Cl:7][C:8]1[CH:9]=[C:10]([NH2:24])[CH:11]=[N:12][C:13]=1[O:14][CH:15]([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17].[N:25](OCCC(C)C)=O>C(O)C>[F:1][B-:2]([F:5])([F:4])[F:3].[Cl:7][C:8]1[CH:9]=[C:10]([N+:24]#[N:25])[CH:11]=[N:12][C:13]=1[O:14][CH:15]([C:16]([F:19])([F:18])[F:17])[C:20]([F:21])([F:22])[F:23]
Reactant: CC(C)CCON=O
Reactant: Nc1cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Product: N#[N+]c1cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
An aqueous solution of tetrafluoroboric acid (48% weight, 1.86 mL, 14.2 mmol) was added to a solution of 5-chloro-6-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)pyridin-3-amine (Preparation 52, 2.0 g, 6.79 mmol) in ethanol (3 mL) at −5° C. Isopentyl nitrite (960 μL, 7.0 mmol) was added dropwise and the reaction mixture was stirred for 30 minutes at −5° C. The suspension was filtered and the solid was washed with cold ethanol and diethyl ether to afford the title compound as a pink solid (728 mg, 27%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:20][CH2:21][CH2:22][NH2:23].CO.[BH4-].[Na+]>ClCCl>[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:20][CH2:21][CH2:22][NH:23][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: CC1CCCCN1CCCN
Reactant: O=Cc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC1CCCCN1CCCNCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Naphtaldehyde 1 g (6.4 mmol), 3-(2-methyl-piperidin-1-yl)-propylamine 0.99 g (6.4 mmol), in 25 mL of dry dichloromethane was added 5 g of molecular sieve. The reaction was stirred overnight at room temperature. The molecular sieve was filtered and dichloromethane was concentrated under vacuum. To the mixture was added 15 mL of dry methanol and sodium borohydride 0.3 g (8 mmol) after 30 minutes reaction goes to completion, methanol was concentrated under vacuum, and was diluted with chloroform, organic layer was washed with 2 times 20 mL water, followed with brine. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The compound was purified using silica gel chromatography elution, with 3.5% methanol in chloroform, yield 0.6 g oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1>CS(C)=O.O>[S:19]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=[C:11]1[C:8]1[N:6]2[N:7]=[C:2]([NH:32][C@H:33]3[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Clc1ccc2ncc(-c3cc4cccnc4s3)n2n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: O[C@H]1CC[C@H](Nc2ccc3ncc(-c4cc5cccnc5s4)n3n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 6-chloro-3-(thieno[2,3-b]pyridin-2-yl)imidazo[1,2-b]pyridazine (45 mg, 0.157 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (22 mg, 0.157 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (0.784 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 40 mg of the yellow solid, 70%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C(#N)C>C(=O)([O-])[O-].[K+].[K+].O.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>[CH2:24]([NH:23][C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([F:19])=[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])[CH:14]=1)=[O:22])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNC(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1
Reactant: OB(O)c1cccnc1
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: O
Solvent: CC#N
Product: CCCCNC(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1
Temperature: 120 °C
Yield: 61 %

Procedure:
To 1-[3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-4-fluoro-phenyl]-3-butyl-urea (P-1637, 14.0 mg, 0.0000323 mol), 3-pyridylboronic acid (5.96 mg, 0.0000485 mol), and Tetrakis(triphenylphosphine)palladium(0) (0.820 mg, 7.09E-7 mol) were mixed in 1.00 M potassium carbonate in water (1.00 mL) and acetonitrile (2.00 mL, 0.0353 mol). The resulting mixture was heated at 120° C. in the microwave for 40 minutes. The reaction was extracted with ethyl acetate and water twice, and the combined organic layers were washed with 1M sodium bicarbonate followed by brine and the organic layer was dried over magnesium sulfate and filtered. The organic layer was concentrated and purified by reverse phase HPLC (acetonitrile and water with 0.1% formic acid) to give the compound as a white solid (P-1637, 8.5 mg, 61%). MS(ESI) [M+H+]+=432.3.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:45])([F:44])[C:38](N(OC)C)=[O:39]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:38](=[O:39])[C:37]([F:45])([F:44])[F:36])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)C(F)(F)F
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(F)(F)F)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and 2,2,2-trifluoro-N-methoxy-N-methylacetamide. Compound exists in the hydrated form.