Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:35])([C:29]2[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]3[C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH:24]=O)=[CH:4][CH:3]=1.Cl.[CH2:37]([O:44][NH2:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.CO>[CH2:37]([O:44][N:45]=[CH:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)([OH:35])[C:29]4[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=4)[CH:10]=3)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=2)[CH:22]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(C=O)c1)cc(=O)n2C
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(C=NOCc3ccccc3)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-{6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-2-oxo-1,2-dihydro-quinolin-4-yl}-benzaldehyde (202 mg, 0.418 mMol) was dissolved in a solution of DCM (2.0 mL) and MeOH (2.0 mL) under an atmosphere of dry N2. To this solution was added O-benzylhydroxylamine hydrochloride (66.8 mg, 418 mMol) and the mixture was stirred for 24 hours at ambient temperature. The reaction mixture was concentrated under vacuum and was purified by radial chromatography eluting with MeOH/EtOAc/NH4OH (5:95:0.1) to give the titled compound as an oil.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([C:40]([CH:42]2[CH2:44][CH2:43]2)=[O:41])[C:36]([O:38]C)=O)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:28]=[C:29]2[C:30](=[CH:31][CH:32]=1)[N:33]=[CH:34][C:35]([C:40]([CH:42]1[CH2:44][CH2:43]1)=[O:41])=[C:36]2[OH:38]
Reactant: COC(=O)C(=CNc1ccc(Br)cc1)C(=O)C1CC1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=C(c1cnc2ccc(Br)cc2c1O)C1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.9 %

Procedure:
Dowtherm was heated to 250° C., methyl 3-(4-bromophenylamino)-2-(cyclopropanecarbonyl)acrylate (24 g, 74.1 mmol) was added portionwise and upon complete addition the reaction mixture was stirred for 20 min. The reaction mixture was cooled to room temperature, diluted with 2:1 hexanes/diethyl ether and filtered to afford the desired product (9.71 g, 45%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.51 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 7.89 (dd, J=8.8, 2.3 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 3.73-3.49 (m, J=7.5, 5.0 Hz, 1H), 1.15-0.76 (m, 4H).
Reaction SMILES: [C:1]([N:3]=[CH:4]OCC)#[N:2].[C:8]([C:10]1[CH:23]=[CH:22][C:13]2[O:14][C:15]([CH3:21])([CH3:20])[C@@H:16]([OH:19])[C@H:17]([NH2:18])[C:12]=2[CH:11]=1)#[N:9]>C(OCC)(=O)C>[C:8]([C:10]1[CH:23]=[CH:22][C:13]2[O:14][C:15]([CH3:21])([CH3:20])[C@@H:16]([OH:19])[C@H:17]([NH:18][CH:4]=[N:3][C:1]#[N:2])[C:12]=2[CH:11]=1)#[N:9]
Reactant: CCOC=NC#N
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC=NC#N)[C@@H]1O
Reaction time: 2 h

Procedure:
To 1.18 g of ethyl N-cyanoformimidate, 2.29 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-amino-2H-benzo[b]pyran-3-ol was added, and the mixture was reacted under stirring at a temperature of from 100° to 120° C. for 2 hours. The reaction mixture was cooled, then dissolved in 100 ml of ethyl acetate, washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residual solid was recrystallized from methylene chloride/isopropanol/petroleum ether to obtain 1.75 g of the above identified compound in the form of crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[NH:14][N:13](C3CCCCO3)[CH:12]([C:21]([F:24])([F:23])[F:22])[CH:11]=2)[N:6]=[N:7][CH:8]=1.CO>Cl.O.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[NH:14][N:13]=[C:12]([C:21]([F:24])([F:22])[F:23])[CH:11]=2)[N:6]=[N:7][CH:8]=1
Reactant: COc1cnnc(OC2=CC(C(F)(F)F)N(C3CCCCO3)N2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cnnc(Oc2cc(C(F)(F)F)n[nH]2)c1
Reaction time: 1 h
Yield: 65 %

