Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.Br[CH2:16][C:17]1[C:18]([CH3:24])=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1.Cl>O1CCCC1.O>[Cl:23][C:20]1[N:19]=[C:18]([CH3:24])[C:17]([CH2:16][O:3][CH:4]2[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Cc1nc(Cl)ccc1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(Cl)ccc1COC1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (170 mg of 60%, 4.26 mmol) was suspended in tetrahydrofuran (12 mL) and cooled to 0° C. tert-Butyl 3-hydroxyazetidine-1-carboxylate (246 mg, 1.420 mmol) was added and the slurry was stirred for 30 minutes at 0° C. 3-(Bromomethyl)-6-chloro-2-methylpyridine (Example 421, Step 2) (313 mg, 1.420 mmol) was added and the solution was heated to 50° C. overnight. The reaction mixture was cooled to ambient temperature, diluted with water, acidified with 1 N hydrochloric acid, and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered, concentrated and purified via silica gel chromatography (0-2% methanol in ethyl acetate) to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.CN([CH:23]=[O:24])C>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]=[C:23]=[O:24])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Product: O=C=NCCc1ccc([N+](=O)[O-])cc1

Procedure:
2-(4-Nitrophenyl)ethylamine (0.5 mmol) and p-nitrophenylchloroformate (0.5 mmol) were allowed to react in the presence of triethylamine (1 mmol) in 5 ml of DMF to provide 2-(4-nitrophenyl)ethyl isocyanate. Without isolation, the isocyanate was mixed with N-(2(S)-amino-4-methylpentyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester dihydrochloride (0.4 mmol) and triethylamine (1 mmol) in 4 mL of DMF to provide the title compound. C34H45N5O6S.0.15 hexane
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:32])[NH:21][C:22]([CH3:31])=[CH:23][C:24]=1[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)CCl.CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:32])[NH:21][C:22]([CH3:31])=[CH:23][C:24]=2[C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Reactant: Cc1cc(-c2ccncc2)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: Cc1cc(-c2ccncc2)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.2 %

Procedure:
To a reaction vial were added 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (90 mg, 0.318 mmol), 3-(aminomethyl)-6-methyl-4,4′-bipyridin-2(1H)-one (103 mg, 0.477 mmol), 1-hydroxy-7-azabenzotriazole (64.9 mg, 0.477 mmol), EDC (91 mg, 0.477 mmol) and DMSO (10 mL) followed by N-methylmorpholine (0.140 mL, 1.272 mmol) in one portion. The reaction contents were stirred at RT for 12 hr, after which time an additional 20 mg each of amine, EDC, and HOAt were added. After stirring for an additional 2 h, the reaction mixture was poured onto ice water (10 mL), stirred for 20 min, allowed to stand for 10 min, and filtered. The collected solid was rinsed with water (10 mL), and then purified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA). The product fractions were treated with NaHCO3 (sat aq), extracted with EtOAc, and evaporated from water to afford the final product as a white solid (69 mg, 43%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (s, 1H), 8.63-8.65 (d, 2H), 8.60 (s, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.61 (s, 1H), 7.42 (d, 2H), 6.00 (s, 1H), 5.02 (m, 2H), 4.15 (s, 2H), 2.23 (s, 3H), 1.45 (d, 6H); MS (ES) [M+H]+ 481.8.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[CH:10]=[C:9]([CH3:11])[O:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:15].C(Cl)(Cl)Cl.CCCCCC>C(OC(=O)C)(=O)C>[Cl:15][C:4]1[C:5]2[CH:10]=[C:9]([CH3:11])[O:8][C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2oc(C)cc2c(=O)[nH]1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(Cl)c2cc(C)oc2n1
Yield: 85 %

