Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([NH2:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[F:41][C@@H:42]1[C@H:46]([CH:47]=O)[CH2:45][N:44]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[CH2:43]1>C(Cl)Cl>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([NH:26][CH2:47][C@H:46]1[C@@H:42]([F:41])[CH2:43][N:44]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[CH2:45]1)[C:22]([CH3:23])([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@@H](N)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Reactant: O=C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[C@@H](NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a solution of (R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropan-1-amine (140 mg, 0.378 mmol) in CH2Cl2 (7.0 mL) was added NaBH(OAc)3 (400 mg, 1.89 mmol). To this solution, the crude (3R,4S)-benzyl 3-fluoro-4-formylpyrrolidine-1-carboxylate (obtained from 2.0 equiv. of (3R,4R)-benzyl 3-fluoro-4-vinylpyrrolidine-1-carboxylate) in CH2Cl2 (1.0 mL) was added over 3 minute at room temperature. After stirred for 20 min, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified on preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield (3R,4R)-benzyl 3-(((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (138 mg, 60%). LC/MS (uplc) MH+ 608.3, 1.14 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[CH2:18][C:19]#[N:20].[OH-].[Na+]>C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[C:18]1[C:19]([NH2:20])=[N:1][C:2]2[C:7]([CH:8]=1)=[CH:6][N:5]=[CH:4][CH:3]=2
Reactant: Nc1ccncc1C=O
Reactant: N#CCc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc2ccncc2cc1-c1c(Cl)cccc1Cl
Temperature: 65 °C
Yield: 84.4 %

Procedure:
4-Aminonicotinaldehyde (100 mg, 0.78 millimole (hereinafter “mmol”)), 2,6-dichlorophenylacetonitrile (217 mg, 1.2 mmol), 10% aqueous NaOH (0.101 mL, 0.25 mmol) and 700 uL of absolute ethanol are combined and heated at 65° C. for 24 hours (hereinafter “h”). The reaction mixture is cooled to ambient temperature and the solvents are evaporated under reduced pressure. The residue is diluted with 700 uL of DMSO filtered and purified with preparative reverse phase chromatography to afford the title compound as a yellow solid (191 mg, 84% yield). MS ES+ m/z=290.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:4][CH:3]=1.[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][N:16]([C:25]3[CH:26]=[CH:27][C:22]([C:20](=[O:21])[CH3:19])=[CH:23][CH:24]=3)[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)nnn3C)c2)cc1
Temperature: 120 °C
Yield: 47 %

Procedure:
A mixture of 4-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-[1,2,3]triazole (73 mg, 0.30 mmol), 4-fluoroacetophenone (37 μL, 0.30 mmol) and potassium carbonate (83 mg, 0.60 mmol) in DMF (1.5 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (51 mg, 47%) as an off white solid after recrystallisation from ethyl acetate. MS: m/e=362.2 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)=O.C(N(CC)CC)C.O>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C@@H:14]3[OH:19])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCc2c1cccc2S(=O)(=O)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)c1cccc2c1CC[C@@H]2O
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
Under nitrogen a solution of the material from Step 2 (0.39 g) in CH2Cl2 (10 mL) is added dropwise to a stirred mixture of formic acid (0.20 mL) and triethylamine (0.61 mL) with cooling in an ice-bath. Chloro([1S,2S)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido)(mesitylene)ruthenium(II) (26 mg) is added and the reaction mixture stirred at 0° C. for 3 hours. Water is added and the resulting mixture extracted twice with ethyl acetate. The combined organic layers are washed (saturated aqueous NaHCO3), dried and purified by column chromatography (silica gel, cyclohexane:ethyl acetate gradient 100:0 to 50:50), to obtain the desired material (0.39 g). LC (METHOD 14): tR=0.83 min; Mass spectrum: m/z=257 [M+H−H2O]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2Cl)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1(C=C)OB([CH:28]=[CH2:29])OB(C=C)O1.C1C=CN=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[CH:28]=[CH2:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1cc(C)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 99.3 %