Procedure:
5-Methoxy-3-[[2-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (Compound No. 36, 0.75 g (0.0021 mole), 4 drops of 37% hydrochloric acid, and 10 mL of methanol were heated and held at 50° C. for 1 hour. The mixture was cooled, diluted with 30 ml water and neutralized with sodium bicarbonate. Filtration gave 5-methoxy-3-[[3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (0.36 g, 65% yield) as a white solid.
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]([S:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[C:13]([CH2:31][N:32]1[CH2:37][CH2:36][CH:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]1)=[C:12]2[C:44]([O:46]C)=[O:45])(=[O:8])=[O:7])[CH3:5]>CO.O>[CH3:5][CH:4]([S:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[C:13]([CH2:31][N:32]1[CH2:37][CH2:36][CH:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]1)=[C:12]2[C:44]([OH:46])=[O:45])(=[O:8])=[O:7])[CH3:3]
Reactant: COC(=O)c1c(CN2CCC(N3CCOCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(=O)(=O)C(C)C)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2cc1S(=O)(=O)C(C)C
Temperature: 25 °C
Yield: 88.9 %

Procedure:
Potassium hydroxide (0.665 g, 11.85 mmol) was added to a solution of methyl 6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.77 g, 1.185 mmol) in methanol (60 mL) and water (20 mL). The reaction mixture was heated to reflux overnight, cooled to room temperature, and diluted with water. The methanol was removed under reduced pressure, and the residue was acidified to about pH 6 with 2N HCl and extracted with methylene chloride (three times). The combined organic extracts were washed twice with brine, dried over Na2SO4, filtered, and concentrated to afford 6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.67 g, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ8.81 (s, 1H), 8.03 (s, 1H), 7.91 (t, J=6.53 Hz, 2H), 7.76-7.82 (m, 1H), 7.70 (s, 1H), 4.05-4.12 (m, 5H), 3.81 (dt, J=6.87, 13.61 Hz, 1H), 3.57 (br. s., 4H), 3.01 (d, J=9.79 Hz, 2H), 2.41-2.49 (m, 4H), 2.31-2.40 (m, 1H), 1.78 (d, J=11.54 Hz, 2H), 1.24-1.41 (m, 4H), 1.22 (s, 3H), 1.20 (s, 3H); MS (m/z) 636.2 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6].O.[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:18]1([CH2:24][C:25]([NH:2][CH:3]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[CH2:4][C:5]([OH:7])=[O:6])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC(CC(=O)O)c1ccc2c(c1)OCO2
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CC(NC(=O)Cc1ccccc1)c1ccc2c(c1)OCO2
Temperature: -5 °C
Reaction time: 2 h

Procedure:
20 g of 3-amino-3-(benzo[1,3]dioxol-5-yl)propionic acid hydrochloride are placed in 10 ml of acetone, 30 ml of water and 38 ml of TEA at −5° C. and 14 ml of phenylacetyl chloride in 20 ml of acetone are added dropwise, followed by stirring for 2 hours at −5° C. The acetone is concentrated. The aqueous phase is washed with Et2O and the insoluble material is removed by filtration. The phases are separated again by settling and the aqueous phase is washed with Et2O and then acidified with 1N HCl to pH 2. The resulting phase is poured into DCM and a precipitate forms. The precipitate is filtered off by suction and rinsed with DCM. 24 g of the expected compound are obtained.
Reaction SMILES: CS(O[CH:6]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][N:9]=1)[CH3:7])(=O)=O.[Br-:19].[Li+]>CC(C)=O>[Br:19][CH:6]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][N:9]=1)[CH3:7]
Reactant: CC(OS(C)(=O)=O)c1nnc(-c2ccccn2)s1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC(Br)c1nnc(-c2ccccn2)s1

