Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:25][CH2:26][CH:27]=[C:28]([Cl:30])[Cl:29])[CH:6]=[C:7]([CH2:23][CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16](OCC)[O:17]CC)[CH3:2].C(O)(=O)C.Cl>O>[CH2:23]([C:7]1[CH:6]=[C:5]([O:25][CH2:26][CH:27]=[C:28]([Cl:29])[Cl:30])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]=[O:17])[CH3:24]
Reactant: CCOC(COCCCCOc1c(CC)cc(OCC=C(Cl)Cl)cc1CC)OCC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a mixture of 9.27 g of 3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene, 25 ml of acetic acid, and 5 ml of water was added 1 ml of concentrated hydrochloric acid at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was poured into water, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, aqueous sodium hydrogencarbonate solution, and aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate, and concentrated, which afforded 7.62 g (yield, 98%) of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:54]([O:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH2:55]>CN(C=O)C.O.C(O[Pd]OC(=O)C)(=O)C>[CH2:57]([O:56][C:54]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:8]=[CH:7]2)=[CH2:55])[CH2:58][CH2:59][CH3:60]
Reactant: Brc1cccc2cnc(Nc3ccccc3)nc12
Reactant: C=COCCCC
Agent: CC(=O)O[Pd]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(OCCCC)c1cccc2cnc(Nc3ccccc3)nc12
Temperature: 70 °C
Reaction time: 72 h
Yield: 66.6 %

Procedure:
A solution of 8-bromo-N-phenylquinazolin-2-amine (310.3 mg, 1.034 mmol), diacetoxypalladium (23.21 mg, 0.103 mmol), potassium carbonate (286 mg, 2.068 mmol), 1,3-bis(diphenylphosphino)propane (94 mg, 0.227 mmol), and 1-(vinyloxy)butane (0.147 mL, 1.137 mmol) in a mixture of DMF (4.0 mL) and water (0.800 mL) was stirred under argon in a sealed tube at 70° C. for 3 d. The mixture was adsorbed onto silica gel (DMF was removed in vacuo). Chromatographic purification (silica gel, 0-50% EtOAc/hexanes, 20 min, 254 nm) furnished 8-(1-butoxyvinyl)-N-phenylquinazolin-2-amine (220 mg, 0.689 mmol, 67% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 9.06 (1H, s), 7.95 (1H, s), 7.90 (2H, d, J=8.2 Hz), 7.68 (1H, d, J=8.0 Hz), 7.34-7.37 (2H, m), 7.33 (1H, br. d, J=3.8 Hz), 7.31 (1H, d, J=7.8 Hz), 7.05 (1H, t, J=7.3 Hz), 4.99 (1H, d, J=1.0 Hz), 4.64 (1H, s), 3.99 (2H, t, J=6.7 Hz), 1.81 (2H, quin, J=7.1 Hz), 1.50 (2H, sxt, J=7.5 Hz), 0.96 (3H, t, J=7.4 Hz). m/z (ESI, +ve) 320.1 (M+H)+.
Reaction SMILES: Cl[C:2]([CH3:22])([CH3:21])[CH2:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.Cl.[NH2:24][OH:25].[OH-].[Na+].CCOC(C)=O>CCO.CCCCCC>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[CH2:3][C:2]([CH3:22])([CH3:21])[O:25][N:24]=2)[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]=1[OH:16])([CH3:20])([CH3:19])[CH3:18]
Reactant: NO
Reactant: CC(C)(Cl)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(C)CC(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)=NO1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In a 5 L round bottom flask, equipped with magnetic stirrer and Ar inlet is placed a solution of (77.1 g, 0.24 mol) 3-chloro-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methylbutan-1one and hydroxylamine hydrochloride (20.1 g, 0.28 mol) in EtOH (2.2 L). To the stirred solution is added 2 N NaOH (119 mL,0.24 mol, 1.0 eq) dropwise over 15 min. A rapidly dissipating yellow color is observed on contact of the two solutions. After addition is complete, the reaction is heated at 50° C. The reaction is followed by TLC (EtOAc:hexane, 1:4). After 3 hr, approximately 50% conversion is achieved. The crude product is precipitated by addition of H2O (750 mL), and filtered. The filtrate is set aside. A single recrystallization of the solids from hexane provides 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-4,5-dihydro-5,5-dimethylisoxazole as a faint yellow solid. The H2O/EtOH filtrate is concentrated on a rotary evaporator to remove EtOH, and the resulting suspension is extracted with CH2Cl2 (3×200 mL). The aqueous phase is discarded, and the organic phase is dried (MgSO4), filtered, combined with the hexane mother liquor from the above crystallization, and evaporated to an oily solid. Crystallization from hexane produces 3-(3,5-di-tert-butyl-4-hydroxyphenyl)4,5dihydro-5,5-dimethylisoxazole as a yellow solid slightly less pure than the first batch.
Reaction SMILES: [CH2:1]([O:8][S:9]([O-:12])(=[O:11])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl[Ni:15]Cl>CO>[CH2:1]([O:8][S:9]([O-:12])(=[O:11])=[S:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Ni+2:15].[CH2:1]([O:8][S:9]([O-:12])(=[O:11])=[S:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cl[Ni]Cl
Agent: O=S([O-])(=S)OCc1ccccc1
Agent: [Na+]
Solvent: CO
Product: [Ni+2]
Reaction time: 24 h

