Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](O)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O=S(Cl)[Cl:15]>>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8]([Cl:15])=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Product: CC(=O)N1CCC(C(=O)Cl)CC1
Yield: 97 %

Procedure:
N-acetylisonipecotic acid (0.67 g, 3.9 mmol) was added to SOCl2 (4.1 mL). The acid chloride precipitated from solution and petrol (60 mL) was added. The mixture was filtered and the residue was washed several times with petrol to afford the title compound as a white solid (0.716 g, 97%). m.p. 133-138° C. 1H NMR (DMSO): 1.2-1.5 (m, 2H), 1.65-2.0 (m, 2H), 1.94 (s, 3H), 2.3-2.5 (m, 1H), 2.639 (t, J=11.4Hz, 1H), 3.036 (t, J=11.4Hz, 1H), 3.692 (d, J=13.2Hz, 1H), 4.144 (d, J=13.2Hz, 1H). IR (KBr): 1789, 1745, 1660 (cm−1). MS (m/z): 189, 126, 146, 84.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35]>CN(C=O)C.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)c(OC)c1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1ccc(CN2C(=O)CC[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
80 g (250 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E) was added in portions over 20 minutes to a mixture of NaH (19.98 g, 500 mmol) in anhydrous DMF (400 mL) at 0° C. under nitrogen. After the addition was complete the ice bath was removed and the mixture was stirred at rt for 1 hour before cooling the solution to 0° C. To the cooled solution was added a solution of 1-(chloromethyl)-2,4-dimethoxybenzene (107 g, 575 mmol) in benzene and the reaction mixture was allowed to warm to rt. After 16 hours the reaction mixture was poured into ice water (2 L) and extracted with EtOAc (3×1 L). The organics were pooled, washed with water (3×1 L), sat. aq. NaCl solution (1 L), dried (MgSO4), filtered and concentrated in vacuo to provide a thick yellow oil. Purification on the Combiflash XL (flash column chromatography, Teledyne Isco, Lincoln, Nebr.) using four stacked 330 g columns and one 1.5 kg column and eluting with 35-40-45-50-55% EtOAc/hexanes provided a very pale yellow oil. This was dissolved in benzene and the solvent removed in vacuo and dried under vacuum for 2 days to provide the title compound as a white foam (105.8 g, 90%).
Reaction SMILES: [SH:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10](S(O)(=O)=O)=[CH:9][CH:8]=1>>[CH2:17]([O:4][C:3](=[O:5])[CH:2]([SH:1])[CH3:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(S)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(S)C(=O)OCc1ccccc1

Procedure:
Into a 100 ml reaction flask equipped with thermometer, reflux condenser, hot plate (equipped with magnetic stirring apparatus) and spin bar are placed 21.6 grams benzyl alchol; 29.6 grams of 2-mercaptopropionic acid; and 0.5 grams of para-toluene sulphonic acid.
Reaction SMILES: S([O-])([O-])(=O)=O.[Ca+2].[C:7](Cl)(=[O:10])[CH:8]=[CH2:9].[CH2:12]([NH2:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>ClCCl>[CH2:12]([NH:20][C:7](=[O:10])[CH:8]=[CH2:9])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCN
Reactant: C=CC(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NCCCCCCCC
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 92.7 %

