Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:8][C:4]=2[CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]2>C(O)C>[N:29]1[C:21]([NH:1][C:2]2[CH:19]=[CH:18][C:5]3[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:8][C:4]=3[CH:3]=2)=[C:22]2[C:26]([N:25]=[CH:24][NH:23]2)=[N:27][CH:28]=1
Reactant: Nc1ccc2nc(NC(=O)c3ccccc3)sc2c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCO
Product: O=C(Nc1nc2ccc(Nc3ncnc4nc[nH]c34)cc2s1)c1ccccc1

Procedure:
N-[6-(Purin-6-ylamino)benzothiazol-2-yl]benzamide was prepared by heating a mixture of N-(6-aminobenzothiazol-2-yl)benzamide (IM 2, 50 mg, 0.186 mmol) and 6-chloropurine (29 mg, 0.186 mmol) in ethanol (3 ml) to 80° C. for 4 h. The resulting precipitate was separated by filtration and washed with ethanol (69 mg, 0.178 mmol, 96%). LC/ESI-MS: m/z 388 [M+H]+; m/z=386 [M−H]−; Rt=3.07 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C([O-])(=O)C.[Na+].[I:22]Cl.S(=O)(O)[O-].[Na+]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([I:22])[C:5]([OH:16])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: ClI
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cc(Cl)cc(I)c1O
Reaction time: 0.08 h

Procedure:
Add 5-chloro-2-hydroxybenzophenone (23.2 g., 0.1 mole) to acetic acid (150 ml.) and sodium acetate (9.3 g., 0.11 mole). Treat the mixture with iodine monochloride (16.5 g., 0.1 mole) and warm in a bath at 70°-85° for one hour. Cool and add 20 ml. of sodium bisulfite solution and then more water. After stirring for five minutes, collect and dry the title compound; m.p. 110°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11].[CH2:13]([O:15][C:16](=[O:20])[CH:17](Br)[CH3:18])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH:17]([C:16]([O:15][CH2:13][CH3:14])=[O:20])[CH3:18]
Reactant: CCOC(=O)C(C)Br
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Br)cc1C(=O)OC
Yield: 100 %

Procedure:
A mixture of 5-bromo-2-hydroxy-benzoic acid methyl ester (25.0 g, 103 mmol), 2-bromo-propionic acid ethyl ester (18.6 g, 103 mmol) and potassium carbonate (50.2 g, 360 mmol) in acetone (500 mL) is heated under reflux for 24 h. The reaction mixture is filtered, and the filtrate concentrated by rotary evaporation. The residue is dissolved in dichloromethane and washed twice with water. The organic layer is dried over Na2SO4, filtered and concentrated at reduced pressure to afford the title compound as a colorless oil (34.1 g, 103 mmol, 100%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.91 (d, J=2.7 Hz, 1H), 7.49 (dd, J=8.8, 2.7 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 4.71 (q, J=6.8 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 3.88 (s, 3H), 1.65 (d, J=6.8 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H). MS (ES+): 331 (M(C13H1579BrO5)+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12].[H-].[Na+].F[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12]
Reactant: CCOC(=O)c1cc2c(Cl)ccc(O)c2n1C
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ccc(Oc3cccc([N+](=O)[O-])c3)c2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
After 0.50 g (1.97 mmol) of ethyl 4-chloro-7-hydroxy-1-methyl-2-indolecarboxylate was added to a suspension of 0.16 g (3.94 mmol) of 60% sodium hydride and 10 ml of dimethylformamide, the suspension was stirred at room temperature for 30 minutes. Then 0.28 g (1.97 mmol) of 1-fluoro-3-nitrobenzene was added to the solution at room temperature followed by stirring for 3 hours at 150° C. After cooling, the reaction mixture was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate. The combined extracts were washed with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was isolated and purified by silica gel column chromatography to give 0.18 g (24.3%) of ethyl 4-chloro-1-methyl-7-(3-nitrophenoxy)-2-indolecarboxylate.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH2:17])=[NH:16])=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]2[NH:17][CH:2]=[C:3]([CH3:4])[N:16]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(=N)N)cc1
Reactant: CC(=O)CCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cc2nc(C)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 43 h