Procedure:
A mixture of 4-bromo-3-chlorotoluene (2.1 g), Boc-piperazine (1.9 g), palladium acetate (112 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (312 mg), sodium tert-butoxide (1.4 g) and toluene (20 mL) was refluxed for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (3.1 g). To a mixture of 4-(2-chloro-4-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (932 mg), 2,4,6-trivinylcyclotriboroxane pyridine complex (1 g), palladium acetate (74 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (271 mg) and potassium fluoride (697 mg) was added tetrahydrofuran (4 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 4-(4-methyl-2-vinylphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.9 g). 4-(4-Methyl-2-vinylphenyl)piperazine-1-carboxylic acid tert-butyl ester (0.9 g) was dissolve in chloroform (2 mL), 4N hydrogen chloride/ethyl acetate (1 mL) was added, and the mixture was stirred at room temperature for 3 hr. 1N aqueous sodium hydroxide solution (8 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give 1-(4-methyl-2-vinylphenyl)piperazine (606 mg). 1-(4-Methyl-2-vinylphenyl)piperazine (606 mg) was dissolved in tetrahydrofuran (8 mL), 4-iodobenzoyl chloride (1.1 g) and 1N aqueous sodium hydroxide solution (4 mL) were added, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give the title compound (1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](S(C)(=O)=O)[N:9]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=1>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nccc(-c2ccc(Cl)cc2)n1
Reactant: NC(=O)c1ccc(N)cc1
Solvent: CC(C)O
Product: NC(=O)c1ccc(Nc2nccc(-c3ccc(Cl)cc3)n2)cc1

Procedure:
To a solution of 4-(4-chlorophenyl)-2-(methylsulfonyl)pyrimidine (0.10 g, 0.37 mmol) and 4-aminobenzamide in 2-propanol (3 ml) was heated to 120° C. in a sealed vessel for 14 hours. The crude material was concentrated and purified by preparative HPLC to provide the title compound as a beige solid: LC/MS Retention Time; 6.30 min (Method A), M+1; 325.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.CO[CH2:16][Cl:17].[Sn](Cl)(Cl)(Cl)Cl.O>ClCCl>[Cl:17][CH2:16][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(OC)cc1
Reactant: COCCl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC)c(CCl)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
Ethyl 4-methoxybenzoate (28.0 mL) and 26.0 mL of methoxymethyl chloride were dissolved in 500 mL of dichloromethane, and the solution was cooled to 0° C. To this solution, 10.0 mL of tin (IV) chloride was added dropwise over 15 minutes, and then the mixture was stirred for 5 hours. The reaction mixture was poured into 1 L of water, and the organic layer was separated, whereafter the aqueous layer was extracted twice with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and washed with dichloromethane. The filtrate and the washings were combined, and dichloromethane was distilled off under reduced pressure. The resulting residue was recrystallized from a mixture of n-hexane and ethyl acetate. The resulting crystals were separated by filtration, then washed with n-hexane, and dried under reduced pressure to obtain 23.8 g (60%) of ethyl 3-chloromethyl-4-methoxybenzoate.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][P:6]([O-:9])([O-:8])=[O:7])#N.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C[O:23][C:24](=[O:56])[C@H:25]([CH2:48][C:49]1C=CC(O)=[CH:51][CH:50]=1)[NH:26][C:27](=[O:47])[CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C1(N=C=NC2CCCCC2)CCCCC1.Cl>C(#N)C.O>[C:27]([NH:26][C@H:25]([C:24]([OH:56])=[O:23])[CH2:48][C:49]1[CH:50]=[CH:51][C:4]([O:5][P:6]([OH:9])([OH:8])=[O:7])=[CH:3][CH:1]=1)(=[O:47])[CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH:34]=[CH:35][CH2:36][CH:37]=[CH:38][CH2:39][CH:40]=[CH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Reactant: N#CCCOP(=O)([O-])[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC#N
Product: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](Cc1ccc(OP(=O)(O)O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 120 h
Yield: 23 %

