Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:22]=[CH:23][C:24](B2OC(C)(C)C(C)(C)O2)=[C:25]([CH:28]=1)[C:26]#[N:27]>>[F:20][C:21]1[CH:28]=[C:25]([C:26]#[N:27])[C:24]([C:2]2[CH:3]=[C:4]([N:9]3[C:17]4[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=4[N:11]=[CH:10]3)[CH:5]=[CH:6][C:7]=2[F:8])=[CH:23][CH:22]=1
Reactant: Cn1ccc2c(ncn2-c2ccc(F)c(Br)c2)c1=O
Reactant: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Product: Cn1ccc2c(ncn2-c2ccc(F)c(-c3ccc(F)cc3C#N)c2)c1=O
Yield: 55 %

Procedure:
1-(3-Bromo-4-fluorophenyl)-5-methyl-1,5-dihydroimidazo[4,5-c]pyridin-4-one was coupled to 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile, in the same way as in Example 1, to give 4,2′-difluoro-5′-(5-methyl-4-oxo-4,5-dihydroimidazo[4,5-c]pyridin-1-yl)biphenyl-2-carbonitrile as an off-white solid (360 mg, 55%): δH (400 MHz, d6-DMSO) 3.54 (3H, s), 6.67 (1H, d, J 7), 7.61 (1H, d, J 7), 7.69 (1H, t, J 9), 7.75-7.87 (4H, m), 8.09 (1H, dd, J 9 and 3), 8.38 (1H, s); m/z (ES+, 363 [MH+].
Reaction SMILES: C(O)(=O)C.[C:5]([N:8]1[C:17]2[CH:16]=[CH:15][C:14]([NH2:18])=[CH:13][C:12]=2[C:11]2[N:19]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[N:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:10]=2[CH2:9]1)(=[O:7])[CH3:6].[Cl:34][C:35]1[N:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](O)=[O:38].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>CN(C=O)C>[C:5]([N:8]1[C:17]2[CH:16]=[CH:15][C:14]([NH:18][C:37]([C:36]3[C:35]([Cl:34])=[N:43][CH:42]=[CH:41][CH:40]=3)=[O:38])=[CH:13][C:12]=2[C:11]2[N:19]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[N:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:10]=2[CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc4c(c3)OCO4)c2-c2cc(N)ccc21
Reactant: O=C(O)c1cccnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc4c(c3)OCO4)c2-c2cc(NC(=O)c3cccnc3Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
The title material of Example 17 (100 mg, 0.00025 mol) was dissolved in DMF (2 mL), and to the solution was added 2-Chloronicotinic acid (40 mg, 0.00025 mol), HATU (144 mg, 0.00038 mol), and DIEA (49 mg, 0.00038 mol). The reaction was blanketed with argon and stirred at room temperature for 18 hours. The solution was concentrated in vacuo, and the resulting solid were washed with water and then filtered. The product was then recrystallized from ethanol, and isolated by vacuum filtration. 25 mg. (MW=530.93, 19% yield). LC/MS m/z=531.7 (m+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[NH:14][C@@H:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:12][S:11]2)=[C:5]([CH2:19][CH3:20])[CH:4]=1)#[N:2].[CH2:21](Br)[CH:22]([CH3:24])[CH3:23]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[N:14]([CH2:21][CH:22]([CH3:24])[CH3:23])[C@@H:13]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:12][S:11]2)=[C:5]([CH2:19][CH3:20])[CH:4]=1)#[N:2]
Reactant: CC(C)CBr
Reactant: CCc1cc(C#N)ccc1N=C1N[C@@H](CC(C)C)CS1
Product: CCc1cc(C#N)ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was reacted with SOCl2 followed by 4-cyano-2-ethylphenyl isothiocyanate according to Method C2a to give (4S)-2-(4-cyano-2-ethylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-cyano-2-ethylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>CC(C)=O>[N:1]1[N:2]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:3]=[N:4][CH:5]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cn2ncnn2)cc1
Reaction time: 19 h