Procedure:
A solution of chloroacetone (5.27 g, 0.057 m) in CHCl3 (90 mL) was added to a stirred suspension of 4-methoxyphenylacetamidine (28.0 g, 0.17 m) in CHCl3 (470 mL) over 1 hour. The mixture was heated at reflux for 75 minutes and then stirred at ambient temperature for 43 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The oily residue was chromatographed on alumina and eluted with CHCl3 to yield 8.14 g (71%) of I; m.p. 108°-109° C. (CHCl3 -C6H14).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH3:6])(=[O:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:35][CH2:36][C:37]1[C:38]([OH:45])=[N:39][C:40]([CH3:44])=[CH:41][C:42]=1[CH3:43]>ClCCl>[C:1]([NH:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:35][CH2:36][C:37]2[C:38]([OH:45])=[N:39][C:40]([CH3:44])=[CH:41][C:42]=2[CH3:43])=[O:13])=[CH:14][CH:15]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)c1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1
Temperature: 20 °C
Reaction time: 13 h
Yield: 135.6 %

Procedure:
To a solution of 4-(1-acetamidoethyl)benzoic acid (414 mg, 2.0 mmol), 1-hydroxybenzotriozole (405 mg, 3.0 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (576 mg, 3.0 mmol), triethylamine (0.83 mL) in dichloromethane (30 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (82 mg, 0.54 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 4-(1-acetamidoethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide as a white solid (250 mg, 37%). LRMS (M+H+) m/z: calcd 341.17. found 341. HPLC Purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.35-8.26 (m, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 5.85 (s, 1H), 4.90 (q, J=7.2 Hz, 1H), 4.28 (d, J=5.1 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 3H), 1.83 (s, 3H), 1.1 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][CH:60]1[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:59][CH:60]5[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-amino 1-N-methyl piperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.93 (m, 2H) 1.18-1.31 (m, 2H) 1.50-1.80 (m, 6H) 1.83-2.00 (m, 4H) 2.17 (s, 3H) 2.71-2.95 (m, 2H) 3.29 (s, 3H) 3.67-3.87 (m, 3H) 3.94 (s, 3H) 4.89 (d, J=8.59 Hz, 1H) 5.30-5.47 (m, 2H) 6.01 (ddd, J=17.49, 12.69, 10.74 Hz, 1H) 7.41-7.54 (m, 2H) 7.82 (s, 1H) 8.12 (s, 2H) 8.30 (d, J=8.34 Hz, 1H). [M+H] calc'd for C29H38FN7O3, 552. found 552.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([CH2:8][C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH3:10])[N:5]([CH2:20][CH2:21][CH3:22])[N:4]=1)#[N:2].[Br:23]Br>C(Cl)(Cl)Cl>[Br:23][C:7]1[C:3]([C:1]#[N:2])=[N:4][N:5]([CH2:20][CH2:21][CH3:22])[C:6]=1[CH2:8][C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH3:10]
Reactant: CCCn1nc(C#N)cc1CC(C)(C)NC(=O)OC(C)(C)C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCn1nc(C#N)c(Br)c1CC(C)(C)NC(=O)OC(C)(C)C

Procedure:
tert-Butyl 2-(3-cyano-1-propyl-1H-pyrazol-5-yl)-1,1-dimethylethylcarbamate (5.15 g, 16.8 mmol) was brominated using a modified version of the method described in Part F of Examples 1-4. In the reaction, 1.4 equivalents of bromine were used instead of 1.1 equivalents, chloroform was used instead of dichloromethane in the work-up, and no chromatographic purification was performed. The product, tert-butyl 2-(4-bromo-3-cyano-1-propyl-1H-pyrazol-5-yl)-1,1-dimethylethylcarbamate (6.97 g), was isolated as a clear, colorless oil that may have contained some chloroform.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:13]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C(=O)OC)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of 35.5 g of methyl 4-hydroxybenzoate and 50.2 g of methyl 2-chloro-5-nitrobenzoate dissolved in 500 ml of N,N-dimethylformamide (DMF), was added 48.4 g of anhydrous potassium carbonate, and the mixture was stirred for 3 hours at 80° C. Water was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained crude product was recrystallized from methanol to yield 67.7 g of methyl 2-(4-methoxycarbonylphenoxy)-5-nitrobenzoate (melting point: 103-105° C.) (Reaction Scheme (24) described below).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:16][C:17]([N:19]1[CH2:23][CH:22]([CH3:24])[C:21]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:25]([OH:27])=[O:26])[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:32]([O:31][C:29](=[O:30])[CH2:28][C:21]1([C:25]([O:27][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:26])[CH:22]([CH3:24])[CH2:23][N:19]([C:17]([O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18])[CH2:20]1)([CH3:34])([CH3:33])[CH3:35]
Reactant: CC1CN(C(=O)OCc2ccccc2)CC1(CC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OCc2ccccc2)CC1(CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 5 °C
Yield: 98.2 %