Procedure:
A 500 ml four-necked flask equipped with a thermometer, mechanical stirrer, calcium sulfate-filled drying tube, and pressure-equalizing addition funnel is charged with a solution of 45.3 g of acryloyl chloride (0.5 mole) in 180 g of dichloromethane. The solution is cooled to 0° C. and to it is then slowly added a mixture of 66.6 g of n-octylamine (0.5 mole), 50.6 g of triethylamine (0.5 mole), and 125 g of dichloromethane, over a period of 2.5 hrs., at such a rate that the temperature does not exceed 5° C. Upon completion of the addition, the mixture is allowed to warm gradually to ambient temperature. The product is then stored at -15° C. overnight to complete crystallization of the byproduct triethylamine hydrochloride. After removal of the salt by filtration, the filtrate is washed successfully with 250 g of deionized water. The product is then dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to afford 85 g of N-(n-octyl)acrylamide, bp. 119°-120° (3 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.Cl.[CH3:43][NH:44][CH3:45]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([N:44]([CH3:45])[CH3:43])[N:4]=1
Reactant: CNC
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1nc(N(C)C)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
A solution of Example C2 (0.13 g, 0.309 mmol) in DCM (5 mL) was treated portion-wise with mCPBA (0.09 g, 0.37 mmol), stirred at RT overnight, treated with TEA (0.5 mL) and N,N-dimethylamine HCl salt (500 mg) and stirred at RT for 2 h. The mixture was treated with satd. NaHCO3, extracted with DCM (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain 4-methoxy-N,N-dimethyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (60 mg, 47%). MS (ESI) m/z: 418.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:19](=[O:20])[CH2:18][Cl:17]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(C)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)CCl
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a 3-necked, 1-liter flask provided with a reflux condenser, an additional funnel and a magnetic stirring bar was charged 36.3 grams (0.3 mole) of 2,6-dimethyl aniline and 30.36 grams (0.3 mole) of triethylamine in 550 milliliters of methylene chloride. To the stirred solution, maintained at 0° to 5° C. by means of an ice bath, was added dropwise, over a period of 30 minutes, 33.9 grams (0.3 mole) of chloroacetyl chloride. The reaction mixture was then stirred at ambient temperature for 21 hours after which it was transferred to a separatory funnel and washed consecutively with 300 milliliter portions of 1 Normal hydrochloride acid, 10 percent aqueous sodium carbonate solution and water. The organic layer was removed, dried over magnesium sulfate and concentrated on a rotary evaporator at 55° C. leaving a bluish-gray solid. This solid was recrystallized from a hot 20:80 volume/volume ethylacetate-ligroin solution yielding 41 grams of gray, solid N-(2,6-dimethylphenyl)-α-chloroacetamide.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(Cl)Cl.[NH2:13][CH2:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][CH:16]=1.[BH4-].[Na+]>CC(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:13][CH2:14][C:15]2[CH:29]=[CH:28][C:18]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCc1ccc(CNCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 4-fluorobenzaldehyde (496 mg, 4.00 mmol) in a mixed solvent of CH2Cl2 (10 mL) and 2-propanol (2 mL) at rt was added tert-butyl 4-(aminomethyl)benzylcarbamate (945 mg, 4.00 mmol, Aldrich). The reaction mixture was stirred at rt overnight. The next morning, sodium borohydride (296 mg, 8.0 mmol) was added, and the mixture was stirred at rt for 2 h. The reaction mixture was quenched by adding 3 mL of MeOH and 3 mL of saturated aq NaHCO3. The mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were dried, concentrated and purified by flash column chromatography on silica gel eluting with CH2Cl2/EtOAc to give the title compound (0.69 g, 48%) as a viscous material. MS (ESI): 345.1 (M+H)+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:22])=O)=[CH:16][CH:15]=1.[C:23]1([C@@H:29]([NH2:31])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:23]1([C:29](=[N:31][C@H:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH3:22])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: C[C@H](N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=N[C@@H](C)c1ccc(C)cc1)c1ccccc1
Yield: 89 %

Procedure:
At first, 0.24 g (1.25 mmol) of p-toluenesulfonic acid monohydrate were added to a toluene solution (25 ml) containing 8.35 g (25 mmol) of 4-methylacetophenone (3c) as a ketone and 3.03 g (25 mmol) of (S)-1-phenylethylamine ((S)-2a) as an optically active primary amine, followed by heating under reflux for 24 hr and by removing water (formed as a by-product) with a Dean-Stark tube during the reaction, in order to conduct the reaction. Then, the reaction liquid after the reaction was washed with a saturated sodium hydrogencarbonate aqueous solution, followed by drying with sodium sulfate anhydride, then filtration, then concentration, and then vacuum drying, thereby obtaining as a crude product 5.66 g of (S)-N-(1-phenylethylidene)-1-(4-methylphenyl)-ethylamine ((S)-3ca, yield: 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[CH2:9]([N:4]1[CH:5]=[CH:6][C:2]([CH3:1])=[N:3]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccn(Cc2ccccc2)n1
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of 3-methyl-1H-pyrazole (5.00 g, 60.9 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (60%) (4.88 g, 203 mmol) in portions at 0° C. and stirred for 30 min under nitrogen. To the above mixture was added benzyl bromide (8.7 mL, 73.1 mmol). The reaction mixture was stirred for 1 h at room temperature, then carefully quenched with 150 mL of water. The aqueous phase was extracted with 3×30 mL of EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 5.66 g (54%) of the title compound as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27].C[O-].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([S:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Reactant: COc1ccccc1S
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1Sc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Reaction time: 18 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.03 g) was added to a deoxygenated mixture of (R)-N-[2-chloro-4-iodophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 20) (0.2 g), 2-methoxybenzenethiol (0.064 ml) and sodium methoxide (0.058 g) in ethanol (10 ml). The mixture was further deoxygenated by evacuation and refilling with argon (3 cycles) then heated under reflux with stirring under argon for 18 hours, treated with a further portion of tetrakis(triphenylphosphine)palladium(0) (0.03 g), heated a further 24 hours then cooled and filtered. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-10% ethyl acetate/hexane to give the title compound (0.166 g) as an oil. NMR (CDCl3): 1.75 (s, 3H), 3.7 (br s, 1H), 3.85 (s, 3H), 6.9 (m, 2H), 7.2 (m, 1H), 7.3 (dd, 1H), 7.35 (m, 2H), 8.3 (d, 1H), 9.8 (br s, 1H); MS: 404 (M−H)−.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[F:21][C:22]([F:30])([F:29])[CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH2:17][N:25]3[CH2:26][CH2:27][CH2:28][CH:23]([C:22]([F:30])([F:29])[F:21])[CH2:24]3)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: FC(F)(F)C1CCCNC1
Product: CCCCN1CCN(C(=O)c2ccc(CN3CCCC(C(F)(F)F)C3)cc2)CC1

