Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][C:14]2[CH:29]=[CH:28][C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)=[CH:28][CH:29]=2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)NCc2ccc(Cc3ccc([N+](=O)[O-])cc3)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)NCc2ccc(Cc3ccc(N)cc3)cc2)cc1
Reaction time: 6 h
Yield: 87.9 %

Procedure:
4-[4-(4-Methoxyphenyl)sulfonylaminomethylbenzyl]-nitrobenzene (791 mg) was dissolved in ethyl acetate (15 mL) and hydrogenated over 5% palladium on carbon at room temperature. The reaction was allowed to proceed for 6 hours, filtered, and evaporated to dryness. The crude product thus obtained was chromatographed on a short silica column, eluting with hexane/ethyl acetate (1:1), to give 4-[4-(4-methoxyphenyl)sulfonylaminomethylbenzyl]-phenylamine (645 mg, 87%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.Cl.[NH2:23][C:24]1([CH3:32])[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[C:16](=[O:18])[N:23]([C:24]1([CH3:32])[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:10]2=[O:12]
Reactant: O=C(O)c1cccc(NCc2cccc(Cl)c2)c1C(=O)O
Reactant: CC1(N)CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC1(N2C(=O)c3cccc(NCc4cccc(Cl)c4)c3C2=O)CCC(=O)NC1=O
Yield: 40.7 %

Procedure:
To a stirred solution of 3-(3-Chloro-benzylamino)-phthalic acid (4 mmol) in pyridine (50 ml) was added 3-amino-3-methyl-piperidine-2,6-dione hydrochloride (0.71 g, 4 mmol). The reaction mixture was heated to reflux for 18 h. The solvent was evaporated in vacuo and the residue dissolved in methylene chloride (150 ml). The methylene chloride mixture was washed with water (2×100 ml), 0.1N HCl (2×100 ml), brine (1×100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give a yellow semi-solid. The residue was purified by preparative HPLC (Symmetry C8, isocratic, 50% acetonitrile/water) to give 0.67 g (41%) of product as a yellow solid: mp 199-201° C.; 1H NMR (DMSO-d6) δ 10.99 (s, 1H), 7.52-7.28 (m, 6H), 6.97-6.89 (m, 2H), 4.54 (d, J=6.1 Hz, 1H), 2.78-2.50 (m, 3H), 2.08-1.98 (m, 1H), 1.89 (s, 3H); 13C NMR (DMSO-d6) δ 172.42, 172.19, 169.62, 167.92, 145.59, 141.82, 136.02, 133.14, 132.06, 130.35, 126.91, 126.78, 125.60, 117.23, 110.42, 109.49, 58.37, 44.74, 29.27, 28.62, 21.02; Anal. Calcd. For C21H18ClN3O4: C, 61.24; H, 4.41; N, 10.20. Found: C, 61.30; H, 4.28; N, 9.97.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[N:18]([CH3:19])[CH:17]=[CH:16][C:10]3=[N:11][C:12]=2[C@@H:13]([NH2:15])[CH3:14])=[C:5]([CH3:20])[O:4][N:3]=1.[NH2:21][C:22]1[N:27]=[C:26](Cl)[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[N:27]=[C:26]([NH:15][C@H:13]([C:12]2[N:11]=[C:10]3[CH:16]=[CH:17][N:18]([CH3:19])[C:9]3=[CH:8][C:7]=2[C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:20])[CH3:14])[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1
Reactant: Cc1noc(C)c1-c1cc2c(ccn2C)nc1[C@H](C)N
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2-c2c(C)noc2C)c1C#N
Temperature: 120 °C
Yield: 39 %