Procedure:
Sodium benzylthiosulphate (57.5 g) and anhydrous NiCl2 (14.2 g) were mixed in absolute methanol (150 ml) at room temperature, and the mixture was stirred for 24 hours. It was then filtered, and methanol was evaporated from the filtrate. The residue was treated with water (50 ml) to displace the residual methanol, and the resulting solution was evaporated to dryness under vacuum, at a temperature not exceeding 50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][O:10]C.[N+:12]([C:15]1[O:21][C:18]([CH2:19]O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C1C=CC=CC=1.C(OCC)C.FB(F)F>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:19][C:18]1[O:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[CH:9]=[O:10]
Reactant: O=[N+]([O-])c1ccc(CO)o1
Reactant: COC=Cc1ccccc1Cl
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=CC(=Cc1ccc([N+](=O)[O-])o1)c1ccccc1Cl
Reaction time: 1 h

Procedure:
4.0 g of 1-(2-chlorophenyl)-2-methoxyethylene are added dropwise within 20 minutes to 9.55 g of 5-nitrofurfurol in 12 cc of dry benzene at room temperature after the addition of one drop of diethyl ether/trifluoroborane. The mixture is stirred at 35°-40° for 1 hour and is then successively washed with a 5% aqueous sodium acetate solution and water, the benzene solution is dried over magnesium sulphate and concentrated by evaporation. The residue is taken up in 3 cc of concentrated hydrochloric acid, 17 cc of water and 120 cc of glacial acetic acid, and the mixture is stirred at 80°-85° for 3 hours. The mixture is concentrated in a vacuum, and, after cooling, the title compound is obtained as yellow crystals having a M.P. of 148°-151°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:14]=2)[C:9](=[O:22])[C:8]([C:23]([O:25]CC)=[O:24])=[CH:7]1.[Li+].[OH-]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[N:14]=2)[C:9](=[O:22])[C:8]([C:23]([OH:25])=[O:24])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCCC3)c(F)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3cc(F)c(N4CCCC4)nc32)c(OC)c1
Reaction time: 1.5 h

Procedure:
A solution of Example 51B (17.9 g) in THF (750 mL) and methanol (70 mL) was treated with 1M LiOH (196 mL), stirred for 1.5 hours, and filtered. The filtrant was dissolved in 2:1 methanol/water (1.5 L), and this solution was treated with 1M HCl and water (500 mL total) and filtered.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:14])=[N:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)([O-])=O.[H][H]>CO>[N:6]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[C:4]([NH2:1])[C:5]=1[NH2:14]
Reactant: [H][H]
Reactant: Nc1nc2c(cc1[N+](=O)[O-])CCCC2
Solvent: CO
Product: Nc1cc2c(nc1N)CCCC2
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
A mixture of intermediate (9) (0.0658 mol) in NH3/CH3OH 7N (60 ml) was stirred at 120° C. for 12 hours in an autoclave. The solvent was evaporated till dryness. The residue was taken up in 2-propanone. The precipitate was filtered off and dried, yielding 8.6 g 5,6,7,8-tetrahydro-3-nitro-2-quinolinamine (intermediate 10). d) A mixture of intermediate (10) (0.031 mol) in methanol (100 ml) was hydrogenated at room temperature under a 3.105 Pa (3 bar) pressure for 30 minutes in a Parr apparatus. After uptake of hydrogen (3 equivalents), the catalyst was filtered through celite, rinced with methanol and the filtrate was evaporated till dryness. The product was used with further purification, yielding 5.07 g 5,6,7,8-tetrahydro-2,3-quinolinediamine (intermediate 11).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([OH:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].[C:32]1(O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([O:30][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCCCCCN(CCc1ccc(CC(O)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Reactant: Oc1ccccc1
Product: CCCCCCCN(CCc1ccc(CC(Oc2ccccc2)C(=O)OCC)cc1)C(=O)OC(C)(C)C

