Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:19])([F:18])[F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([Br:21])[C:3]=1[NH2:22].C(N(CC)CC)C.[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[N:42]1[CH:46]=[N:45][CH:44]=[N:43]1)[C:36](O)=[O:37])([O-:32])=[O:31].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:17])([F:18])[F:19])[C:9]([F:14])([F:15])[C:10]([F:11])([F:13])[F:12])[CH:5]=[C:4]([Br:21])[C:3]=1[NH:22][C:36](=[O:37])[C:35]1[CH:39]=[CH:40][C:41]([N:42]2[CH:46]=[N:45][CH:44]=[N:43]2)=[C:33]([N+:30]([O-:32])=[O:31])[CH:34]=1
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br
Reactant: O=C(O)c1ccc(-n2cncn2)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br)c1ccc(-n2cncn2)c([N+](=O)[O-])c1
Yield: 65 %

Procedure:
To a suspension of 2,6-dibromo-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-phenylamine (Example I1) (635 mg, 1.35 mmol) in 1,2-dichloroethane (6.5 ml) was added triethylamine (0.57 ml, 4.06 mmol), followed by 3-nitro-4-(1H-1,2,4-triazol-1-yl)benzoic acid (634 mg, 2.7 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP—Cl”) (689 mg, 2.7 mmol). The reaction mixture was stirred at reflux for 16 hours. The progress of the reaction was followed by thin layer chromatography and, because it was necessary in this case, further doses of 3-nitro-4-(1H-1,2,4-triazol-1-yl)benzoic acid (4×0.675 mmol), bis(2-oxo-3-oxazolidinyl)phosphonic chloride (4×1.35 mmol) and triethylamine (4×1.35 mmol) were added over the course of 48 hours. The reaction was quenched by addition of aqueous hydrochloric acid (1M) and the phases were separated. The organic phase was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:2) to give Compound No. A4 of Table A (605 mg, 65% yield).
Reaction SMILES: [Cl:1][CH:2]([Cl:8])[CH:3]1[NH:7][CH2:6][CH2:5][O:4]1.C(N(CC)CC)C.[Cl:16][CH:17]([Cl:21])[C:18](Cl)=[O:19]>C(Cl)(Cl)Cl>[Cl:1][CH:2]([Cl:8])[CH:3]1[N:7]([C:18](=[O:19])[CH:17]([Cl:21])[Cl:16])[CH2:6][CH2:5][O:4]1
Reactant: ClC(Cl)C1NCCO1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(C(Cl)Cl)N1CCOC1C(Cl)Cl
Yield: 98.4 %

Procedure:
2nd part: By operating as in the second part of Example 13, but using 23.5 g (0.15 mole) of 2-dichloromethyl-1,3-oxazolidine, 18 g (0.18 mole) of triethylamine and 24.3 g (0.165 mole) of dichloroacetyl chloride in 200 ml of chloroform, after the removal of the chloroform by distillation under vacuum, 39.4 g (yield 98%) of crude 2-dichloromethyl-3-dichloroacetyl-1,3-oxazolidine is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1F
Reaction time: 16 h
Yield: 93 %