Procedure:
(1S)-1-(6-(3,5-Dimethylisoxazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (107 mg, 0.395 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (100 mg, 0.593 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.21 mL, 1.2 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 45% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound (62 mg, 39%). 1H NMR (500 MHz, CD3OD) δ ppm 1.31-1.42 (m, 3 H), 2.01 (s, 2 H), 2.15 (s, 1 H), 2.19 (s, 1 H), 2.32 (d, J=4.39 Hz, 5 H), 3.86 (s, 3 H), 5.39-5.48 (m, 1 H), 6.65-6.69 (m, 1H), 7.59 (d, J=3.42 Hz, 1 H), 7.68-7.73 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C2H22N8O, 403; found 403.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:15])(=[O:14])[NH:12][CH3:13].[CH2:16]([C:18]1[O:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[CH:19]=1)[CH3:17]>>[CH2:16]([C:18]1[O:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])[CH:4]=1)[CH3:17]
Reactant: CNS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CCc1cc2ccccc2o1
Product: CCc1oc2ccccc2c1C(=O)c1ccc(Cl)c(S(=O)(=O)NC)c1

Procedure:
is obtained as described in Example 1 from 10.7 g 4-chloro-3-methylsulfamoylbenzoyl chloride and 6.4 g 2-ethylbenzo[b]furan in the form of amorphous solids having a softening point of 63° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1)(=O)=O.[C-:20]#[N:21].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[C:20]([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1)#[N:21]
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)nc1C(F)(F)F
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#N)nc1C(F)(F)F
Temperature: 0 °C

Procedure:
Under an atmosphere of nitrogen and with stirring, a solution of 0.596 g of ethyl 6-methylsulfonyl-2-trifluoromethylpyridin-3-ylcarboxylate in 5 ml of dimethylformamide is treated with 160 mg of solid potassium cyanide and a spatula tipful of 18-crown-6, and the mixture is heated at 80° C. for 3 hours. The mixture is cooled overnight, and the next day another 30 mg of potassium cyanide are added and the mixture is heated further until the starting material has disappeared (approximately 2 hours). The mixture is then cooled, added to ice-water and extracted with ethyl acetate. The extracts are washed with water, dried, evaporated and freed from traces of dimethylformamide under high vacuum at approximately 40° C. This gives 480 mg (yield virtually quantitative) of ethyl 6-cyano-2-trifluoromethylpyridin-3-ylcarboxylate in the form of an oil which slowly solidifies. 1H NMR (CDCl3, ppm): 8.29 (1H,d); 7.97 (1H,d); 4.48 (2H, d); 1.43 (3H,t).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:21])[CH2:6][C:7]([CH3:20])([O:9][O:10][C:11](=[O:19])[CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[CH3:8])=[O:3].[NH2:22][NH2:23].C(Cl)(Cl)=O>>[C:2]([O:4][CH:5]([CH3:21])[CH2:6][C:7]([CH3:20])([O:9][O:10][C:11](=[O:19])[CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[CH3:8])(=[O:3])[NH:22][NH2:23]
Reactant: NN
Reactant: CCCCC(CC)C(=O)OOC(C)(C)CC(C)OC(=O)Cl
Agent: O=C(Cl)Cl
Product: CCCCC(CC)C(=O)OOC(C)(C)CC(C)OC(=O)NN

Procedure:
1,3-Dimethyl-3-(2-ethylhexanoylperoxy)butyl carbazate was prepared by reacting 1,3-dimethyl-3-(2-ethylhexanoylperoxy)butyl chloroformate with 11 molar excess of 54% aqueous hydrazine. 1,3-Dimethyl-3-(2-ethyl-hexanoylperoxy)butyl chloroformate was initially prepared with a purity of 72% by reacting 3-hydroxy-1,1-dimethylbutyl peroxy-2-ethylhexanoate with excess phosgene followed by removal of excess phosgene.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[NH2:17][NH2:18]>O1CCOCC1>[Br:1][C:2]1[C:3]([NH:17][NH2:18])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2ccnc(Cl)c2Br)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccnc(NN)c2Br)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-(3-bromo-2-chloropyridin-4-yl)benzonitrile (0.59 g, 2.02 mmol) in dioxane (7 mL) at room temperature was added anhydrous hydrazine (1 mL). The resulting mixture was stirred at 80° C. for 2 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional anhydrous hydrazine (1 mL) was added, and the reaction mixture was stirred at 90° C. for 5 h more. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the resulting suspension was sonicated for 5 min. The resulting slurry was filtered, and the collected solid was washed with water (10 mL×2), then dried in a 45° C. vacuum oven for 16 h to afford 510 mg of the title compound as a beige solid. HPLC/MS: retention time=1.74 min, [M+H]+=289.
Reaction SMILES: Br[CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH:3]=O.[NH2:14][C:15]([NH2:17])=[S:16]>CCO>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:2]2[S:16][C:15]([NH2:17])=[N:14][CH:3]=2)=[CH:7][CH:8]=1
Reactant: NC(N)=S
Reactant: COc1ccc(CC(Br)C=O)cc1
Solvent: CCO
Product: COc1ccc(Cc2cnc(N)s2)cc1
Yield: 75.2 %