Procedure:
To a 50 mL flask was added 4 (1.64 g, 10 mmol) and 10 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added 30 mL of CHCl3 and 3 g of silica gel. The solvent was evaporated to afford a plug. Column chromatography of the plug with hexane:acetyl acetate=20:1 as eluent afford 1.55 g (85%) of 5 as a yellow solid: TLC Rf0.26 (Hexane/EtOAC 15:1); mp 47.6-48.1° C.; 1H NMR (DMSO-d6) δ 2.48 (s, 3 H) 2.63 (s, 3 H), 6.77 (s, 1 H).
Reaction SMILES: CON(C)[C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[CH:7]=1)=[O:5].[CH3:16][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[S:14]1[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[CH:7]=[C:6]1[C:4](=[O:5])[CH3:16]
Reactant: CON(C)C(=O)c1cc2cnccc2s1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cc2cnccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methoxy-N-methylthieno[3,2-c]pyridine-2-carboxamide (D′-2) (11.1 g, 50 mmol) in anhydrous THF (150 mL) was added MeMgBr (3M in ethyl ether, 25 mL, 75 mmol) at 0° C. under N2. The reaction mixture was allowed to warm to the ambient temperature and stirred overnight. Saturated aqueous NH4Cl solution was added to quench the reaction. The resulting mixture was then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford the title compound. MS (m/z): 178 (M+1)+.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[C:9]([F:16])=[CH:10][C:11]([I:15])=[C:12]([CH:14]=1)[NH2:13].[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[N:23]1[CH:27]=[C:26]([C:28](F)=[O:29])[CH:25]=[N:24]1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:7][C:8]1[C:9]([F:16])=[CH:10][C:11]([I:15])=[C:12]([NH:13][C:28]([C:26]2[CH:25]=[N:24][N:23]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[CH:27]=2)=[O:29])[CH:14]=1
Reactant: Nc1cc(Cl)c(F)cc1I
Reactant: O=C(F)c1cnn(C2CCCCO2)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)c(F)cc1I)c1cnn(C2CCCCO2)c1
Reaction time: 0.25 h
Yield: 28.3 %

Procedure:
Potassium t-butoxide (12.52 g, 111.6 mmol) is added at room temperature to a solution of 5-chloro-4-fluoro-2-iodoaniline (5.0 g, 22.3 mmol) in 250 mL of anhydrous THF under nitrogen. After stirring for 15 minutes, a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylic acid fluoride (5.67 g, 24.6 mmol) in 30 mL of anhydrous THF is added dropwise. The reaction mixture is stirred for 4 hours at room temperature and then poured into saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic phase is washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated to dryness. After purification by flash chromatography on silica (cyclohexene/EtOAc: 95/5 to 80/20), a red solid is obtained, which is purified by flash chromatography on amine phase (DCM) to give 2.84 g of a white solid (yield: 31%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:6]=1[C:7]([NH:9][C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)=[O:8])(=[O:4])=[O:3].[H-].[Na+].Cl[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])O.[Na+]>C1COCC1.O>[CH3:1][S:2]([C:5]1[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][C:6]=1[C:7]([N:9]([C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)[C:27](=[O:28])[O:29][CH3:30])=[O:8])(=[O:3])=[O:4]
Reactant: Cn1nnnc1NC(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O)c1nnnn1C
Reaction time: 0.17 h

Procedure:
To a solution of 175 mg (0.5 mmol) of 2-(methylsulfonyl)-N-(1-methyl-1H-tetrazol-5-yl)-4-(trifluoromethyl)benzamide in 4 ml of THF (abs.) under protective gas at 0° C. are added 14 mg (0.55 mmol) of sodium hydride (95%). After stirring for 10 min, 46 μl (0.6 mmol) of methyl chloroformate are added at 0° C. The reaction mixture is stirred at RT for 1 h. Subsequently, the reaction mixture is adjusted to pH 7 with an aqueous sat. sodium hydrogencarbonate solution, and 10 ml of water are added. Then the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. Yield: 231 mg (57%)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][CH:9]=[C:10]([Cl:13])[C:11]=2[Cl:12])=[N:5][C:4]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[N:3]1.C([O-])(=O)C.[Na+].[Br:27]Br.C(Cl)Cl>C(O)(=O)C>[CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]([Br:27])=[C:10]([Cl:13])[C:11]=2[Cl:12])=[N:5][C:4]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[N:3]1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1scc(Cl)c1Cl
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1sc(Br)c(Cl)c1Cl
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
To a mixture of 1-methyl-3-(2-chloro-6-fluorophenyl)-5-(3,4-dichlorothien-2-yl) [1,2,4]triazole (33.4 g, 92.1 mmol) and sodium acetate (7.6 g, 92.1 mmol) in acetic acid (250 mL) was added bromine (58.9 g, 368.4 mmol) dropwise at a rate which maintained the reaction temperature below 35° C. The resulting mixture was slowly heated to 70° C. and stirred for 2.5 hours, cooled to 50° C. and stirred overnight, and cooled to room temperature. TLC analysis (methylene chloride) indicates full consumption of the starting material. The reaction was slowly poured into a mixture of 10% aqueous sodium bisulfite and ice (300 mL), and the resulting pale yellow suspension was stirred for 20 minutes. The solids were collected by vacuum filtration, washed with water, and dissolved in methylene chloride. The organics were dried (sodium sulfate), filtered, and the solvent evaporated at reduced pressure to give 39.3 g (96%) of desired product as a tan solid: mp 178-180° C. 1H NMR (CDCl3) δ4.04 (s, 3H), 7.08-7.14 (Ar-m, 1H), 7.29-7.40 (Ar-m, 2H).
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[C:8]=2[Cl:11])[C:3]1=O.BrC1CC2C(=CC=CC=2F)C1=[O:25].ClC1C(Cl)=CC=C2C=1CCC2=O>[Cu](Br)Br.O1CCOCC1>[Br:1][CH:2]1[CH2:3][C:4]2[C:9](=[C:8]([Cl:11])[C:7]([Cl:12])=[CH:6][CH:5]=2)[C:10]1=[O:25]
Reactant: O=C1c2ccc(Cl)c(Cl)c2CC1Br
Reactant: O=C1c2cccc(F)c2CC1Br
Agent: Br[Cu]Br
Agent: O=C1CCc2c1ccc(Cl)c2Cl
Solvent: C1COCCO1
Product: O=C1c2c(ccc(Cl)c2Cl)CC1Br