Procedure:
A mixture of (RS)-2-[5-(1-methanesulfonyloxy-ethyl)-1,3,4-thiadiazol-2-yl]-pyridine (1.0 gm), lithium bromide (0.5 gm) in acetone (20 ml) was stirred at reflux over a period of 1 h. The reaction mixture was evaporated under vacuum to provide a crude mass. Crude mass was stirred with ice cold water and extracted with dichloromethane (50 ml×2). The combined organic layer was evaporated under vacuum to afford the title compound in 0.8 gm quantity (85%) as oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:22]([F:25])([F:24])[F:23])=[C:5]([C:20]#[N:21])[CH:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:19])[C:7]=1[C:8]#[N:9].[C:26](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C.CO>[CH3:26][N:3]1[C:4]([C:22]([F:25])([F:23])[F:24])=[C:5]([C:20]#[N:21])[CH:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:19])[C:7]([C:8]#[N:9])=[C:2]1[CH3:1]
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)N1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)N1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 375 mg (1.09 mmol) 2-methyl-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile (Example 4) in DMF (11.5 ml) was cooled to 0° C. 534 mg (1.64 mmol) caesium carbonate were added at this temperature, and after 15 min 48 μl (0.77 mmol) methyl iodide were added dropwise at room temperature. After stirring overnight at rt, additional methyl iodide (20 μl) and a small amount of caesium carbonate were added, and the reaction mixture was stirred at rt for further 3 h before water and methanol were added. The resulting solution was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) to give 75 mg (19% of th.) of the racemic title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H]4CCCNC4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][CH2:37][CH:38]1[CH2:40][O:39]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:5]4[CH2:4][CH2:3][CH2:2][CH2:7][N:6]4[CH:37]([O:36][CH3:35])[C@@H:38]([OH:39])[CH3:40])[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[C:5]2=[N:6][CH:7]=1
Reactant: COCC1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Solvent: CCO
Product: COC([C@H](C)O)N1CCCCC1Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Cl)cc23)ncc1F
Temperature: 140 °C

Procedure:
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.20 g, 0.40 mmol) in ethanol was added 2-(methoxymethyl)oxirane (0.04 mL, 0.40 mmol). The reaction mixture was heated in a microwave reactor at 140° C. for 5 minutes. The reaction was evaporated to dryness and the resulting residue was purified via silica gel chromatography (0-10% MeOH: CH2Cl2) to afford the desired product (1d).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>ClCCl>[F:8][C:6]1[C:5]([F:9])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:3]([F:11])=[C:2]([F:1])[N:7]=1
Reactant: C1COCCN1
Reactant: Fc1nc(F)c(F)c(F)c1F
Solvent: ClCCl
Product: Fc1nc(F)c(F)c(N2CCOCC2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pentafluoropyridine (3.4 g; 20 mmol) was dissolved in dichloromethane (50 mL) and chilled in an ice bath. To the solution was added morpholine (3.48 g; 40 mmol) and the reaction was allowed to warm to room temperature with stirring overnight. The organic phase was washed with saturated ammonium chloride solution (2×20 mL), dried over magnesium sulfate, evaporated, and purified by column chromatography to give 4-(2,3,5,6-tetrafluoro-pyridin-4-yl)-morpholine.
Reaction SMILES: [Br-].[Mg+2].[Br-].Cl[C:5]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[C:9]([CH3:19])[C:6]=1[C:7]#[N:8].[OH-].[NH4+].[OH-].[Na+].[CH2:24]1COCC1>[Cu](Br)Br>[CH3:24][C:5]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[C:9]([CH3:19])[C:6]=1[C:7]#[N:8]
Reactant: Cc1cc(-c2ccccc2)nc(Cl)c1C#N
Reactant: C1CCOC1
Agent: Br[Cu]Br
Agent: [Br-]
Agent: [Mg+2]
Product: Cc1cc(-c2ccccc2)nc(C)c1C#N
Reaction time: 0.33 h
Yield: 55 %