Procedure:
6.3 g of tetrazole, 8.28 g of potassium carbonate and 0.675 g of potassium iodide are added in succession to a solution of 12 g of 4-bromomethylbenzonitrile in 400 ml of acetone and the mixture is then stirred for 19 hours at 40°-45°. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between CH2Cl2 and water. The organic phase is washed with brine, dried over sodium sulfate and then concentrated by evaporation. Subsequent chromatography (silica gel) yields first, with toluene/ethyl acetate (2:1), 4-(2-tetrazolyl)methyl-benzonitrile [TLC (hexane/ethyl acetate, 1:2) Rf =0.76); 1H-NMR (CDCl3): δ=5.8 (2H, s), 7.4 and 7.7 (4H, m), 8.5 (1H, s) ppm], and then, with ethyl acetate, 4-(1-tetrazolyl)methyl-benzonitrile [TLC (hexane/ethyl acetate, 1:2), Rf =0.36); 1H-NMR (CDCl3): δ=5.63 (2H, s), 7.4 and 7.7 (4H, m), 8.6 (1H, s) ppm].
Reaction SMILES: [N:1]([C@H:4]1[C:7](=[O:8])[NH:6][C@H:5]1[CH2:9][O:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[N+]=[N-]>C(O)(=O)C.[Zn]>[NH2:1][C@H:4]1[C:7](=[O:8])[NH:6][C@H:5]1[CH2:9][O:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2N=[N+]=[N-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2N)cc1
Reaction time: 0.5 h

Procedure:
Zinc dust (2.0 g, 0.03 mole) was slowly added with cooling to a solution of 5.0 g (0.011 mole) of cis-3-azido-4-oxo-2-p-toluenesulfonyloxymethylazetidine in 50 ml of 50% aqueous acetic acid. The reaction mixture was stirred for 30 minutes and filtered. The solids were washed with water and the filtrate was saturated with hydrogen sulfide, filtered and concentrated to near dryness. The residue was dissolved in ethyl acetate-water and the pH was adjusted to 8.0 by addition of sodium carbonate and sodium hydroxide solutions. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The extracts were combined, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].Cl.CN(C)[CH:22]=[O:23]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: Fc1cc2cc[nH]c2cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(F)c(F)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5,6-difluoro-1H-indole (1.0 g) in N,N-dimethylformamide (10 mL) was added phosphoryl chloride (1.2 g) at 0° C., and this mixture was stirred at room temperature for 4 hours. To this mixture was added 2 mol/L aqueous sodium hydroxide solution (5 mL), and this resulting mixture was stirred at 70° C. for 0.5 hours. After cooling to ambient temperature, this mixture was poured into 1 mol/L hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.1 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:7]2[C:8]3[C:13]([N:14]=[C:15](O)[C:6]2=[N:5][N:4]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:30]>C(#N)C>[Cl:30][C:15]1[C:6]2[N:7]([C:3]([C:2]([F:18])([F:17])[F:1])=[N:4][N:5]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: Oc1nc2ccccc2n2c(C(F)(F)F)nnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: FC(F)(F)c1nnc2c(Cl)nc3ccccc3n12

Procedure:
To a suspension of 1-(trifluoromethyl)[1,2,4]triazolo[4,3-a]quinoxalin-4-ol (2.5 g; 0.01 mole) in 60 ml of acetonitrile, Et4N+Cl- (2.4 g) followed by N,N-dimethylaniline (1.7 ml) and POCl3 (3.75 ml) were added. Reaction mixture was refluxed for 20 hours. Volatiles were removed under reduced pressure, residue was dissolved in CHCl3 (100 ml) and added to the ice-water. Layers were separated, the aqueous layer was extracted with chloroform (2×200 ml). The combined extract was washed with 5% NaHCO3 (2×120 ml) followed by brine (2×50 ml). It was dried over MgSO4, filtered, and volatiles were removed. The residue was crystallized from chloroform-hexane affording 1.78 g of 4-chloro-1-(trifluoromethyl)[1,2,4]triazolo[4,3-a]quinoxaline; mass spectrum m/e, 272 (m+).
Reaction SMILES: [CH2:1]([C:3]1([OH:21])[CH2:8][CH2:7][CH:6]([CH2:9][NH:10]C(=O)OCC2C=CC=CC=2)[CH2:5][CH2:4]1)[CH3:2]>O1CCCC1.[Pd]>[NH2:10][CH2:9][CH:6]1[CH2:7][CH2:8][C:3]([CH2:1][CH3:2])([OH:21])[CH2:4][CH2:5]1
Reactant: CCC1(O)CCC(CNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC1(O)CCC(CN)CC1

