Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:19][NH2:20].O>C(O)C>[CH2:1]([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH:19][NH2:20])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C(=O)OC)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCCCCOc1ccc(C(=O)NN)cc1
Yield: 98 %

Procedure:
A solution of Methyl 4-n-hexyloxybenzoate (2.00 g) and hydrazine hydrate (4.24 g) in ethanol (10 ml) was refluxed for 6 hours. After cooling, the reaction mixture was poured into water. The precipitate was collected by filtration, washed with water and dried over P2O5 under reduced pressure to give N-(4-n-hexyloxybenzoyl)hydrazine (1.96 g).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20]I>C1COCC1>[CH3:20][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][C:11]1=[O:19]
Reactant: CI
Reactant: O=C1CC(c2ccccc2)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)CC(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (1.2 eq., 0.537 g of 60% dispersion in mineral oil) in THF (50 mL) under N2 at 0° C. was added the product from Step A (1.0 eq., 2.50 g) in THF (50 mL) via cannula over a period of 5 minutes. The resulting pale yellow mixture was stirred at 0° C. for 10 minutes, then MeI (2.0 eq., 1.39 mL) was added. The opaque yellow mixture was allowed to slowly (ice bath not removed) warm to ambient temperature with stirring for 15 hours. 1 M Aq. HCl (50 mL) and EtOAc (250 mL) were added and the phases partitioned. The organic phase was washed with dilute NaHCO3 (1×100 mL), brine (1×100 mL), then dried over MgSO4, filtered, concentrated, and the residue purified by flash chromatography eluting with CH2Cl2/EtOAc (19:1 gradient to 15:1) to provide 1-methyl-4-phenyl-3,4-dihydrocarbostyril.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][NH:8][C@@H:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C@@H:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:21]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)[C@@H](NCc1ccc(OC)cc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)[C@H](c1ccccc1)N(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of (S)-methyl 2-((4-methoxybenzyl)amino)-2-phenylacetate (1.6 g, 5.61 mmol) in anhydrous dichloroethane (20 mL) was added 4-methoxy benzaldehyde (0.76 g, 5.61 mmol) and few drops of HOAc. After 30 min, the reaction mixture was cooled to 0° C., sodium triacetoxy borohydride (2.38 g, 11.22 mmol) was added and the contents were allowed to stir at ambient temperature. After 2 h, the reaction was quenched with ice cold H2O (10 mL), and the organic contents were extracted with CH2Cl2 (2×25 mL). The combined organic extracts were washed with brine (1×20 mL), dried over Na2SO4, concentrated and the residue thus obtained was purified by flash column chromatography to afford (S)-methyl 2-(bis(4-methoxybenzyl)amino)-2-phenylacetate as pale yellow liquid (1.5 g, 66%). MS: [M+H]+ m/z 406.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:18]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][C@@H:20]([CH3:24])[CH2:19]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][CH:10]=2)[CH:7]=1.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C@@:18]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][C@@H:20]([CH3:24])[CH2:19]2)[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12](/[C:15](=[N:28]/[OH:29])/[CH3:16])=[CH:11][CH:10]=2)[CH:7]=1
Reactant: NO
Reactant: CO[C@]1(c2cc(F)cc(Sc3ccc(C(C)=O)cc3)c2)CCO[C@@H](C)C1
Agent: Cl
Product: CO[C@]1(c2cc(F)cc(Sc3ccc(/C(C)=N/O)cc3)c2)CCO[C@@H](C)C1
Yield: 66 %

Procedure:
Using an analogous procedure to that described in Example 25, 4'-{5-fluoro-3-[(2S,4R)-4-methoxy-2-methyltetrahydropyran-4-yl]phenylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{5-fluoro-3-[(2S,4R)-4-methoxy-2-methyltetrahydropyran-4-yl]phenylthio}acetophenone oxime in 66% yield, m.p. 105° C.;
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=1)=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Product: COC(=O)c1c(CNC(=O)c2ccc(F)cc2)c(=O)c2ccc(OC)cc2n1-c1ccccc1