Procedure:
A solution of pyridinium cyanoethylphosphate (2 mmol) in anhydrous acetonitrile (3 ml) was added to dry N-arachidonoyl-L-tyrosine methyl ester. N,N′-Dicyclohexylcarbodiimide (413 mg, 2 mmol) was then added and the mixture was stirred at room temperature. After 5 days, the mixture was cooled to 0° C., water (0.5ml) was added and, after stirring for 30 min at room temperature, the precipitated N,N′-dicyclohexylurea was separated by filtration. The filtrate was evaporated in vacuo and the residue obtained was fractionated by short column chromatography on silica gel. The desired phosphorylated N-acyl-L-tyrosine methyl ester was eluted from column with chloroform-methanol (70-60:30-40, v/v). The composition of the eluates was controlled by TLC on Silica gel 60 plates (system B) using a molybdate spray for detecting the spots. The appropriate fractions were combined, evaporated to dryness in vacuo and residue was dissolved in 1 ml tetrahydrofuran. The solution obtained was added, dropwise over a period of 5 min, to a cooled (ice-bath), stirred 1.5 M NaOHaq (4 ml). After a further 25 min, the mixture was acidified with 1 N HCl to pH 2-3 and extracted with chloroform-methanol (2:1, v/v). The extract was washed with methanol-water (10:9, v/v), concentrated in vacuo and applied to a column of silica gel. The desired products was eluted from column with chloroform-methanol (30-20:70-80, v/v), the fractions containing pure substance stained on the TLC plates with molybdate spray were combined and evaporated to dryness to give 63 mg (23%) of (8): Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.3 (s, 8H, 4CH2); 2.0-2.4 (m, 6H, 2CH2CH═CH and CH2CO); 2.7-2.9 (br s, 6H, 3HC═CHCH2CH═CH); 2.9-3.1 (m, 2H, CH2Ar); 4.3-4.4 (m, 1H, NHCHCO); 5.2-5.4 (br s, 8H, 4HC═CH); 7.0-7.2 (q, 4H, Ar); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]=[CH:13][C:14]([F:17])([F:16])[F:15])(=O)=O)=CC=1.[F:19][C:20]([F:32])([F:31])[CH2:21][CH2:22][S:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:15][C:14]([F:17])([F:16])[CH:13]=[CH:12][CH2:11][CH:26]([S:23]([CH2:22][CH2:21][C:20]([F:19])([F:31])[F:32])(=[O:24])=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)OCC=CC(F)(F)F)cc1
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(CC=CC(F)(F)F)S(=O)(=O)CCC(F)(F)F
Reaction time: 16 h
Yield: 47.9 %

Procedure:
To a solution of 2.4 g of 4,4,4-trifluoro-2-butenyl p-toluenesulfonate and 2.0 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide, 1.2 g of potassium carbonate was added at room temperature and stirred at the same temperature for 16 hours. To the reaction mixture, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 1.40 g of methyl 6,6,6-trifluoro-2-(3,3,3-trifluoropropylsulfonyl)-4-hexenoate (hereinafter referred to as the present compound (17)).
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:6]=[C:7](O)[CH:8]=[CH:9][CH:10]=1.IC1C=CC([OH:21])=CC=1>>[CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([OH:21])=[CH:9][CH:10]=1
Reactant: Oc1ccc(I)cc1
Reactant: C[Si](C)(C)C#Cc1cccc(O)c1
Product: C[Si](C)(C)C#Cc1ccc(O)cc1

Procedure:
4-TMSE-phenol was prepared in a similar manner as 3-TMSE-phenol, using 4-iodophenol (5.0 g) instead of 3-iodophenol. This gave 3.5 g (82% yield) of a brown oil. 1H NMR (acetone-d6, 300 MHz, ppm): 8.80 (s, 1H, Ar—OH), 7.34 (d, 2H, J=8.4 Hz, Ar—H), 6.85 (d, 2H, J=8.4 Hz, Ar—H), 0.21 (s, 9H, TMS). 13C NMR (CDCl3, 75 MHz, ppm): 156.1, 133.9, 115.6, 115.5, 105.3, 92.7, 0.2.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26](OCC)=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH-:32].[Na+]>>[Cl:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([C:26]([N:4]3[CH2:5][CH2:6][CH:7]([OH:32])[CH2:2][CH2:3]3)=[O:27])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: [OH-]
Reactant: CCOC(=O)c1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)cn1
Agent: [Na+]
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1cnc(C(=O)N2CCC(O)CC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 174.1 %