Procedure:
The 2-bromo-4,5-dichloro-1-indanone can be prepared as in Example 14 for the preparation of 2-bromo-4-fluoro-1-indanone but starting with 12.67 g of 4,5-dichloro-1-indanone, 37.3 g of copper bromide and 400 ml of dioxane. 16.79 g of 2-bromo-6,7-dichloro-1-indanone are thus obtained which melt at 131° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:13][CH2:14][C:15]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:2]=1[Br:1])=[O:16]
Reactant: Nc1ccc(S(N)(=O)=O)cc1Br
Reactant: O=C(Cl)CCl
Product: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Br)c1
Yield: 78.6 %

Procedure:
2-Bromo-4-sulphamoylaniline (20.0 g) and α-chloroacetyl chloride (25.0 g) were refluxed together for 60 min. and the product worked up as in Example 2(a) to yield 20.5 g white needles, m.p. 174°-175°
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].[Li][CH3:16].[BH4-].[Na+].Cl>CO.C1COCC1>[NH2:12][CH:11]([C:10]1[CH:9]=[CH:8][C:7]([C:3]2([C:1]#[N:2])[CH2:6][CH2:5][CH2:4]2)=[CH:14][CH:13]=1)[CH3:16]
Reactant: [Li]C
Reactant: N#Cc1ccc(C2(C#N)CCC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1ccc(C2(C#N)CCC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
4-(Cyanocyclobutyl)benzonitrile (335 mg, 1.84 mmol) is mixed with THF (10.0 mL) and cooled to −78° C. under N2 gas. MeLi (1.15 mL, 1.84 mmol, 1.60M in Et2O) is added, and the mixture is stirred at −78° C. for 15 minutes. A mixture of NaBH4 (70.0 mg, 1.84 mmol) in MeOH (10.0 mL) is added, and the solution is warmed to 0° C. for 1 hour. 1N HCl (40.0 mL) is added, and the solution is concentrated to dryness on the rotovaporator. The product is purified by HPLC: Gilson prep pumps, flow rate: 30 ml/min, column: Synergi Gemini (5 u) 21.2×50 mm (high pH), mobile phase: A=water (10 mM NH4CO3) B=MECN, (95.0 mg, 0.475 mmol, 26%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.23 (d, J=6.64 Hz, 3H) 1.90-2.06 (m, 1H) 2.16-2.35 (m, 1H) 2.52-2.64 (m, 2H) 2.64-2.78 (m, 2H) 4.00 (q, J=6.64 Hz, 1H) 7.36 (d, J=8.59 Hz, 2H) 7.42 (d, J=8.20 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][C:3]=1[CH3:11].CC1C=CC([S:19]([NH:22][NH2:23])(=O)=O)=CC=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]=[N:22][S:19][CH:9]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: CC(=O)c1ccc(Br)c(C)c1
Solvent: CCO
Product: Cc1cc(-c2csnn2)ccc1Br
Reaction time: 5 h
Yield: 27.9 %