Procedure:
3-[(4-Fluoro-benzoylamino)-methyl]-7-methoxy-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was prepared starting from intermediate K and 4-fluorobenzoyl chloride. MS calcd. for C26H21FN2O5 [(M+H)+] 461.1, obsd. 460.9.
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[CH2:4][CH:5]([OH:33])[CH2:6][N:7]1[C:19]2[C:18]3[NH:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]=3[C:16]3[C:27](=[O:32])N(C)[C:29](=[O:30])[C:15]=3[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:2].Cl.[OH-:37].[K+]>>[CH2:34]([N:3]([CH2:1][CH3:2])[CH2:4][CH:5]([OH:33])[CH2:6][N:7]1[C:19]2[C:18]3[NH:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]=3[C:16]3[C:27](=[O:37])[O:32][C:29](=[O:30])[C:15]=3[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:35]
Reactant: CCN(CC)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5[nH]c4c21)C(=O)N(C)C3=O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: CCN(CC)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5[nH]c4c21)C(=O)OC3=O

Procedure:
The starting material is prepared in the following manner: 440 mg (0.94 mmol) (±)-12-(3-diethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole are heated under reflux for 1.5 hours in 100 ml 10% methanolic potassium hydroxide solution. After cooling the reaction mixture is acidified with semi-concentrated hydrochloric acid, filtered and the filtrate evaporated. The residue is taken up in 10% potassium carbonate solution and ethyl acetate and the organic phase is washed with water and dried over anhydrous sodium sulphate. It is filtered, evaporated and the residue is stirred with 25 ml diisopropyl ether and the crystals formed are filtered off. (±)-12-(3-Diethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-5,7-dioxoindolo-[2,3-a]furano[3,4-c]carbazole is obtained in the form of yellow crystals which decompose from about 200° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][N:5]2[C:9]([CH:10]=1)=[C:8]([C:11]([OH:13])=O)[C:7]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[CH3:22])=[C:6]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:11]([C:8]2[C:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=3[CH3:22])=[C:6]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:5]3[C:9]=2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4]3)=[O:13])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(F)cccc1Cc1c(C(=O)O)c2cc(Br)ccn2c1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1c(F)cccc1Cc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2cc(Br)ccn2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of the crude compound obtained in step 2 (219 mg, 0.50 mmol), 1-tert-butoxycarbonyl-piperazine (98 mg, 0.55 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol) and 1-hydroxybenzotriazole (88 mg, 0.58 mmol) in DMF (5 ml) was added N-methyl-morpholine (330 μl, 3.00 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (HEP/EA). 300 mg of the title compound were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]=2)=[CH:3][CH:2]=1.[H][H].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C.O=[Pt]=O>[NH:15]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]=[C:9]1[CH2:8][CH2:7][CH:4]1[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]1
Reactant: c1cc(CCC2=NCCCCN2)ccn1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: C1CCNC(CCC2CCNCC2)=NC1
Yield: 76.7 %