Procedure:
A mixture of 2-bromo-3-(4-methoxy-phenyl)-propionaldehyde (9c) and thiourea (0.84 g, 11.0 mmol) in 95% EtOH (20.0 mL) was heated at reflux for 60 minutes. The solution was concentrated under reduced pressure and the residue was re-dissolved in ethyl acetate. The solution was washed with saturated aqueous NaHCO3, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 5-(4-methoxy-benzyl)-thiazol-2-ylamine (9d, 1.01 g, 4.54 mmol) as yellow solids in 75.2% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1.[CH2:14]([NH2:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[I-].[K+]>C(O)C>[CH3:13][S:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:22][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:7][CH:8]=1
Reactant: CSc1ccc(OCCCCl)cc1
Reactant: CCCCCCCCN
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCNCCCOc1ccc(SC)cc1
Yield: 22 %

Procedure:
A solution of 1-chloro-3-[4-(methylthio)phenoxy]propane (5.0 g., 0.023 mole) in 30 ml. of ethanol is treated with n-octylamine (2.84 g., 0.022 mole) and 30 mg. of potassium iodide. After refluxing for a period of 18 hrs., the reaction mixture is concentrated to dryness under reduced pressure, treated with 3N potassium hydroxide solution and ether, and the layers separated. The ether layer is washed with water, concentrated under reduced pressure, and heated on a steam bath at 0.1 mm Hg pressure to remove residual n-octylamine. The residue of N-[3-[4-(methylthio)phenoxy]propyl]octylamine base thus obtained is dissolved in ethanol, treated with excess 6N hydrochloric acid and activated charcoal, filtered and concentrated to dryness under reduced pressure. Crystallization of the residue from isopropyl alcohol-ether affords 1.7 g. (22% yield) of analytically pure N-[3-[4-(methylthio)phenoxy]propyl]octylamine hydrochloride, m.p. 214.5°-215.5° C. (corr.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>CCO>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([O:11][C:10]([F:9])([F:19])[F:20])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)(F)Oc1ccc(Nc2cc(Cl)ncn2)cc1
Yield: 84 %

Procedure:
4,6-Dichloropyrimidine (250 mg, 3.3 mmol) and 4-trifluoromethoxy aniline (330.5 mg, 1.8 mmol) were dissolved in EtOH and DIEA (312.5 uL, 1.8 mmol) was added and the mixture was refluxed for 4 h. It was then cooled, concentrated and work-up with ethyl acetate. The organic layer was separated and dried (Na2SO4). Concentrated and purified by silica-gel column chromatography (Ethyl acetate/hexane). 400 mg (84% Yield). MS m/z 290.04 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCNC(=O)Cc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.4 %

Procedure:
2-({4-[2-(Heptylamino)-2-oxoethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (12.0 g) obtained in Example 303-1 was dissolved in tetrahydrofuran (120 mL), 1 M-borane/tetrahydrofuran complex (100 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, and methanol (400 mL) was added dropwise. After warming to room temperature, the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, piperidine (120 mL) was added, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; dichloromethane:methanol=20:1 to 10:1) to give the title compound (5.5 g) as a slightly yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:33]=[CH:32][C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=O)[O:26]C(C)(C)C)[CH3:23])[CH2:16][CH2:15]4)[O:13][C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.Cl.[C:35](OCC)(=O)C>>[CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:33]=[CH:32][C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:26])[CH3:35])[CH3:23])[CH2:16][CH2:15]4)[O:13][C:9]=3[CH:8]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(OCCC4CC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COC1CCN(c2nc3ccc(OCCC4CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To tert-butyl [(1S)-2-({1-[6-(2-cyclopropylethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate (190 mg) was added 4M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 15 min, and concentrated. Pyridine (10 mL) and acetic anhydride (5 mL) were added to the residue, and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate/methanol), and recrystallized from ethyl acetate/hexane to give the title compound (43 mg).
Reaction SMILES: [CH2:1]([C:8]1([CH3:22])[CH2:16][C:15]2[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([O:17]C)[CH:14]=2)[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>O>[CH2:1]([C:8]1([CH3:22])[CH2:16][C:15]2[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([OH:17])[CH:14]=2)[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(Cc1ccccc1)C2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC1(Cc2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 180 °C
Yield: 34.8 %