Procedure:
A mixture of 1-(4-bromo-3-methylphenyl)ethanone (500 mg) and 4-methylbenzenesulphonic acid hydrazide (437 mg) was heated to reflux in ethanol (15 ml) containing a few 4A molecular sieves for 5 h. On cooling, colourless needles were formed, which were collected by filtration (577 mg). 300 mg of this intermediate hydrazone were dissolved in thionyl chloride (2 ml) and was stirred at 20° for 5 h. The mixture was neutralised with 2N sodium carbonate (40 ml) and extracted with ethyl acetate (2×30 ml). The dried extracts were then evaporated to give a yellow solid. This material was chromatographed on silica eluting with dichloromethane;hexane (1:1) to give the title compound as pale yellow solid (167 mg).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].[CH:12]1([N:18]=[C:19]=[S:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([NH:18][C:19](=[S:20])[NH:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][NH:3][CH:1]=[O:2])=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(NNC=O)cc1
Reactant: S=C=NC1CCCCC1
Product: O=CNNc1ccc(NC(=S)NC2CCCCC2)cc1

Procedure:
Procedure (12.) was employed with 1-formyl-2-(4-aminophenyl)hydrazine (7.5 g, 0.05 mole) and cyclohexyl isothiocyanate 7.1 g, 0.05 mole). Yield 9.6 g (66%), m.p. 158°-160° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:10]3([C:19]([CH3:21])([CH3:20])[O:18][C:12]4([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)[C:11]3=[O:22])[O:9]2)=[C:4]([CH2:23][CH3:24])[CH:3]=1.BrC1C=CC(C2C3(C(=O)C(C)(C)OC43CCCCC4)O2)=C(CC)C=1.S(=O)(=O)(O)O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:11](=[O:22])[C:12]3([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:18][C:19]([CH3:21])([CH3:20])[C:10]2=[O:9])=[C:4]([CH2:23][CH3:24])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C1OC12C(=O)C1(CCCCC1)OC2(C)C
Agent: CCc1cc(Br)ccc1C1OC12C(=O)C(C)(C)OC21CCCCC1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCc1cc(Br)ccc1C1C(=O)C(C)(C)OC2(CCCCC2)C1=O
Temperature: 7.5 °C
Reaction time: 0.92 h

Procedure:
To an ice cold solution of mixture of 2-(4-bromo-2-ethylphenyl)-12,12-dimethyl-1,11-dioxadispiro[2.1.5.2]dodecan-4-one and 2-(4-bromo-2-ethylphenyl)-11,11-dimethyl-1,10-dioxadispiro[2.0.5.3]dodecan-12-one (15 g, 0.038 mol) in dichloromethane (7.5 ml) is added concentrated sulphuric acid (45 ml), dropwise, over 50-60 minutes, maintaining the temperature of the reaction mixture at 5-10° C. The reaction mixture is maintained at 5-10° C. for 10-15 minutes, quenched into crushed ice (225 g) and extracted with dichloromethane (3×100 ml). The organic phases are combined, washed with water and dried over anhydrous sodium sulfate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2,2-dimethyl-1-oxaspiro[5.5]undecane-3,5-dione (3 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[N:26]=[C:25]([O:27][CH2:28][C:29](O)=[O:30])[CH:24]=[CH:23][N:22]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]([OH:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])=[N:10][CH:9]=2)[CH:7]=1.O[N:33]1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[N:26]=[C:25]([O:27][CH2:28][C:29]([NH2:33])=[O:30])[CH:24]=[CH:23][N:22]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]([OH:19])([CH3:18])[C:14]([F:16])([F:15])[F:17])=[N:10][CH:9]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(OCC(=O)O)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nccc(OCC(N)=O)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
The product of Step 1 (10 mg, 0.018 mmol), N-hydroxybenzotriazole (5.4 mg, 0.035 mmol), diisopropylethylamine (31 μL, 0.18 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (6.7 mg, 0.035 mmol) were taken-up in N,N-dimethylformamide (0.5 mL). Ammonium chloride (6.6 mg, 0.12 mmol) was added in one portion, and the resulting mixture was stirred overnight at room temperature. The resulting mixture was directly purified via reverse phase HPLC (10-80% acetonitrile/water+0.05% TEA modifier). Desired fractions were combined, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate (1×) and 10% aqueous ammonium hydroxide (1×). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2-{[2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}acetamide (6 mg, 0.013 mmol, 76% yield) as a white solid. MS ESI: [M+H] m/z 454.1. 1H NMR (500 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.25 (d, J=5.5 Hz, 1H), 8.07 (s, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 7.64 (s, 1H), 7.49 (s, 1H), 7.31 (s, 1H), 7.09 (s, 1H), 6.35 (d, J=5.5 Hz, 1H), 4.76 (s, 2H), 2.32 (s, 3H), 1.76 (3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[O:3][C:4]([CH:6]=[CH2:7])=[CH2:5].[C:10]1(=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[O:3][C:4]1[CH2:5][C:10]2([CH2:12][CH2:11]2)[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7][CH:6]=1
Reactant: CCOC(=O)C=C1CC1
Reactant: C=CC(=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC=C(O[Si](C)(C)C)CC12CC2
Temperature: 130 °C