Procedure:
Synthesized from 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester using a procedure analogous to that used for Example 50 and substituting phenol as the nucleophile to give an approximate 1:1 mixture of ethyl and methyl ester as a clear film (35 mg, 61%).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCCCCCCCCCCCCCBr
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 58.2 %

Procedure:
Diethyl 2-acetamidomalonate (3.0 g) was dissolved in 50 ml of dry ethanol and 1.3 g of sodium ethoxide was added thereto. A solution of 6.0 g of icosyl bromide in 20 ml of dry ethanol was added thereto while stirring at room temperature. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. The mixture was neutralized with a 1N aqueous hydrochloric acid solution and concentrated. The concentrate was purified by silica gel column chromatography to give 4 g of diethyl 2-acetamido-2-icosylmalonate.
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[CH:15]=[N:14][NH:13][C:10]2=[CH:11][N:12]=1.CN([CH:19]=[O:20])C>C1COCC1>[NH:13]1[C:10]2=[CH:11][N:12]=[C:7]([CH:19]=[O:20])[CH:8]=[C:9]2[CH:15]=[N:14]1
Reactant: CN(C)C=O
Reactant: Brc1cc2cn[nH]c2cn1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=Cc1cc2cn[nH]c2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
t-BuLi (27 mL, 1.7 M in pentane) was added to 100 mL of THF at −78° C. 5-bromo-1H-pyrazolo[3,4-c]pyridine (3.0 g, 15 mmol) was added dropwise to the solution in 50 ml of THF via addition funnel. The resulting mixture was stirred for 1 h, at which point DMF (6.0 mL, 76 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred 2 h. The reaction was then carefully quenched with aq. NH4Cl and diluted with EtOAc. The resulting biphasic mixture was partitioned in a separatory funnel. The aqueous portion was extracted three tines with EtOAc, and the combined organic extracts were washed with brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (100% CH2Cl2 to 7.5% MeOH/CH2Cl2), afforded the desired 1H-pyrazolo[3,4-c]pyridine-5-carbaldehyde (1.1 g, 50% yield) as a white solid. H1 NMR (MeOD, 400 MHz) keto tautomer: 10.17 (s, 1H), 9.19 (s, 1H), 8.56 (s, 1H), 8.46 (s, 1H); enol tautomer: 9.00 (s, 1H), 8.25 (s, 1H), 8.05 (s, 2H), 5.73 (s, 1H). MS (API-ES) m/z (%): 147 (100%, M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]=[C:19]([CH3:30])[CH:18]=2)[C@H:14]([C:31]([NH:33][C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)=[O:32])[CH2:13]1)(=[O:11])=[O:10].[C:39]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)([CH3:42])([CH3:41])[CH3:40]>>[C:37]([C:34]1([NH:33][C:31]([C@@H:14]2[CH2:13][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([N:46]4[CH2:47][CH2:48][N:43]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:44][CH2:45]4)=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:16][N:15]2[C:17]2[N:21]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]=[C:19]([CH3:30])[CH:18]=2)=[O:32])[CH2:36][CH2:35]1)#[N:38]
Reactant: CC(C)(C)N1CCNCC1
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(CCc2ccccc2)n1
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CCN(C(C)(C)C)CC4)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(CCc2ccccc2)n1