Procedure:
A mixture of 3-fluoro-4-nitrophenol (1.6 g, 10 mmol), 4-(2-chloroethyl)morpholine hydrochloride (1.9 g, 10 mmol), and potassium carbonate (5.5 g, 52 mmol) in acetone (50 mL) was heated to reflux with stirring for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was partitioned between water (100 mL) and ethyl acetate (100 mL), and the organic phase was washed with water (100 mL) and brine (100 mL), was dried (MgSO4), and evaporated, providing 2.6 g, in 93% yield; 1H NMR (DMSO-d6) δ 2.47 (t, 4H, J=4.6), 2.71 (t, J=5.6 Hz, 2H), 3.57 (t, J=4.6, 4H), 4.25 (t, J=5.6 Hz, 2H), 6.99 (dd, J=9.3 Hz, J=2.7 Hz, 1H), 7.19-7.24 (m, 1H), 8.14 (t, J=9.3 Hz, 1H).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([C:21]#[N:22])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([C:21]#[N:22])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 26b (0.8 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 100%).
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:17]Br>CCCCC>[C:1]([N:5]=[N:6][C:7]([Br:17])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=NNC(C)(C)C
Reactant: BrBr
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CC(C)(C)N=NC(C)(C)Br
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Into a solution of 25.6 grams (0.2 mole) of acetone t-butylhydrazone and 20.3 grams (0.2 mole) of triethylamine in 200 ml of pentane, cooled to 5° C in a 500 ml 4-neck round bottom flask equipped with a mechanical stirrer and thermometer, was added 31.9 grams (0.2 mole) of bromine from an addition funnel. After the addition was complete the reaction was stirred an additional 1/2 hour at 5° C, filtered to remove the triethylamine hydrobromide and the pentane evaporated from the filtrate under reduced pressure. The residue was an orange yellow liquid weighing 40 grams (96.6% crude yield). The infrared spectrum of the residue was in agreement with the structure of 2-t-butylazo-2-bromopropane.
Reaction SMILES: Cl[S:2]([C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:4])=[O:3].O.[NH3:18]>C1COCC1>[NH2:18][S:2]([C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:4])=[O:3]
Reactant: CCOC(=O)c1c(C)nn(C)c1S(=O)(=O)Cl
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nn(C)c1S(N)(=O)=O
Reaction time: 1 h

Procedure:
4.6 g of ethyl 5-chlorosulfonyl-1,3-dimethylpyrazole-4-carboxylate is dissolved in 8 ml of THF, and the solution is added dropwise to 25 ml of ammonia water at 5° C. to 7° C. The reaction mixture is stirred at the same temperature for 1 hour, and then concentrated to dryness under reduced pressure. To the residue is added ethyl acetate, followed by filtration to remove impurities, and the filtrate is concentrated under reduced pressure. The residue is diluted with n-hexane, and then cooled with ice to give crystals. The crystals are filtered and dried to yield 3.6 g of the title compound. mp. 112° to 113° C.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[C:11]1([CH2:20][C:19](=[O:21])[CH:18]([C:22](=[O:25])[CH2:23][CH3:24])[C:17](=[O:26])[CH2:16]1)[CH2:10][CH2:9]2.[C:27](Cl)(=[O:29])[CH3:28].Cl>ClCCCl.ClC(Cl)C>[C:27]([C:14]1[C:13]([CH3:15])=[C:12]2[C:8]([CH2:9][CH2:10][C:11]32[CH2:16][C:17](=[O:26])[CH:18]([C:22](=[O:25])[CH2:23][CH3:24])[C:19](=[O:21])[CH2:20]3)=[CH:7][C:6]=1[CH3:5])(=[O:29])[CH3:28]
Reactant: CCC(=O)C1C(=O)CC2(CCc3cc(C)cc(C)c32)CC1=O
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CCC(=O)C1C(=O)CC2(CCc3cc(C)c(C(C)=O)c(C)c32)CC1=O
Temperature: 20 °C
Reaction time: 12 h

Procedure:
To a stirred suspension of aluminium trichloride (4.8 g, 33 mmol) in 1,2-dichloroethane (80 ml) at 20° C. was added a solution of 5', 7'-dimethyl-4-propionylspiro[cyclohexane-1,1'-indan]-3,5-dione (3.2 g, 11 mmol) in dichloroethane (10 ml). A solution of acetyl chloride (1.0 g, 13 mmol) in dichloroethane (10 ml) was added and the mixture was stirred at 20° C. for 12 hours. The solution was poured onto cold dilute hydrochloric acid and then extracted with diethyl ether. The ether layer was separated, dried (MgSO4) and evaporated and the crude product was purified by passage through silica gel eluting with methylene chloride. A mixture of 4'-acetyl-5',7'-dimethyl-4-propionylspiro[cyclohexane-1,1'-indan]-3,5-dione and 6'-acetyl-5',7'-dimethyl-4-propionylspiro[cyclohexane-1,1'-indan]-3,5-dione was obtained as a colourless oil (1.0 g, 29%). Pmr spectrum (CDCl3, δ in ppm): 1.16 (3H, t); 1.9-3.3 (17H, complex m); 3.09 (2H, q); 6.84 (0.6H, s); 6.93 (0.4H, s); 18.26 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH:10]([CH3:23])[N:9]=1.[CH2:24]([N:27]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]1=2)[C:25]#[CH:26].C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[C:40](=[O:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]3=4)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH:10]([CH3:23])[N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2C
Reactant: C#CCn1c(=O)c2ccccc2c2ccccc21
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(C#CCn3c(=O)c4ccccc4c4ccccc43)cc1C(c1ccccc1Cl)=NC2C