Procedure:
Copper bromide (2.56 g, 17.49 mmol) was suspended in 20 mL of anhydrous THF, dropwisely added with magnesium bromide (3.0M ether, 11.66 mL, 34.99 mmol) at −78° C. and stirred for about 20 minutes. A 10 mL of anhydrous TNF was dropwisely added with a solution, wherein 2 chloro-6-phenyl-4-methyl-nicotinonitrile was dissolved, at the above temperature and then stirred for about 1 hour at room temperature. The mixture was added with a saturated solution of ammonium hydroxide and adjusted its pH to 10 with 1 N NaOH. Then, it was extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. A silica gel column chromatography (5% EtOAc/Hexane) was performed on the resulting residue and 550 mg (55%) of 2,4-dimethyl-6-phenyl-nicotinonitrile was obtained in white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]C(C)C)=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH3:19])[C:15]([CH:20]([F:22])[F:21])=[N:14]1>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH3:19])[C:15]([CH:20]([F:21])[F:22])=[N:14]1
Reactant: CC(C)Oc1cc(-n2nc(C(F)F)n(C)c2=O)c(Cl)cc1Cl
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)F)nn(-c2cc(O)c(Cl)cc2Cl)c1=O
Yield: 71.7 %

Procedure:
Hydrolysis of 2.2 g (0.0063 mole) of 1-[2,4-dichloro-5-(1-methylethoxy)phenyl]-3-difluoromethyl-4,5-dihydro-4-methyl-1,2,4-triazol-5(1H)-one in 5 mL of concentrated sulfuric acid produced 1.4 g of 1-(2,4-dichloro-5-hydroxyphenyl)-3-difluoromethyl-4,5-dihydro-4-methyl-1,2,4-triazol-5(1H)-one (mp 176°-179° C.).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH2:12])=O)[N:5]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1>O=S(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]#[N:12])[N:5]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(C(N)=O)c2)n1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1cc(N)n(-c2cccc(C#N)c2)n1
Yield: 72.8 %

Procedure:
A solution of 3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)benzamide (5.2 g, 20 mmol) in SOCl2 (50 mL) was heated at reflux for 6 h. After removal of the solvent, the residue was dissolved in EtOAc (100 mL). The organic layer was washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, and purified by column chromatography to afford 3-(5-amino-3-t-butyl-1H-pyrazol-1-yl)benzonitrile (3.5 g, 73% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([CH:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[N:10][C:5]2=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]([CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)[CH2:31][C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:32](=[O:33])[CH2:31][C@H:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:35][C:36]4[CH:45]=[CH:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH:37]=4)[CH2:12]3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: COCCCn1c(C2CCCNC2)nc2ccc(Cl)nc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCn1c(C2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(Cl)nc21
Yield: 61.5 %