Procedure:
2-(Trimethylsiloxy)-1,3-butadiene (900 mg, 6.33 mmol) and ethyl cyclopropylideneacetate (2195 mg, 17.40 mmol) were combined in toluene (3 ml) and heated to 130° C. for 14 h. The mixture was then allowed to cool to room temperature and concentrated in vacuo to yield ethyl 7-[(trimethylsilyl)oxy]spiro[2.5]oct-6-ene-4-carboxylate that was used without further purification in the subsequent reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13](O)=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8](O)=[O:9])([O-:3])=[O:2].CO>C1COCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[C:6]([CH2:13][OH:14])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CO)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-nitrophthalic acid (40 g, 189.5 mmol) in THF (500 mL) was added dropwise over 1.5 h to a solution of borane-THF complex (1 M, 490 mL, 490 mmol), keeping the reaction temperature between 0° C. and 5° C. After the addition, the reaction mixture was allowed to warm slowly to ambient temperature and stirred for 18 h. MeOH (100 mL) was added carefully and the precipitated solid dissolved. The mixture was concentrated in vacuo to about 500 mL, cooled to 0° C., and 10 N NaOH was added to adjust the pH to 10-11. This mixture was extracted with EtOAc (3×600 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=207 (M−OH+CH3CN).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:26].[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]([CH3:24])[CH3:25])[CH2:20][CH2:21]2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclohexyl amino}-1,5-naphthyridin-3-yl)ethanone (20 mg, 0.055 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (29 mg, 0.10 mmol) followed by formation of the dihydrochloride salt to afford the desired product (18 mg, 58%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.46 (d, J=9.1 Hz, 1H), 8.33 (d, J=9.1 Hz, 1H), 8.12 (s, 2H), 5.75-5.67 (m, 1H), 3.09 (d, J=6.6 Hz, 2H), 2.94 (s, 6H), 2.76 (s, 3H), 2.48-2.41 (m, 2H), 2.09-1.98 (m, 1H), 1.75-1.63 (m, 1H), 1.48-1.36 (m, 2H). ESI MS m/z 487 [M+H]+; HPLC>99% (AUC), tR=9.67 min.
Reaction SMILES: [CH2:1]([Zn]CC)C.C(O)(C(F)(F)F)=O.ICI.[CH2:16]([O:23][CH2:24][C:25]1[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[Cl-].[NH4+]>C(N(CC)CC)C.ClCCl>[CH2:16]([O:23][CH2:24][C:25]12[CH2:1][CH:26]1[CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(COCc2ccccc2)CC1
Reactant: CC[Zn]CC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(COCc3ccccc3)CC2C1
Reaction time: 0.67 h

Procedure:
Under an argon atmosphere, after diethyl zinc (1.0M hexane solution: 27.0 ml) was added to dichloromethane (40 ml) with ice cooling, a TFA (2 ml)/dichloromethane (10 ml) solution was added dropwise, and stirring was performed under ice cooling for 40 minutes. Then, after a diiodomethane (7.24 g)/dichloromethane (10 ml) solution was added dropwise and further stirring was performed at the same temperature for 40 minutes. Tert-butyl 4-[(benzyloxy)methyl]-3,6-dihydropyridine-1(2H)-carboxylate (3.28 g)/dichloromethane (30 ml) solution was added dropwise, and stirring was performed at room temperature for 15 hours. After adding triethylamine under ice cooling and adjusting pH to 7 to 8, di-tert-butyl dicarbonate (2.83 g) was added, and stirring was performed at room temperature for 5 hours. A saturated ammonium chloride aqueous solution was added, extraction was performed with chloroform, followed by washing with saturated brine and drying over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl 6-[(benzyloxy)methyl]-3-azabicyclo[4.I.0]heptane-3-carboxylate (2.22 g).