Procedure:
Prepared from the product of Example 13 and 3-trifluoromethylpiperidine.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C:6]1[C:7]([CH3:16])=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[O:10][CH2:9]2)[O:4][CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>C(Cl)Cl>[CH3:5][O:4][C@H:3]([C:6]1[C:7]([CH3:16])=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[O:10][CH2:9]2)[CH:2]=[O:1]
Reactant: CO[C@@H](CO)c1ccc2c(c1C)COC2=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CO[C@@H](C=O)c1ccc2c(c1C)COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-5-(2-Hydroxy-1-methoxyethyl)-4-methylisobenzofuran-1(3H)-one (500 mg, 2.25 mmol) was dissolved in DCM (10 mL) and treated with Dess-Martin periodinane (954 mg, 2.25 mmol). The reaction mixture was stirred at room temperature under nitrogen overnight. The crude product was used directly. LC-MS (IE, m/z): 239.2 (M+H2O+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[CH:4][C:3]=1[C:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH:21]=1>CO.C(OCC)(=O)C.[Pt](=O)=O>[NH2:8][C:7]1[CH:6]=[C:5]([NH:11][C:12](=[O:15])[O:13][CH3:14])[CH:4]=[C:3]([CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[C:2]=1[Cl:1]
Reactant: COC(=O)Nc1cc(C2=CCN(C)CC2)c(Cl)c([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Nc1cc(N)c(Cl)c(C2CCN(C)CC2)c1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
A mixture of methyl (4-chloro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitrophenyl)carbamate (213 mg, 0.654 mmol) and platinum (IV) oxide (240 mg, 0.654 mmol) in a mixture of MeOH (50 mL) and ethyl acetate (3 mL) was hydrogenated (balloon of H2). The reaction completed within 1 h. The catalyst was removed by filtration through a celite pad and the pad was rinsed with MeOH. The solvent was removed and radial silica gel chromatography, eluting with DCM containing 0 to 3% MeOH gave methyl (3-amino-4-chloro-5-(1-methylpiperidin-4-yl)phenyl)carbamate (131 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:18]([NH:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1)=[O:19]>CS(C)=O>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][C@H:17]([C:18](=[O:19])[NH:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1nnn[nH]1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccccc1)C(=O)Nc1nnn[nH]1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-phenyl-N-(1H-tetrazol-5-yl)-propionamide (prepared by reaction of N-Boc-L-phenylalanine with isobutyl chloroformate followed by 5-amino-1H-tetrazole) in DMSO to provide the title compound in moderate yield.
Reaction SMILES: [Br:1]NC(=O)CCC(N)=O.[N+:10]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1)([O-:12])=[O:11]>O1CCCC1>[Br:1][C:17]1[C:16]2[C:20](=[CH:21][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=2)[NH:19][CH:18]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(Br)c[nH]c2c1
Reaction time: 18 h
Yield: 86 %

Procedure:
Add N-bromosuccinamide (NBS) to 6-nitroindole 1 (22.72 g, 140.12 mmol) dissolved in tetrahydrofuran (600 mL) and allow the resulting mixture to stir for 18 hours. Quench the reaction mixture with saturated aqueous sodium thiosulfate solution (600 mL), dilute with ethyl acetate (EtOAc) (600 mL), and separate the layers. Sequentially, wash the organic layer with saturated aqueous sodium bisulfate (100 mL), saturated aqueous sodium bicarbonate (100 mL), water (100 mL), and brine (100 mL). Dry the resulting organic layer over Na2SO4 and filter. Concentrate the filtrate to give a yellow solid. Recrystallize the solid from dichloromethane and hexane to give 29.21 g of the title compound (86%). LRMS (API ES+)=263.0 (M+Na).
Reaction SMILES: [CH:1]([N:4]1[C:8]([SH:9])=[N:7][C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:5]1)([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH2:25]Cl)[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:27])[CH2:25][S:9][C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)n1nc(-c2ccncc2)nc1S
Reactant: O=C(CCl)Nc1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1nc(-c2ccncc2)nc1SCC(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of the thiol TFA salt from Step A (100 mg, 0.30 mmol), N-(3-Chlorophenyl)-2-chloroacetamide (61 mg, 0.30 mmol), and triethylamine (0.145 mL 1.040 mmol) in dichloromethane (2.0 mL) was stirred at room temperature for 6 h. The solvent was removed by evaporation, and the crude product was purified by HPLC to afford the title compound as a colorless solid, 127 mg (85%). MS (ES): 388 (M+H)+
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]=[O:21]>CN(C=O)C>[C:15]([C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:20](=[O:21])[NH:19][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)#[N:16]
Reactant: N#Cc1ccc(CNOCc2ccccc2)cc1
Reactant: CCOC(=O)CN=C=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)N(Cc1ccc(C#N)cc1)OCc1ccccc1
Temperature: 50 °C