Procedure:
A mixture of ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate (1.03 g, 2.3 mmol) in 1N NaOH (3.4 ml, 3.45 mmol, EtOH/water 1:1 v/v) stirred at room temperature for 2 hours. The reaction mixture was quenched with 5% citric acid and filtered. The solid was washed with water and dried to afford the desired product (1.011 g, 100%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ 9.02 (s, 1H), 8.60 (s, 1H), 7.60 (m, 1H), 7.04 (m, 2H), 6.55 (s, 1H), 5.50 (s, 2H), 5.30 (s, 2H), 2.52 (s, 3H); ES-HRMS m/z 422.0732 (M+H calculated for C19H15N3O4ClF2 requires 422.0714).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[C:7]([N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH2:1]=[C:17]1[CH2:18][CH2:19][N:14]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a thoroughly heated apparatus flooded with protecting gas, methyltriphenyl-phosphonium bromide (53.82 g, 150 mmol) was suspended in diethyl ether (300 ml) and cooled to 0° C. Potassium tert-butylate (15.78 g, 140 mmol) was added in portions, and the suspension was stirred for 30 min. Boc-4-piperidone (20 g, 100 mmol), dissolved in diethyl ether (200 ml), was slowly added dropwise, and then the mixture was warmed to room temperature and stirred for 15 h. The reaction mixture was cooled, and ammonium chloride solution (300 ml, 10%) was added thereto; after phase separation, the aqueous phase was extracted with ether (3×200 ml), and the combined organic phases were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ether/hexane (1:1). Yield: 18.57 g (93%)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=O.[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][NH2:19])=[N:16][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][NH:19][C:8]([C@@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][N:2]2[CH3:1])=[O:10])=[N:16][CH:17]=1
Reactant: CN1CCCC[C@H]1C(=O)O
Reactant: NNc1ccc(F)cn1
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: ClCCl
Product: CN1CCCC[C@H]1C(=O)NNc1ccc(F)cn1
Temperature: 45 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
To a solution of (S)-1-methyl-piperidine-2-carboxylic acid (250 mg, 1.74 mmol) and (5-fluoro-pyridin-2-yl)-hydrazine (244 mg, 1.92 mmol) in DCM (20 mL) was added HATU (790 mg, 2.09 mmol) and DIPEA (606 μL, 3.48 mmol) and the reaction stirred for 18 h. The reaction was then heated to 45° C. for 1 h then cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM to give the title compound (272 mg, 62%). LCMS (Method 4): Rt 0.87 min, m/z 253 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and cyclohexanamine as a yellow-brown solid (46%). MS 428 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:14][NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:11]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:44]=[N+:45]=[N-:46].[Na+]>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:14][NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]4[NH:46][N:45]=[N:44][N:21]=4)=[CH:18][CH:17]=3)[C:11]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(NCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(CNc3ccc(-c4nnn[nH]4)cc3)C3CCCCC3)c2cc1F
Temperature: 145 °C

Procedure:
To a suspension of 0.08 g (0.16 mmol) 4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethylamino}-benzonitrile in 2 ml o-xylene were added 0.112 g (0.81 mMol) triethylamine hydrochloride and 0.053 g (0.82 mmol) sodium azide. The resulting mixture was heated to 145° C. After 72 h another 0.112 g (0.81 mMol) triethylamine hydrochloride and 0.053 g (0.82 mMol) sodium azide were added and the temperature of the oil bath was elevated to 160° C. After 24 h the oil bath was removed and the reaction mixture was poured on saturated aqueous ammonium chloride solution. The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The resulting light brown solid was dissolved in ethyl acetate. Upon evaporation a suspension formed which was filtered and washed with ethyl acetate. The resulting solid was taken up in 2 ml acetonitrile, heated to reflux and then cooled down to 4° C. The suspension was filtered, the solid washed with acetonitrile and dried under high vacuum. Light brown solid (25%). MS (Turbo Spray): m/z=534.2 [M+H].
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C@@H:13]3[CH2:17][O:16][C:15](=[O:18])[NH:14]3)=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]N(C)C=O.CI>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C@@H:13]3[CH2:17][O:16][C:15](=[O:18])[N:14]3[CH3:21])=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N[C@H](c2ncc(-c3cccc(Br)n3)s2)CO1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)OC[C@H]1c1ncc(-c2cccc(Br)n2)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
(S)-4-[5-(6-bromopyridin-2-yl)thiazol-2-yl]oxazolidin-2-one (488 mg, 1.50 mmol) obtained in Step 4 and sodium hydride (60% oily, 72 mg, 1.80 mmol) were suspended in tetrahydrofuran (5 ml) and dimethylformamide (5 ml) in an Ar stream and methyl iodide (0.1 ml, 1.65 mmol) was added while ice-cooled and stirred at room temperature for 12 hours. After the reaction solution was concentrated, water was added and it was extracted with ethyl acetate. After the organic layer was washed with a saturated brine and dried over magnesium sulfate, it was concentrated and the residue was purified by flash chromatography on silica gel (chloroform:methanol=20:1) and the title compound (205 mg, 40%) was obtained.