Procedure:
A mixture of EXAMPLE 447A (500 mg) and 10% Pd/C (100 mg) in tetrahydrofuran (15 mL) was stirred under H2 for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])=[CH:7][C:6]=2[C:5]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[C:4]([F:24])[CH:3]=1.C1C(=O)N([Br:32])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:32][CH2:11][C:8]1[O:9][C:10]2[C:2]([Cl:1])=[CH:3][C:4]([F:24])=[C:5]([C:12]3[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=3)[C:6]=2[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(-c3ccc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(CBr)cc23)c1=O
Yield: 78.8 %

Procedure:
0.98 g (2.72 mmol) of 3-(7-chloro-5-fluoro-2-methylbenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 25 ml of carbon tetrachloride, and 0.51 g (2.86 mmol) of NBS and 0.04 g (0.27 mmol) of 2,2′-azobisisobutyronitrile were added thereto, followed by refluxing for 2 hours. Succinic acid imide was removed by filtration. Then, carbon tetrachloride was distilled off under reduced pressure, and the obtained residue was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained crude crystals were washed with n-hexane to obtain 0.94 g (yield: 79%) of the desired product. Melting point: 142-144° C. 1H-NMR (300 MHz, CDCl3) δ value: 3.73(3H,s), 4.56(2H,s), 6.66(1H,s), 6.80(1H,d), 7.20(1H,d), 7.55(1H,d)ppm.
Reaction SMILES: [N:1]([CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[CH2:5][CH2:6][CH:7]=[CH2:8])=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[NH2:1][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCC(N=[N+]=[N-])c1ccccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CCCC(N)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 116.3 %

Procedure:
To a solution of 5-azido-5-(2-methoxyphenyl)-1-pentene (1.59 g. 7.33 mmol) in anhydrous ether (10 mL) at 0° C. was added to LiAlH4 in diethyl ether (1.0M, 7.33 mL) dropwise over a period of 20 minutes. The ice bath was removed and the reaction mixture was kept at room temperature for 25 minutes. The reaction solution was cooled to 0° C. to 40° C. and saturated Na2SO4 solution was added dropwise until no hydrogen gas was evolved. Anhydrous Na2SO4 was added followed by diethyl ether (70 mL), the resulting suspension was stirred at room temperature for 1 hour and the solution was then filtered through a pad of Celite™. The filtrate was evaporated to give the title compound (1.63 g) as a colorless oil, which was used for the Preparation 19 without purification. 1H NMR (CDCl3, 400 MHz) δ: 7.22 (2H), 6.93 (3H), 5.80 (1H), 4.92 (2H), 4.13 (1H), 3.82 (3H, OMe), 1.2-2.2 (6H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13](=[O:20])[C:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][OH:17].C(N(CC)CC)C>ClCCl.O>[CH3:11][O:12][C:13](=[O:20])[C:14]([CH3:19])([CH3:18])[CH2:15][CH:16]=[O:17]
Reactant: COC(=O)C(C)(C)CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C)(C)CC=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
Step C To a solution of oxalyl chloride (1.09 mL, 12.5 mmol) (Aldrich) in dichloromethane (20 mL) at −78° C. was added the solution of dimethyl sulfoxide (1.77 mL, 25 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 4-hydroxy-2,2-dimethyl-butyric acid methyl ester (1.5 g, 11.3 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (5.7 mL, 41 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 2,2-dimethyl-4-oxo-butyric acid methyl ester as a light yellow oil (Yield: 1.2 g, 81%).
Reaction SMILES: Cl[O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:11]([C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[CH2:12].C(N(C(C)C)C(C)C)C>CCOCC>[C:5]1([C:4]2[CH2:12][CH:11]([C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([O:17][CH3:18])=[O:16])[O:2][N:3]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClON=Cc1ccccc1
Reactant: C=Cc1ccccc1C(=O)OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COC(=O)c1ccccc1C1CC(c2ccccc2)=NO1
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a stirred solution of 9.4 g (0.0604 mol) of benzaldehyde chlorooxime and 10.76 g (0.0664 mol) of methyl o-vinyl-benzoate in 100 ml of ether at 0°-5° C. was added dropwise a solution of 7.81 g (0.0604 mol) of ethyldiisopropylamine in 35 ml of ether during 30 minutes. The mixture was stirred in an ice bath for 4 hours, diluted with another 400 ml of ether, extracted three times with water, and concentrated under vacuum to a solid. This solid was washed with 200 ml of hexane. The undissolved solid product, 14.21 g, had mp 90°-94° C. Crystallization of this from 100 ml of methanol gave 13.50 g (79%) of white solid, mp 93.5°-95° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][NH2:16])[N:10]=2)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[C:34](O)=[O:35])(=[O:28])=[O:27])=[CH:22][CH:21]=1.ON1C2C=CC=CC=2N=N1.CCN(CC)CC>CO.CN(C=O)C>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][NH:16][C:34]([C@@H:30]3[CH2:31][CH2:32][CH2:33][N:29]3[S:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)(=[O:28])=[O:27])=[O:35])[N:10]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: NCc1nccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1nccc(-c2ccc(C(F)(F)F)cc2)n1)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.2 %