Procedure:
The 4,5,6,7-tetrahydro-2[2-(4-pyridyl)ethyl]-1H-1,3-diazepine (1.9 g, 0.009 M) and PtO2 (0.25 g) in ethanol (20 ml) and 2 NHCl (15 ml) was reduced at 45 psig of hydrogen. After the hydrogenation, the solvent was removed and the residue was crystallized from ethanol-ether to give 1.5 g of 4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]piperidine (60% yield) as dihydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:16]([O:23][CH2:24][C@H:25]([NH:29]C(OC(C)(C)C)=O)[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:29][C@@H:25]([CH2:24][O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:26]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 48.7 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-chlorophenoxy)aniline (329 mg, 1.5 mmoles) and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid (487 mg, 1.65 mmoles), gave (S)-2-amino-3-(benzyloxy)-N-(4-(4-chlorophenoxy)phenyl)propanamide (290 mg, 48%).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:27]([F:30])([F:29])[F:28])[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]([N+:24]([O-])=O)[CH:21]=[CH:22][CH:23]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1>C(O)C.[Fe]>[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:27]([F:29])([F:28])[F:30])[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[NH2:24])[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: O=[N+]([O-])c1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
To an aqueous 2.5% acetic acid solution (1 ml) was added an iron powder (10-20 mesh; 192 mg). To the mixture was added a suspension of 3-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]nitrobenzene (232 mg) obtained by Reference Production Example 1 in ethanol (1.5 ml) at 75° C. After stirring at the same temperature for 15 minutes, an additional iron powder (300 mg) was added thereto, and the mixture was stirred at room temperature for 1 hour. After cooling to room temperature, the reaction mixture was filtrated and washed with ethyl acetate. Then, the filtrate was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 3-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]aniline (198 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C([Li])CCC.[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1>C1(C)C=CC=CC=1.[Cl-].[NH4+]>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:18]2([OH:21])[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[N:6][CH:7]=1
Reactant: CN1CCC(=O)CC1
Reactant: Brc1cnc(I)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CN1CCC(O)(c2ncc(Br)cn2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
5-Bromo-2-iodopyrimidine (2 g, 7.02 mmol) was dissolved in dry toluene (30 mL) and cooled to −78° C. under nitrogen. n-Butyllithium (2.5M solution in hexanes, 2.95 mL) was added dropwise, and the reaction mixture was stirred for 30 minutes before dropwise addition of 1-methylpiperidin-4-one (0.9 mL, 0.01 mol). The reaction mixture was stirred at −78° C. for 1 h. The reaction mixture was allowed to warm to room temperature, then diluted with 5% aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (50 mL) and dried over magnesium sulphate, then the solvent removed under reduced pressure. The resulting crude material (1.55 g) was sonicated in ethyl acetate (10 mL) and DCM (1 mL), then heptane was added. The solid that formed was filtered to afford the title compound (580 mg, 29.4%) as a brown solid. LCMS Method F: MH+: m/z 272/274, RT 1.20 minutes.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH:22]([CH3:24])[CH3:23])[C:20](=[O:25])[C@@H:19]([CH2:26][CH2:27][OH:28])[O:18][C@H:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:16]=2[CH:36]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH:22]([CH3:23])[CH3:24])[C:20](=[O:25])[C@@H:19]([CH2:26][CH:27]=[O:28])[O:18][C@H:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:16]=2[CH:36]=1
Reactant: CC(C)N1C(=O)[C@@H](CCO)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N1C(=O)[C@@H](CC=O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
A solution of oxalyl chloride (0.72 ml) in methylene chloride (10 ml) was cooled to -65° C., to which was added dropwise a solution of dimethyl sulfoxide (0.63 ml) in methylene chloride (2 ml) taking 5 minutes, followed by stirring for 5 minutes. To the mixture was added dropwise, taking 15 minutes, a solution of trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethanol (2.5 g) obtained in Example 47 in methylene chloride (15 ml), which was stirred for 10 minutes. To the resultant mixture was added triethylamine (3.45 ml) taking 5 minutes, then the cooling bath was removed. The mixture was stirred for 10 minutes at room temperature, to which was then added 1N hydrochloric acid (50 ml), followed by stirring. The methylene chloride layer was dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure to leave trans-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehyde (2.3 g) as an oily product.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1([CH3:34])[C@@H:8](/[CH:9]=[CH:10]\[C:11](=O)[OH:12])[C@H:7]1[C:14]([O:16][C@H:17]([C:32]#[N:33])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)=[O:15]>C(Cl)Cl>[CH3:5][C:6]1([CH3:34])[C@@H:8](/[CH:9]=[CH:10]\[C:11](=[O:12])[Cl:3])[C@H:7]1[C:14]([O:16][C@H:17]([C:32]#[N:33])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:19]=1)=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Cl
Reaction time: 1.75 h