Procedure:
Benzyl bromide (4.48 ml, 37.7 mmol) was added to a mixture of (3RS,4SR)-1-[(benzyloxy)carbonyl]-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Reference Example 1b (14.5 g, 38.5 mmol), potassium carbonate (10.6 g, 77 mmol) and N,N-dimethylformamide (50 ml) with stirring under ice-cooling (internal temperature: 3 to 7° C.), and the mixture was stirred for one hour, returned to mom temperature and stirred overnight. Water was added to the reaction liquid, which was extracted with ethyl acetate three times. The organic layers were combined, sequentially washed with a saturated aqueous ammonium chloride solution (five times), water (twice) and brine, and then dried over sodium sulfate, filtered and concentrated to give the title compound (17.67 g, yield: 98.2%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[NH2:26]>N1C=CC=CC=1>[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[NH:26][C:10]1[CH:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N[C@@H]3CCCC[C@H]3N)cc21
Yield: 66.3 %

Procedure:
A mixture of 2.53 g of 1-ethyl-6 7-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid and 4.6 g of trans-(-)-1,2-diaminocyclohexane in 10 ml of pyridine was reacted as described in Example 1 to give 2.3 g of the desired product, m.p. 230°-231°C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1>Cl.O1CCOCC1.ClCCl>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:19][C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: Nc1ccncc1
Reactant: Clc1ncnc2ccc(I)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Ic1ccc2ncnc(Nc3ccncc3)c2c1

Procedure:
To a vial was added 4-chloro-6-iodo-quinazoline (100 mg; 0.34 mmol, commercially available), pyridin-4-amine (3 equiv., 1.03 mmol, 97.19 mg, commercially available), and 2 drops of 4M HCl/dioxane. The reaction vial was heated until solids melted. LCMS of resultant solution showed clean product formation. Upon cooling the product re-solidified. The solid was suspended in dichloromethane:water, and collected by filtration. 95 mg of 6-iodo-N-(4-pyridyl)quinazolin-4-amine was recovered as an orange solid, which was carried on directly to the Suzuki step. LCMS M/Z (M+H)=350.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[N:17][OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[CH2:20]([O:22][C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32]Br)[CH2:26]1)=[O:24])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:22][C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][O:18][N:17]=[C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:15][CH2:16][CH:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:26]1)=[O:24])[CH3:21]
Reactant: ON=C1c2ccccc2CCC1c1ccccc1
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCON=C2c3ccccc3CCC2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 240 h
Yield: 34 %