Procedure:
In analogy to the procedure described in example 392, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(3-methyl-1-phenethyl-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide (example 484c) was reacted with 1-tert-butylpiperazine (CAS Reg. No. 38216-72-7) to give the title compound as colorless oil. MS (ESI): m/z=678.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:15]>>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1c(Cl)cc(I)cc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c(Cl)cc(I)cc1Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 2,6-dichloro-4-iodobenzoic acid (65 mg, 0.21 mmol) in SOCl2 (3 mL) was heated to reflux under nitrogen atmosphere overnight and then cooled to room temperature. The reaction was conentrated under reduced pressure to afford 2,6-dichloro-4-iodobenzoyl chloride (70 mg, 100% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].Cl[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][N:7]=1>>[OH:4][CH2:3][CH2:2][NH:1][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][N:7]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: NCCO
Product: O=Cc1ccc(NCCO)nc1
Temperature: 135 °C
Reaction time: 14 h

Procedure:
10.12 g (165.68 mmol) of 2-aminoethanol are added to 1.00 g (7.06 mmol) of 6-chloronicotinaldehyde, and the reaction mixture is then stirred at 135° C. for 14 h. This gives a yellow solution which is fractionated by distillation in a kugelrohr apparatus (2.2 mbar, 100° C.). The fraction comprising the desired product is then directly reacted further.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([C:15]([OH:17])=O)[CH:6]=1)[CH3:3].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH:49]1[CH2:54][CH2:53][CH:52]([N:55]2[CH2:58][C:57]([CH2:81][C:82]#[N:83])([N:59]3[CH:63]=[C:62]([C:64]4[C:65]5[CH:72]=[CH:71][N:70](COCC[Si](C)(C)C)[C:66]=5[N:67]=[CH:68][N:69]=4)[CH:61]=[N:60]3)[CH2:56]2)[CH2:51][CH2:50]1>O1CCCC1>[CH3:3][N:2]([CH2:4][C:5]1[N:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[N:8]=[C:7]([C:15]([N:49]2[CH2:50][CH2:51][CH:52]([N:55]3[CH2:56][C:57]([CH2:81][C:82]#[N:83])([N:59]4[CH:63]=[C:62]([C:64]5[C:65]6[CH:72]=[CH:71][NH:70][C:66]=6[N:67]=[CH:68][N:69]=5)[CH:61]=[N:60]4)[CH2:58]3)[CH2:53][CH2:54]2)=[O:17])[CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1cc(C(=O)O)nc(C(F)(F)F)n1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)Cc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Reaction time: 0.25 h