Procedure:
Compound 35C (0.288 mmol, 0.122 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.455 mmol, 0.150 g) and N-methylmorpholine (1.15 mmol, 0.127 mL) were then added and the solution was allowed to stir at it for 5 min. HATU (0.317 mmol, 0.120 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (40-95% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording (R)-tert-Butyl 4-(3-(5-chloro-3-(3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (35D) as a clear oil (0.177 mmol, 0.110 g, 62% yield). ESI-MS: m/z 620.4 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[C:7]([CH:29]=[CH:30][CH2:31][CH2:32][CH3:33])=[C:6]([CH:34]([CH3:36])[CH3:35])[N:5]=1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:17][CH:16]=2)[C:7]([CH:29]=[CH:30][CH2:31][CH2:32][CH3:33])=[C:6]([CH:34]([CH3:35])[CH3:36])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
The intermediate obtained in Step C (6 g, 12.35 mmol) was dissolved in anhydrous tetrahydrofuran (“THF”) (130 mL) under argon and treated dropwise at room temperature with lithium aluminum hydride (“LAH”)(1.0M in THF, 24.7 mL, 24.7 mmol). The reaction mixture was stirred at reflux for 3 hr, cooled to room temperature and quenched by the addition of 0.9 mL H2O, 0.9 mL 20% aqueous NaOH, and 2.7 mL H2O. The resulting suspension was filtered through a cake of Celite and the filtrate concentrated and purified by chromatography through silica (20% ethyl acetate/hexane) to afford 4.76 g of the title compound as a colorless wax. 1H NMR (300 MHz, CDCl3): δ 0.73-0.83 (m, 3 H), 1.37-1.70 (m, 14 H), 1.56 (s, 1 H), 1.92 (dq, J=0.90, 6.90 Hz, 2 H), 3.41 (δ, J=6.60, 13.20, 24.60 Hz, 2 H), 4.43 (d, J=5.1 Hz, 2 H), 5.10 (s, 2 H), 5.27-5.37 (m, 1 H), 5.97 (d, J=15.90 Hz, 1 H), 6.97-7.09 (m, 4 H), 7.35-7.48 (m, 5 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[N:18]=2)=[CH:5][CH:4]=1)#[N:2].[ClH:19].[CH2:20]([OH:22])[CH3:21]>>[ClH:19].[ClH:19].[CH2:20]([O:22][C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]3[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[N:18]=2)=[CH:7][CH:8]=1)=[NH:2])[CH3:21]
Reactant: CCO
Reactant: N#Cc1ccc(-c2nc3c(s2)NCCCC3)cc1
Agent: Cl
Product: CCOC(=N)c1ccc(-c2nc3c(s2)NCCCC3)cc1
Reaction time: 8 h

Procedure:
A solution (700 ml) of 2-(4-cyanophenyl)-5,6,7,8-tetrahydro-4H-thiazolo[5,4-b]azepine (8.00 g) in ethanol was saturated with hydrogen chloride, and allowed to stand overnight. It was concentrated under reduced pressure, and the residue was washed with ethyl ether and dried to give the title compound as a powder.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]([CH2:22][C:23](O)=[O:24])[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])=[O:7].C[CH2:36][N:37](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:8]([CH2:22][C:23](=[O:24])[NH:37][CH3:36])[C:6](=[O:7])[C:5]1[CH:4]=[C:3]([C:2]([F:34])([F:1])[F:33])[CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=1
Reactant: O=C(O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {(3,5-bis-trifluoromethyl-benzoyl)-[4-(2-chloro-phenyl)-pyridin-3-yl]-amino}-acetic acid (100 mg, 199 μmol) in DMF (2 mL) was added DIPEA (129 mg, 169 μL, 994 μmol), HATU (91.5 mg, 239 μmol) and methylamine hydrochloride (16.1 mg, 239 μmol). The reaction mixture was stirred at room temperature for 2 hours and then poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (67 mg, 65%). MS (ESI): m/z=516.091 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][CH3:29])=[CH:23][CH:22]=1)#[N:14].C(N(CC)CC)C>C(O)C.O>[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:22]=[CH:23][C:24]([CH2:27][N:28]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=2)[CH3:29])=[CH:25][CH:26]=1)#[N:14]
Reactant: CCc1cc(Cl)n2nccc2n1
Reactant: CNCc1ccc(-c2ccccc2C#N)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCc1cc(N(C)Cc2ccc(-c3ccccc3C#N)cc2)n2nccc2n1

Procedure:
1.8 g (10 mmol) of the chloro compound of Step B and 2.2 g (10 mmol) of the amine of Step C were dissolved in 60 ml ethanol and heated with reflux for 4 h. After addition of 3 ml triethylamine the heating was continued for an additional hour. The mixture was diluted with water and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, evaporated in vacuo, and the title compound obtained as an oil after purification by column chromatography on silica gel using ethyl acetate/hexane 9:1 as eluent,