Procedure:
A mixture of C-[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-methylamine (92 mg, 0.4 mmol), (S)-1-(4-fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (99 mg, 0.4 mmol), N-(3-dimethylamniopropyl)-N′-ethylcarbodiimide hydrochloride (139 mg, 0.72 mmol), 1-hydroxybenzotriazole (98 mg, 0.73 mmol), Et3N (0.15 mL, 1.10 mmol), and DMF (2 mL) was stirred at rt for 12 hours. After 12 h, MeOH (0.5 mL) was added to the reaction mixture and resulting solution was purified by preparative reverse-phase HPLC to afford (35 mg, 19%) of a white solid. MS (ESI): mass calcd. for C23H20F4N4O3S, 508.1; m/z found, 509.5 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.86 (d, J=5.3, 1H), 8.38 (d, J=8.1, 2H), 8.37-8.33 (m, 1H), 7.99-7.92 (m, 2H), 7.82 (d, J=8.2, 2H), 7.70 (d, J=5.3, 1H), 7.30-7.25 (m, 1H), 4.93-4.76 (m, 2H), 4.31-4.22 (m, 1H), 3.69 (td, J=7.3, 3.7, 1H), 3.25 (td, J=9.8, 6.7, 1H), 2.36-2.29 (m, 1H), 1.97-1.59 (m, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(=O)C.[F:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[OH:17]>O>[F:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([N+:1]([O-:4])=[O:2])[C:11]=1[OH:17]
Reactant: Cc1ccc(O)c(F)c1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(F)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.4 %

Procedure:
70% Nitric acid (d=1.42) (5.5 ml, 87.4 mmol) was dropwise added to an acetic acid (105 ml) solution of 2-fluoro-4-methyl-phenol (10.5 g, 83.2 mmol), taking 20 minutes, followed by stirring at room temperature for 30 minutes. Water was added to the reaction liquid, followed by extraction three times with diethyl ether, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (10:1) was concentrated under reduced pressure to obtain the entitled compound (5.47 g, 31%) as a yellow solid.
Reaction SMILES: N[C@]1(C2C=C(C=CC=2)C#N)[C@H](CO)C[C@H](C)OC1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=1[C@@:28]1([NH:37][C:38]([NH:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[S:39])[C@H:33]([CH2:34][OH:35])[CH2:32][C@H:31]([CH3:36])[O:30][CH2:29]1>>[C:26]([C:23]1[CH:22]=[C:21]([C@@:28]2([NH:37][C:38]([NH:40][C:41](=[O:48])[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[S:39])[C@H:33]([CH2:34][OH:35])[CH2:32][C@H:31]([CH3:36])[O:30][CH2:29]2)[CH:20]=[CH:25][CH:24]=1)#[N:27]
Reactant: C[C@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)c2ccccc2)(c2cc(C#N)ccc2Cl)CO1
Agent: C[C@H]1C[C@@H](CO)[C@](N)(c2cccc(C#N)c2)CO1
Product: C[C@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)c2ccccc2)(c2cccc(C#N)c2)CO1

Procedure:
3-[(3S,4R,6S)-3-Amino-4-(hydroxymethyl)-6-methyltetrahydro-2H-pyran-3-yl]benzonitrile (C22) was converted to the product using the method described for the synthesis of N-{[(3S,4R,6S)-3-(2-chloro-5-cyanophenyl)-4-(hydroxymethyl)-6-methyltetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C19) in Example 6. The resulting product was used in the next step without further purification. Yield: 118 mg, 0.288 mmol, 68%. LCMS m/z 410.2 [M+H+].
Reaction SMILES: [OH-].[Ca+2:2].[OH-].OCC(C)(C)C=O.[C:11]([OH:14])(=[O:13])[CH3:12]>O>[C:11]([O-:14])(=[O:13])[CH3:12].[Ca+2:2].[C:11]([O-:14])(=[O:13])[CH3:12]
Reactant: CC(=O)O
Agent: CC(C)(C=O)CO
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: CC(=O)[O-]
Reaction time: 0.17 h