Procedure:
6-[(Dimethylamino)methyl]-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (22.8 mg, 0.0913 mmol, from Step B) was dissolved in tetrahydrofuran (0.67 mL), and triethylamine (33.9 μL, 0.244 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (32.4 mg, 0.0852 mmol) were added. The mixture was stirred for 15 minutes, followed by the addition of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (30.0 mg, 0.0609 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base). After two hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, 0.1N NaOH and sat. NaCl, dried over sodium sulfate and concentrated. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, and stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) until the deprotection was complete. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH), afforded the desired compound as a white powder. Yield: 0.014 g (39%); LC-MS: 594.4 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.14 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.90 (s, 1H), 7.61 (dd, 1H), 7.07 (dd, 1H), 4.07 (ddd, 1H), 3.77-3.72 (m, 2H), 3.70 (s, 2H), 3.63-3.48 (m, 5H), 3.31-3.22 (m, 1H), 3.16-3.07 (m, 1H), 2.60-2.53 (m, 1H), 2.25 (s, 6H), 1.85-1.73 (m, 1H), 1.71-1.59 (m, 1H), 1.37-1.18 (m, 2H). 19F NMR (400 MHz, DMSO-d6): δ −69.45 (s, 3F).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:14]1[CH2:18][O:17]C(C)(C)[N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][C@H:9]([C:10]([F:11])([F:13])[F:12])[C@@H:14]([NH:15][C:21](=[O:22])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:18][OH:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](OCc2ccccc2)C(F)(F)F)COC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CO)[C@H](OCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h
Yield: 49.9 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-1-(benzyloxy)-2,2,2-trifluoroethyl)-2,2-dimethyloxazolidine-3-carboxylate (1.21 g, 3.1 mmol) in methanol (100 mL) was added p-toluenesulfonic acid monohydrate (90 mg, 0.47 mmol). The mixture was stirred at room temperature for 5 days, then the methanol was removed and the residue was dissolved with EtOAc. The EtOAc solution was washed with saturated aq. Na2CO3 solution, water, brine and dried over Na2SO4. Removal of the solvent gave a residue which was purified by flash chromatography to afford the title compound tert-butyl (2S,3S)-3-(benzyloxy)-4,4,4-trifluoro-1-hydroxybutan-2-ylcarbamate (0.54 g, 90%) and recovered starting material (0.54 g). 1H NMR (400 MHz, CDCl3, □ in ppm) 7.31˜7.39 (m, 5H), 5.21 (d, J=7.6 Hz, 1H), 4.87 (d, J=11.1 Hz, 1H), 4.58 (d, J=11.1 Hz, 1H), 4.13 (m, 1H), 4.00 (d, J=11.7 Hz, 1H), 3.83 (m, 1H), 3.65 (d, J=11.7 Hz, 1H), 1.40 (s, 9H).
Reaction SMILES: C(S[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=3[O:29][CH3:30])=[CH:14][CH:15]=[N:16]2)=[CH:11][N:10]=1)C1C=CC=CC=1.C(Cl)Cl.C(O)(=O)C.[S:38]([Cl:42])(Cl)(=[O:40])=[O:39]>O>[CH3:30][O:29][C:20]1[CH:21]=[C:22]([C:25]([F:28])([F:26])[F:27])[CH:23]=[CH:24][C:19]=1[C:13]1[C:12]2[C:17](=[CH:18][C:9]([S:38]([Cl:42])(=[O:40])=[O:39])=[N:10][CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(SCc3ccccc3)ncc12
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(S(=O)(=O)Cl)ncc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.5 %

Procedure:
A round bottomed flask cooled to 0° C., was charged with 7-(benzylthio)-4-(2-methoxy-4-(trifluoromethyl)phenyl)-1,6-naphthyridine (0.129 g, 0.302 mmol), DCM (2.88 ml), acetic acid (0.072 ml), and water (0.072 ml). After stirring for 5 minutes at 0° C., sulfuryl chloride (0.025 ml, 0.302 mmol) was added and stirring was continued for an additional 1 hour at 0° C. The reaction was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 0.093 g of 4-(2-methoxy-4-(trifluoromethyl)phenyl)-1,6-naphthyridine-7-sulfonyl chloride as an off white solid. m/z (ESI) 402.9 (M+H)+.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[CH2:19]([S:24]([CH:27]1[CH2:30][NH:29][CH2:28]1)(=[O:26])=[O:25])[CH2:20][CH2:21][CH2:22][CH3:23].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:19]([S:24]([CH:27]1[CH2:30][N:29]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:28]1)(=[O:26])=[O:25])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCCCCS(=O)(=O)C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCS(=O)(=O)C1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (40 mg, 0.16 mmol), DMF (3.9 mL), 3-(pentylsulfonyl)azetidine hydrochloride (39 mg, 0.17 mmol; which may be prepared as described in Step 4), DIPEA (106 μL, 0.64 mmol), DMAP (2 mg, 0.02 mmol) and EDAC (36 mg, 0.19 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: 90/10 DCM/MeOH) then triturated in pentane with a drop of acetone to give the title compound (12 mg, 19%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1>C(O)C.O1CCCC1.[Pt]>[OH:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1
Reactant: OCc1ccc2ccccc2n1
Agent: [Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: OCC1CCc2ccccc2N1

Procedure:
Sodium borohydride (21.7 g, 0.57 mol) was added in portions to a solution of quinoline-2-carboxaldehyde (30 g, 0.191 mol) in ethanol (300 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred at room temperature for 2 hrs, and quenched by water. Volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate, washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography. Fractions containing product were combined and concentrated under reduced pressure to provide the desired compound and 2-(hydroxymethyl)quinoline. A solution of the recovered 2-(hydroxymethyl)quinoline in ethanol (250 mL) and tetrahydrofuran (250 mL) was hydrogenated at 60 psi in the presence of 5% platinum on carbon at 40° C. for 48 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to provide the title compound.