Procedure:
2-Benzyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone (6 g.) is mixed with pyridine hydrochloride (60 g.) and the mixture is heated at 180°C. for three hours. The dark liquid is poured into water (1 l.) and the dark powdery product is collected and crystallized from acetic acid to obtain 2-benzyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (2 g.), m.p. 219°-221°C. The product is identified by its nuclear magnetic resonance spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11].CCN(CC)CC.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:15][C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nccn1Cc1cc(Cl)cc(Cl)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylamine was dissolved in CH2Cl2 and Et3N was added followed by benzoyl chloride. The reaction mixture was stirred at room temperature for 2 h and washed with 1N HCl, saturated NaHCO3 and water. The organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH to afford N-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-benzamide (40 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:16][CH2:8][C:5]1[N:4]=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(-c2cccc(F)c2)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cccc(-c2nc(CBr)ccc2Cl)c1
Temperature: 74 °C

Procedure:
To a solution of 3-chloro-2-(3-fluorophenyl)-6-methylpyridine (0.435 g, 2.0 mmol) in CCl4 (40 mL) was added N-bromosuccinimide (0.350 g, 2.0 mmol). The reaction mixture was heated to 74° C. and AIBN (0.027 g, 0.16 mmol) was added. The reaction mixture was heated to reflux for 1 d, diluted with EtOAc, washed with H2O (1×), brine (1×), dried over MgSO4, filtered through a pad of silica (1.5 cm), and concentrated. The product, 6-(bromomethyl)-3-chloro-2-(3-fluorophenyl)pyridine, was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:6]1=2.I.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](SC)=[NH:24]>>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[CH:12][C:13]([NH:15][C:23]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)=[NH:24])=[CH:14][C:6]1=2
Reactant: CN(C)CCN1CCOc2ccc(N)cc21
Reactant: CSC(=N)c1cccs1
Agent: I
Product: CN(C)CCN1CCOc2ccc(NC(=N)c3cccs3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred ethanolic solution of 4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine (0.088 g, 0.398 mmol) under an argon atmosphere was added methyl thiophene-2-carbimidothioate hydroiodide (0.227 g, 0.795 mmol). The resulting faintly cloudy yellow mixture stirred overnight at room temperature. After 20 hours, argon was bubbled through the mixture, which was then concentrated to afford a residue. The residue was then partitioned between EtOAc (100 mL) and saturated NaHCO3 (˜10 mL) solution. The aqueous layer (pH ˜9) was further extracted with EtOAc, and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated to yield a yellow residue. Purification on silica gel (dry chromatography, eluting with 5-7.5% (2M NH3 MeOH)/CH2Cl2) yielded the title compound 9 as a yellow residue (70 mg, 53.3%). 1H NMR (DMSO-d6) δ 7.70 (d, 1H, J=2.7 Hz), 7.57 (d, 1H, J=5.0 Hz), 7.07 (dd, 1H, J=5.0, 3.7 Hz), 6.59 (d, 1H, J=8.2 Hz), 6.30 (brs, 2H), 6.14 (s, 1H), 6.00 (d, 1H, J=8.1 Hz), 4.18-4.02 (m, 2H), 3.41-3.25 (m, 4H+H2O), 2.41 (t, 2H, J=6.7 Hz), 2.17 (s, 6H); ESI-MS (m/z, %): 331 (MH+, 100).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[CH:43]=[C:44]([CH3:47])[CH:45]=[CH:46][C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cc1ccc(F)c(B(O)O)c1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@@H](F)CO3)c(N)s2)c1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-5-methylphenyl)boronic acid gave 274. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.90 (d, J=7.4 Hz, 1H), 7.82 (s, 1H), 7.41 (br, 2H), 7.24 (d, J=8.8 Hz, 2H), 5.09-4.68 (m, 2H), 4.22-3.97 (m, 2H), 3.74 (s, 3H), 2.36 (s, 3H), 2.23-2.12 (m, 1H), 1.88-1.73 (m, 2H), 1.68-1.63 (m, 3H). LCMS (ES+) m/z 463 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:24].[NH4+].[OH-]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:24])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1cc(OC)c(OC)cc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(OC)c(OC)cc3nc21
Temperature: 25 °C
Yield: 62 %