Procedure:
2.73 g (11 mmol) of 4-(benzyloxyaminomethyl)benzonitrile are dissolved in 75 ml of DMF and added dropwise at 0° C. to a solution of 1.48 g of ethyl isocyanatoacetate in 75 ml of DMF. The mixture is heated at 50° C. for 3 d, then concentrated in vacuo. The residue is taken up in ethyl acetate and the solution is washed with water. The organic phase is dried (MgSO4) and concentrated in vacuo. The residue is dissolved in a little ethyl acetate and precipitated with ether/petroleum ether. The precipitate produced is reacted without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[Cl:1][CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=Cc1cc(CCl)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=Cc1cc(CCl)cc([N+](=O)[O-])c1O
Temperature: 30 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
1.79 g. (0.01 mole) of 5-chloromethylsalicylaldehyde, prepared according to Angyal, S. J. et al., J. Chem. Soc. 1950, 2145, was dissolved in 20 ml. of glacial acetic acid. To this solution there was added a solution of 0.63 g. fuming nitric acid in 10 ml. glacial acetic acid over 30 minutes, keeping the mixture at 30° C., followed by stirring at 30° C. for 2 hours. The solution was then poured over ice to give a precipitate which was crystallized from methylene chloride giving the title product. Another crop was obtained by extraction of the aqueoue phase, drying with anhydrous sodium sulfate, evaporation and crystallization from methylene chloride. Total yield: 53%.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[F:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31](O)=[O:32])[CH:26]=[C:27]([F:29])[CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:32])[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC(C)c1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Product: CC(C)c1ccc(-c2nn(NC(=O)Cc3cc(F)cc(F)c3)c(=O)c3ccccc23)cc1

Procedure:
The product of Example 168A and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.70-11.81 (m, 1H), 8.40-8.42 (m, 1H), 7.89-8.03 (m, 2H), 7.75-7.78 (m, 1H), 7.51-7.53 (m, 2H), 7.43-7.46 (m, 2H), 7.07-7.22 (m, 3H), 3.77 (s, 2H), 2.94-3.07 (m, 1H), 1.27 (d, J=6.9 Hz, 6H); MS (APCI+) M/Z 434 (M+H)+.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:38])[C@@H:16]([NH:21][C:22](=[O:37])/[CH:23]=[CH:24]/[C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[N:32]2[CH:36]=[N:35][N:34]=[N:33]2)[CH2:17][C:18](O)=[O:19])=[CH:10][CH:9]=1)=[O:7])(C)(C)C.O.[OH-].[Li+].Cl.[CH2:43]1[CH2:47]OCC1>O>[Cl:31][C:29]1[CH:28]=[CH:27][C:26]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[C:25](/[CH:24]=[CH:23]/[C:22]([NH:21][C@@H:16]([CH2:17][C:18]([N:21]2[CH2:43][CH2:47][N:14]([CH3:11])[CH2:15][CH2:16]2)=[O:19])[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]([OH:5])=[O:7])=[CH:9][CH:10]=2)=[O:38])=[O:37])[CH:30]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@H](CC(=O)O)NC(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CN1CCN(C(=O)C[C@H](NC(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)C(=O)Nc2ccc(C(=O)O)cc2)CC1
Reaction time: 1 h

Procedure:
(S,E)-4-(4-(tert-butoxycarbonyl)phenylamino)-3-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamido)-4-oxobutanoic acid: To a solution of 17A (1.8 g, 3.24 mmol) in THF (16 mL) was added lithium hydroxide monohydrate (0.30 g, 7.14 mmol) in H2O (16 mL). After 1 h, the reaction mixture was acidified to pH 5-6 with 1.0M HCl and extracted with EtOAc (3×40 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to afford the desired product as an off-white solid. LCMS m/z 541 [M+H]+.