Procedure:
A mixture of the above oxime (1.0 g, 4.2 mmol), (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (2.2 g, 6.3 mmol, EP 374801), potassium carbonate (1.5 g, 11 mmol) and acetone (25 ml) was stirred at ambient temperature for 10 days. The mixture was filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel (150 g, heptane/ethyl acetate=7/3) to give 0.6 g of (R)-1-(2-(((2-phenyl-1,2,3,4-tetrahydro-1-naphthylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[N:35](C3CCCCO3)[N:34]=[CH:33][CH:32]=2)=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([Cl:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.Cl.[CH3:43][O:44][C:45]([CH:47]1[CH2:51][CH2:50][NH:49][CH2:48]1)=[O:46]>CC(O)C>[Cl:28][C:25]([F:26])([F:27])[O:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15]([C:14]2[CH:29]=[C:30]([C:31]3[NH:35][N:34]=[CH:33][CH:32]=3)[C:11]([N:49]3[CH2:50][CH2:51][CH:47]([C:45]([O:44][CH3:43])=[O:46])[CH2:48]3)=[N:12][CH:13]=2)=[O:16])=[CH:19][CH:20]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: COC(=O)C1CCNC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
DIPEA (181 μL, 1.035 mmol) was added to a mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 36.1, 100 mg, 0.207 mmol), methyl-3-pyrrolidine carboxylate hydrochloride (44.5 mg, 0.269 mmol) and iPrOH (414 μL). in MW vial, which was flushed with argon, sealed and stirred at 130° C. for 24 h. The RM was diluted with EtOAc, treated with brine and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, n-heptane/EtOAc from 40% to 100% EtOAc) followed by preparative TLC (Silica gel, eluent EtOAc). Additional lyophilization from 1,4-dioxane afforded the title compound as a white light solid. UPLC-MS (Condition 6) tR=1.09 min, m/z=492.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.90-2.02 (m, 1H) 2.02-2.14 (m, 1H) 3.06-3.20 (m, 1H) 3.23-3.48 (m, 4H) 3.61 (s, 3H) 6.35-6.48 (m, 1H) 7.34 (d, J=8.78 Hz, 2H) 7.79-7.90 (m, 1H) 7.89 (d, J=8.80 Hz, 2H) 8.03-8.13 (m, 1H) 8.70-8.83 (m, 1H) 10.26 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.CC(C[AlH]CC(C)C)C.O.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1cnc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of ethyl 4,6-dichloronicotinate (500 mg, 2.43 mmol) in DCM at −78° C., DIBAL-H (2.67 mL, 2.67 mmol) was added dropwise and stirred for 3 h at −78° C. The mixture was allowed to warm up to 0° C. then water (0.12 mL) was added dropwise to the mixture followed by aq. NaOH (15%, 0.12 mL). H2O (0.3 mL) was added then the mixture was warmed up to room temperature and stirred for 15 min and the organic layer collected, dried over MgSO4 and filtered with the filtrate concentrated to give the desired product with was used without further purification (280 mg, Yield 65%). LCMS (m/z): 176.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C1C(=O)N([Br:25])C(=O)C1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:25][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCc2c(F)cccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c1ccc(Br)c2F
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of 1,1-dimethylethyl 4-fluoro-2,3-dihydro-1H-indole-1-carboxylate (0.866 g, 3.65 mmol) in Dichloromethane (DCM) (10 mL) was added a solution of NBS (0.650 g, 3.65 mmol) in Dichloromethane (DCM) (10 mL). The reaction was stirred overnight. The reaction mixture was poured into sodium bicarbonate (aq., sat., 50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-30% EtOAc in hexanes, 24-g silica gel column) to afford 1,1-dimethylethyl 5-bromo-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate (1 g, 87% yield) as a (4:1 LCMS, 10:1 by 1H NMR) mixture with the starting material. The mixture was used without further purification. LC-MS (ES) m/z=260, 262 [M+H-t-Bu]+. 1H NMR (400 MHz, DMSO-d6) δ 1.51 (s, 9H), 3.13 (t, J=8.72 Hz, 2H), 3.94-4.08 (m, 2H), 7.26-7.63 (m, 2H).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=1[CH2:23][OH:24].[B:25](OC)(OC)[O:26]C>C1COCC1>[F:20][C:19]([F:22])([F:21])[C:15]1[C:14]2[CH2:23][O:24][B:25]([OH:26])[C:13]=2[CH:18]=[CH:17][CH:16]=1
Reactant: COB(OC)OC
Reactant: OCc1c(Br)cccc1C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB1OCc2c1cccc2C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a 2.5 M solution of n-BuLi in hexane (27.81 mL, 69.53 mmol) in dry THF (30 mL), cooled to −78° C. and under an Argon atmosphere was added a solution of (2-bromo-6-(trifluoromethyl)phenyl)methanol (CXXIX) (5.49 g, 23.16 mmol) in dry THF (30 mL) dropwise very slowly. The reaction mixture was stirred at −78° C. for 2 h before adding trimethyl borate (3.88 mL, 34.76 mmol). The reaction mixture was stirred at −78° C. for an additional 30 min, and then allowed to warm up slowly to room temperature and stirred overnight. The reaction was then cooled to 0° C. and slowly quenched with 2 M HCl and stirred for 2.5 h at room temperature. The reaction mixture was extracted with EtOAc and the organic layer was dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography using (100:1 DCM/MeOH) to give 4-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CXXX) as an orange oil (1.17 g, 5.79 mmol, 25% yield). ESIMS found for C8H6BF3O2 m/z 201.4 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:70][CH2:71][CH2:72][NH:73][C:74](=[O:76])[CH3:75]>C1COCC1>[C:74]([NH:73][CH2:72][CH2:71][NH:70][C:25]([C:24]([CH3:28])([O:23][C:17]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=1[CH:15]1[CH2:14][C:13](=[O:29])[NH:12][CH:11]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[CH3:37])[C:10]21[C:5]1[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[NH:8][C:9]2=[O:38])[CH3:27])=[O:26])(=[O:76])[CH3:75]
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2 mL) was added N-(2-amino-ethyl)-acetamide (19 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (11 mg).