Procedure:
This compound was prepared by reacting rac-4-(2-chloro-phenyl)-2-iodo-6,9-dimethyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3a][4,1]diazepine (from example 108) with 5-(2-propynyl)-6(5H) phenanthridinone under the conditions described in example 37. The product was isolated by chromatography over the 50 -fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The product was crystallized from ethanol to give yellowish crystals of the title compound with mp, 182°-186° with foaming. These crystals contained according to analytical data molar amounts of water.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]([CH3:18])[C:9]([C:11]2[C:16]([CH3:17])=[N:15][CH:14]=[CH:13][N:12]=2)=[O:10])[N:6]=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.C1COCC1>[C:23]1([O:22][C:20](=[O:21])[NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][N:8]([CH3:18])[C:9]([C:11]3[C:16]([CH3:17])=[N:15][CH:14]=[CH:13][N:12]=3)=[O:10])[N:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1nccnc1C(=O)N(C)Cc1csc(N)n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1nccnc1C(=O)N(C)Cc1csc(NC(=O)Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
A mixture of N-((2-aminothiazol-4-yl)methyl)-N,3-dimethylpyrazine-2-carboxamide (555 mg, 1.84 mmol) and DMAP (20 mg) in pyridine (10 mL) was cooled to 0° C. and a solution of phenyl chloroformate (433 mg, 2.8 mmol) in THF was added drop wise. The mixture was stirred overnight and all volatiles were removed in vacuo at 30° C. The residue was triturated with TBME to afford (4-{[Methyl-(3-methyl-pyrazine-2-carbonyl)-amino]-methyl}-thiazol-2-yl)-carbamic acid phenyl ester (125 mg) as a tan colored solid (purity 96%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([C:20]([NH2:22])=[O:21])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>[Pd].CO>[CH2:1]([O:3][P:4]([CH2:9][C@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C@@H:12]([C:20]([NH2:22])=[O:21])[CH2:11]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1cc(C(N)=O)nc2ccccc12)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(C[C@@H]1C[C@H](C(N)=O)Nc2ccccc21)OCC
Reaction time: 24 h

Procedure:
A mixture of 500 mg of 4-(diethylphosphonomethyl)- quinoline-2-carboxamide and 1 g of 10% palladium on charcoal in 75 ml of methanol is hydrogenated at 3 atmospheres pressure for 24 hours, filtered and evaporated to dryness. Chromatography on silica gel using methanol/methylene chloride (1:10) as eluent yields cis-4-(diethylphosphonomethyl)-1,2,3,4-tetrahydroquinoline-2-carboxamide.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([NH:27][CH:28]1[C:54](=[O:55])[N:30]2[C:31]([C:51]([OH:53])=[O:52])=[C:32]([CH2:35][S:36][C:37]3[CH:38]=[CH:39][C:40]4[N:41]([C:43](=[O:50])[N:44]([CH2:46][C:47]([OH:49])=[O:48])[N:45]=4)[N:42]=3)[CH2:33][S:34][C@H:29]12)=[O:26])C)=O)CCC>CCOCC>[CH3:13][NH:15][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([NH:27][CH:28]1[C:54](=[O:55])[N:30]2[C:31]([C:51]([OH:53])=[O:52])=[C:32]([CH2:35][S:36][C:37]3[CH:38]=[CH:39][C:40]4[N:41]([C:43](=[O:50])[N:44]([CH2:46][C:47]([OH:49])=[O:48])[N:45]=4)[N:42]=3)[CH2:33][S:34][C@H:29]12)=[O:26]
Reactant: CCCCOC(=O)N(C)Cc1ccccc1CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3ccc4nn(CC(=O)O)c(=O)n4n3)CS[C@H]12
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccccc1CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3ccc4nn(CC(=O)O)c(=O)n4n3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Trifluoroacetic acid (7 ml.) was added to the t-BOC-derivative 7b (3.8 g., 5.5 m.mole) at 0° C., and the mixture was stirred for 20 minutes at room temperature. Dry ether (100 ml.) was added to the mixture. The resulting precipitate was collected by filtration and washed with dry ether (3×100 ml.). The precipitate was dissolved in a mixture of CH3CN (120 ml.) and water (18 ml.) and the solution was adjusted to pH 5-6 with concentrated NH4OH to give an oily precipitate which was triturated with CH3CN to form solid material. The product 8b was collected by filtration, washed with CH3CN and dried. Yield 2.55 g. (77%).
Reaction SMILES: Br[CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>CO>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[C:7]3=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]3[CH:5]([CH3:16])[CH2:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CC1CCC(Br)c2ncc(C(=O)O)c(=O)n21
Reactant: Nc1ccc(Br)cc1
Solvent: CO
Product: CC1CC=C(Nc2ccc(Br)cc2)c2ncc(C(=O)O)c(=O)n21
Temperature: 25 °C
Yield: 64.6 %