Procedure:
A crude reaction mixture originating from the calcium hydroxide-catalyzed Tishchenko reaction of 375 g of hydroxypivalaldehyde and additionally containing 12 g of water, was treated with 10.2 g of glacial acetic acid at 70° C. and stirred for 10 minutes. 120 g of water were then added, the mixture was stirred at 70° C. for 15 minutes and when phase separation had taken place the lower aqueous phase was separated off. Analytical determination of the salt content of the organic phase gave a value of 1.42% (calculated as calcium acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:22][CH:23]([F:25])[F:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:21])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Br:68][C:69]1[S:70][C:71]([NH:77][C:78]([O:80][C:81]([CH3:84])([CH3:83])[CH3:82])=[O:79])=[C:72]([C:74](O)=[O:75])[N:73]=1>C(Cl)Cl.O>[Br:68][C:69]1[S:70][C:71]([NH:77][C:78](=[O:79])[O:80][C:81]([CH3:83])([CH3:82])[CH3:84])=[C:72]([C:74](=[O:75])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH2:22][CH:23]([F:25])[F:24])[C:6]=2[N:7]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:21])[C:15](=[O:20])[C:16]([F:18])([F:17])[F:19])[CH2:9][CH2:8]2)[N:73]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)O
Reactant: CN(C(=O)C(F)(F)F)[C@@H]1CCCN(c2c(N)cnn2CC(F)F)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C(=O)C(F)(F)F)[C@@H]1CCCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2CC(F)F)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.6 %

Procedure:
To a solution of (R)—N-(1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoro-N-methylacetamide (248 mg, 0.67 mmol) in DCM (20 mL) was added DIPEA (1.0 mL, 5.7 mmol), PyBOP (700 mg, 1.34 mmol) and 2-bromo-5-(tert-butoxycarbonylamino)-thiazole-4-carboxylic acid (282 mg, 0.87 mmol) and the mixture was stirred at room temperature for 20 hr. Water (50 mL) was added and stirring continued for 1 hr. The mixture was extracted with DCM (50 mL), the combined organic layers were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (R)-tert-butyl 2-bromo-4-(1-(2,2-difluoroethyl)-5-(4-(2,2,2-trifluoro-N-methylacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a pale yellow gum (405 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 10.27 and 10.26 (2s, 1H), 8.32 and 8.27 (2s, 1H), 7.88 and 7.85 (2s, 1H), 6.36-6.02 (m, 1H), 4.67-4.11 (m, 2H), 3.41-3.08 (m, 5H), 3.08 and 2.95 (2s, 3H), 2.22-1.71 (m, 4H), 1.31-1.18 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([OH:14])=[O:13])=[CH:9][C:8]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:6]=2.[C:29](Cl)(=O)C(Cl)=O.CN(C)C=O>CO>[CH3:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:29])=[O:13])=[CH:9][C:8]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:7][CH:6]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc2c1C(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a suspension of 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (4.07 g, 9.94 mmol) at 0° C. was added oxalyl chloride (1.305 mL, 14.91 mmol) and N,N-dimethylformamide (0.1 mL). The resulting mixture was stirred at 0° C. for 1 h. Methanol (5 mL) was added, and the mixture was warmed to room temperature and stirred overnight. The solvent was removed under reduced pressure, and the residue diluted with saturated aqueous NaHCO3. The aqueous mixture was extracted with methylene chloride, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was absorbed onto florisil and purified via column chromatography (ISCO, 5-100% ethyl acetate/hexanes) to afford methyl 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.665 g, 60% yield). MS (m/z) 424.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:17][CH2:18][O:19][CH3:20])[C:6]1[O:7][CH2:8][C:9](=[O:16])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:8]2[O:7][C:6]([N:5]([CH2:17][CH2:18][O:19][CH3:20])[CH2:4][CH2:3][O:2][CH3:1])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]2=[O:16])=[CH:22]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(N(CCOC)CCOC)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(N(CCOC)CCOC)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 11.6 %

Procedure:
To a solution of ethyl 2-[bis(2-methoxyethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in ethanol (5.0 mL), L-proline (0.023 g, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.048 g, y. 11%).