Procedure:
10 ml of thionyl chloride were added all at once at 20° C. to a solution of 4.5 g of the product of Step C in 20 ml of methylene chloride and the mixture was stirred for 105 minutes and was evaporated to dryness under reduced pressure to obtain 4.7 g of (S)α-cyano-3-phenoxy-4-fluorobenzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-chloro-1-propenyl]cyclopropane-carboxylate.
Reaction SMILES: [CH:1]([Si:4]([C:11]#[CH:12])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C([Li])[CH2:14][CH2:15][CH3:16].[Br:18][C:19]1[CH:32]=[CH:31][C:30]2[C:29](=O)[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Br:34])[CH:27]=3)[C:22](=O)[C:21]=2[CH:20]=1.[Sn](Cl)Cl>Cl.O.C1COCC1.CCCCCC>[Br:18][C:19]1[CH:32]=[CH:31][C:30]2[C:21](=[C:22]([C:2]#[C:1][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:15]([CH3:16])[CH3:14])[CH:5]([CH3:7])[CH3:6])[C:23]3[C:28]([C:29]=2[C:12]#[C:11][Si:4]([CH:5]([CH3:6])[CH3:7])([CH:1]([CH3:3])[CH3:2])[CH:8]([CH3:10])[CH3:9])=[CH:27][C:26]([Br:34])=[CH:25][CH:24]=3)[CH:20]=1
Reactant: O=C1c2ccc(Br)cc2C(=O)c2ccc(Br)cc21
Reactant: [Li]CCCC
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C#Cc1c2ccc(Br)cc2c(C#C[Si](C(C)C)(C(C)C)C(C)C)c2ccc(Br)cc12)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Triisopropylsilylacetylene (12.32 g, 67.5 mmol) and dry hexane (140 mL) were added under a dry nitrogen blanket to an oven-dried round bottom flask (1 L). Butyl lithium (2.7 M in hexane, 14.5 mL, 39.2 mmol) was added dropwise under dry nitrogen through a syringe to the mixture. The mixture was stirred at room temperature for 2 hours. To this colorless solution, dry THF (300 mL) and 2,6-dibromoanthraquinone (5.49 g, 15.0 mmol) were added under dry nitrogen. The solution turned red immediately and the 2,6-dibromoanthraquininone dissolved in minutes. The mixture was stirred at room temperature overnight and the solution became dark red. Deionized (DI) water (6.0 mL) was added, the color changed to light red, and a white precipitate appeared. Tin (II) chloride (8.088 g, 42.6 mmol) in HCl (18 mL, 10%) aqueous solution was then added. The mixture was heated to 60° C. for 2 hours and then cooled to room temperature. The solvent was removed by rotary evaporation. DI water (100 mL) was added to the mixture which was then extracted with hexane (100 mL×3). The hexane solution washed with DI water until neutral. It was concentrated and purified through a column chromatography (silica gel/hexane, Rf=0.7). A bright yellow solid (8.55 g, yield: 82%) was obtained as the product. 1H NMR (400 MHz, CDCl3). δ ppm 8.797-8.802 (d, 2H, J=2.0 Hz), 8.431-8.454 (d, 2H, J=8.8 Hz), 7.647-7.674 (dd, 2H, J=8.8 Hz, J=2.0 Hz), 1.259 (s, 36H), 1.247 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Cl[CH2:10][CH2:11][CH2:12][OH:13]>CN(C=O)C>[CH3:1][C:2]1[N:3]([CH2:10][CH2:11][CH2:12][OH:13])[CH:4]=[CH:5][N:6]=1
Reactant: OCCCCl
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1CCCO

Procedure:
The starting material may be prepared as follows. A mixture of 2-methylimidazole (6.15 g.), a 50% w/w dispersion of sodium hydride in oil (5.4 g.) and DMF (20 ml.) was treated with 3-chloropropanol (10.6 g.) and the mixture heated at 100° for 24 hours and then evaporated to dryness. The residue was treated with concentrated aqueous hydrochloric acid (8 ml.) and the solution washed with chloroform, and then basified with potassium carbonate. The mixture was extracted with chloroform, and the extract was dried and evaporated to dryness to give 2-methyl-1-(3-hydroxypropyl)imidazole which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[CH2:21][CH2:22][CH3:23])[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH2:21][CH2:22][CH3:23])[CH3:2]
Reactant: CCCc1cc(OCc2ccccc2)ccc1OCC(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1cc(O)ccc1OCC(=O)OCC
Yield: 57.3 %