Procedure:
2.0 g. (6.97 mmoles) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 1.72 g. of p-bromo-aniline are added to 20 cm3 methanol. The mixture is heated under stirring until a solution is obtained. The solution is cooled to room temperature and stirred for 2-3 days. The precipitated crystals are filtered and washed with methanol. 1.7 g. (64.6%) of 9-[(4-bromo-phenyl)-amino]-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is obtained which melts at 202°-204° C. after recrystallization from methanol.
Reaction SMILES: Cl[N:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[C:3]1([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][N:2]=1
Reactant: ClN1C=Cc2ccccc2C1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Product: c1ccc2c(N3CCNCC3)nccc2c1
Temperature: 0 °C
Yield: 105.6 %

Procedure:
A solution of 2-chloroisoquinoline (5 g) in 20 mL of toluene is added dropwise to a refluxing solution of piperazine (20 g) in 150 mL of toluene. The solution is heated for an additional 48 h. After cooling to 0° C. for 0.5 h, the solution is filtered. The filtrate is then extracted with 10% acetic acid. The aqueous extracts are washed with ether, basified and subsequently extracted with dichloromethane. The dichloromethane layer is finally washed with water, dried and concentrated. The material is placed under vacuum overnight to yield the title compound (6.8 g, m.p. 54-56° C.). 1H NMR (CDCl3) 8.14 (d, J=5.5 Hz, 1 H), 8.10 (d, J=8.5 Hz, 1 H), 7.74 (d, J=8.5 Hz, 1 H), 7.60 (t, J=7.2 Hz, 1 H), 7.50 (t, J=7.6 Hz, 1 H), 7.24 (d, J=5.5 Hz, 1 H), 3.39 (t, J=5.0Hz, 4 H), 3.16 (t, J=5.0Hz, 4 H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][CH3:14]>CCO>[CH3:14][NH:13][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1cccc2ccc(Cl)nc12
Reactant: CN
Solvent: CCO
Product: CNc1ccc2cccc(O)c2n1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-8-hydroxyquinoline* (2.0 g, 11.1 mmol) in EtOH (40 mL) was added H2NMe (40% aqueous solution, 40 mL, 464 mmol). The mixture was heated in a sealed Pyrex tube at 100° C. for 24 h. The solvent was evaporated and the resulting crude product was purified by column chromatography [gradient: CH2Cl2/MeOH (99:1) to 1% NH4OH in CH2Cl2/MeOH (80:20)] to give the title compound as a black-green solid. Yield 1.31 g (67%); MS m/z 174 (M)+. Anal. (C10H10N2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2C(OC)=O)=[CH:4][CH:3]=1>Br>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(Cl)cc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3ccc(Cl)cc3)C2)o[nH]1
Yield: 71.2 %