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-4,5-dimethoxy anthranilic acid (12.8 g, 44 mmol) and POCl3 (75 ml) is refluxed for 8 hours. The reaction mixture is cooled to room temperature, poured into ice water and neutralized with concentrated NH4OH. The mixture is extracted with CH2Cl2, and the CH2Cl2 layer is dried over MgSO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with CH2Cl2 /ether (9/1) to afford 8.0 g (62%) of 1-ethyl-4-chloro-6,7-dimethoxy-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([CH2:7][C:8]2([S:11]([O-])(=[O:13])=[O:12])[CH2:10][CH2:9]2)[CH2:4][O:3]1.[Na+].P(Cl)(Cl)([Cl:19])=O>>[CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([CH2:7][C:8]2([S:11]([Cl:19])(=[O:13])=[O:12])[CH2:10][CH2:9]2)[CH2:4][O:3]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)OC[C@@H](CC2(S(=O)(=O)[O-])CC2)O1
Agent: [Na+]
Product: CC1(C)OC[C@@H](CC2(S(=O)(=O)Cl)CC2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium (R)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropane-1-sulfonate (1 eq) and phosphoryl trichloride (POCl3, 0.7 mL/mmol) is heated at 80° C. for 1 hour. The reaction mixture is cooled to room temperature, poured onto ice, stirred for 30 minutes and extracted with chloroform (2×). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[CH:11]=[C:12]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]3[CH2:38][CH2:37][CH:36]([C:39]([F:42])([F:41])[F:40])[CH2:35][CH2:34]3)=[O:32])=[CH:27][CH:26]=2)[CH:13]=[C:14]([Cl:24])[C:15]=1[CH2:16][C@@H:17]1[CH2:21][CH:20](O)[O:19][C:18]1=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:24][C:14]1[CH:13]=[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([N:33]3[CH2:38][CH2:37][CH:36]([C:39]([F:42])([F:41])[F:40])[CH2:35][CH2:34]3)=[O:32])=[CH:29][CH:30]=2)[CH:11]=[C:10]([Cl:9])[C:15]=1[CH2:16][C@@H:17]1[CH2:21][CH2:20][N:1]([N:2]2[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]2)[C:18]1=[O:19]
Reactant: O=C1OC(O)C[C@H]1Cc1c(Cl)cc(-c2ccc(C(=O)N3CCC(C(F)(F)F)CC3)cc2)cc1Cl
Reactant: NN1CCC(O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
Dissolve 1-Amino-piperidin-4-ol (0.204 g, 1.1 eq.) in acetonitrile (3 mL) and heat the solution to 50° C. When the temperature reaches 35° C., add (R)-3-[3,5-Dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-5-hydroxy-dihydro-furan-2-one (0.829 g, 1 eq.) and continue heating to 50° C. for 1 hour. Allow the reaction to cool to room temperature and add sodium triacetoxyborohydride (0.508 g, 1.5 eq.). Allow the reaction to stir overnight at room temperature. Add water and extract with EtOAc. Remove the solvent and chromatograph the residue on silica gel to afford 200 mg of the titled compound. MS (m/z): 598 (M+1, 35Cl), 600 (M+1, 37Cl).