Procedure:
A solution of (4-benzyloxy-2-propylphenoxy)acetic acid ethyl ester (0.60 g, 1.83 mmol) in THF (15 mL) is treated with 5% Pd/C (75 mg) and hydrogen (60 psi) at ambient temperature for 24 h. The mixture is filtered and concentrated. The crude product is purified by radial chromatography using 15% ethyl acetate in hexanes to give a tan solid (0.25 g, 57%). 1H NMR (400 MHz, CDCl3) δ 6.66 (d, J=2.9 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 6.57 (dd, J=8.8, 2.9 Hz, 1H), 4.56 (s, 1H), 4.40 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.63 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H); MS (FIA) m/e 239 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]#[C:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: [H][H]
Reactant: CN(C)CC#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)CCCc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Yield: 48.8 %

Procedure:
A mixture of 7-chloro-5-(3-dimethylamino-prop-1-ynyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.102 g, 0.24 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-chloro-5-(3-dimethylamino-propyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.050 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.84 (m, 2H), 2.4 (s, 6H), 2.48 (t, 2H), 2.72 (t, 2H), 4.22 (s, 2H), 4.76 (s, 2H), 7.15-7.39 (m, 6H).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([C:16]1([CH2:19][CH3:20])[CH2:18][NH:17]1)[CH2:13][CH2:14][CH3:15]>CO>[CH2:12]([C:16]1([CH2:19][CH3:20])[NH:17][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][CH2:18]1)[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)c1ccccc1S
Reactant: CCCCC1(CC)CN1
Solvent: CO
Product: CCCCC1(CC)CSc2ccccc2C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of methyl thiosalicylate (25.0 g, Aldrich) in methanol (95 ml) at 0° C. was added 2-butyl-2-ethylaziridine (20.0 g, Synthetic Example 1(f)) and the mixture was stirred at room temperature for 18 hours. Solvent was evaporated and toluene (200 ml) and sodium methoxide (8.2 g) were added. The mixture was heated to reflux for 4.5 hours, removing water through a Dean-Stark trap. Solvent was evaporated and the residue was partitioned between 5% HCl (500 ml) and dichloromethane (400 ml). The organic layer was separated, dried and concentrated. Crystallization from hexanes/ethyl acetate provided the title compound as a white solid (38.0 g), mp 92°-93° C. 1H NMR consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[CH:14]12[CH2:19][CH:18]1[CH2:17][NH:16][CH:15]2[C:20](O)=[O:21].C[Al](C)C.O>C(Cl)Cl>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([NH:6][C:20]([CH:15]2[NH:16][CH2:17][CH:18]3[CH:14]2[CH2:19]3)=[O:21])=[C:4]([F:13])[CH:3]=1
Reactant: O=C(O)C1NCC2CC21
Reactant: C#CCOc1cc(N)c(F)cc1Cl
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: O
Product: C#CCOc1cc(NC(=O)C2NCC3CC32)c(F)cc1Cl
Temperature: 5 °C
Yield: 35.7 %

Procedure:
To a mixture of 2.36 g (11.79 mmol) of 4-chloro-2-fluoro-5-(2-propynyl)oxyaniline and 1.5 g (11.79 mmol) of (±)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid in methylene chloride (150 mL) stirred under nitrogen and cooled to 5° C. was added trimethylaluminum dropwise (2.0M, 11.8 mL, 23.58 mmol). The resultant mixture was stirred at room temperature for 48 h. Water (100 mL) was added dropwise at ice-bath temperature. The solid inorganic material which formed was filtered, and the filtrate was dried (MgSO4) and evaporated under reduced pressure to dryness. Flash chromatography on silica gel yielded 1.3 g of the product of Step F as a tan solid; m.p. 113°-115° C. IR (mineral oil, cm-1): 1687.1 (C=O); 2123.5 (C≡C).