Procedure:
(2R,4S)-Methyl 2-(4-chlorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (253 mg, 0.72 mmol) was stirred in HBr (33% in AcOH) overnight (24 hours). Evaporation of solvents and the residue was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 5% to 45% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. 5-((2R,4S)-2-(4-chlorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (150 mg, 71%) was isolated. 1H NMR (400 MHz, cd3od) δ 1.37-1.50 (m, 1H), 1.61-1.77 (m, 1H), 2.01-2.13 (m, 2H), 2.78-2.98 (m, 4H), 3.18-3.28 (m, 1H), 3.28-3.36 (m, 1H), 5.51 (s, 1H), 7.24 (d, 2H), 7.34 (d, 2H). HRMS Calcd for [C15H17ClN2O2+H]+: 293.1057. Found: 293.1043.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]([N:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:1][CH2:2][CH2:3][CH:4]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:5][C:6]([N:8]([CH3:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)CC(CCO)c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccccc1)c1ccccc1
Yield: 100.3 %

Procedure:
Beta-(2-hydroxyethyl)-N-methyl-N-phenylbenzenepropanamide (5.0 g) in CH2Cl2 (100 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (2.23 g), and methanesulfonyl chloride (2.53 g). After two hours the reaction mixture was washed with water(3×50 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (6.4 g).
Reaction SMILES: [C:1]([C:4]1[CH:44]=[CH:43][C:7]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:45][Mg]Br.Cl>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)=[CH:43][CH:44]=1)([CH3:45])[CH3:2]
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(C(C)=O)cc3)CC2)c2ncnn12
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(C(C)(C)O)cc3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4′-({4-[trans-4-(4-Acetylphenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.27 g) was dissolved in tetrahydrofuran (1 mL), methylmagnesium bromide (1.4 mL, 1.0 M tetrahydrofuran solution) was added dropwise, and the mixture was stirred at room temperature for 16 hr. Methylmagnesium bromide (0.11 mL, 1.0 M tetrahydrofuran solution) was further added dropwise, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[C:23]([C:25](=[O:30])[NH:26][CH2:27][CH2:28][OH:29])[CH:22]=[CH:21][C:20]=4[Cl:31])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:32]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([O:29][CH2:28][CH2:27][NH:26][C:25](=[O:30])[C:23]1[CH:22]=[CH:21][C:20]([Cl:31])=[C:19]([N:17]([CH3:18])[C:15]([C:13]2[S:12][C:11]3[C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:32][C:6]=4[O:7][CH2:8][CH2:9][C:10]=3[CH:14]=2)=[O:16])[CH:24]=1)(=[O:35])[CH3:34]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)NCCO)ccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCNC(=O)c1ccc(Cl)c(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Temperature: 0 °C
Yield: 83.5 %

Procedure:
8-Bromo-N-(2-chloro-5-(2-hydroxyethylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (0.5 g, 0.933 mmol) was dissolved in 5 mL of pyridine. The mixture was stirred at 0° C. and acetic anhydride (0.2 g, 2 eq) was added dropwise. It was stirred at room temperature for overnight. The mixture was poured into ice water and the mixture was extracted by DCM. The combined organics were dried and evaporated in vacuum to afford the acetylated product, 2-(3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzamido)ethyl acetate (0.45 g, yield: 83%). LC-MS: (ESI, m/z)=577 [M+H]+
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]>C1COCC1.O.C1COCC1>[OH:4][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
A solution of NaBH4 (0.53 g, 14 mmol) in THF/H2O (4:1) (12 mL) was added dropwise to an ice-cold stirred solution of 4-formylcinnamic acid (2.47 g, 14 mmol) in THF (25 mL), and the mixture was stirred at room temperature for 3 h. The reaction was quenched by adding 4 N HCl (20 mL), and the THF was removed by a rotary evaporator. The solid residue was treated with H2O (20 mL), and extracted with EtOAc (4×50 mL). The EtOAc extracts were washed with H2O (50 mL) and brine (50 mL), and dried. The crude product was recrystallized from EtOAc to afford pure 4-hydroxymethylcinnamic acid 124 (1.3 g, 52% yield) as yellow solid, with its identity verified by 1H NMR (300 MHz, CD3OD).