Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[F:4][C:5]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:6]=1[C:7]([C:9]1[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[NH:12][CH:13]=1)=[O:8].[N+](=[CH2:25])=[N-]>C(OCC)C>[F:4][C:5]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[C:6]=1[C:7]([C:9]1[CH:10]=[C:11]([C:14]([O:16][CH3:25])=[O:15])[NH:12][CH:13]=1)=[O:8]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1
Reaction time: 3 h

Procedure:
To a dichloromethane 70 mL suspension of 4-(2,4,6-trifluorobenzoyl)-1H-pyrrole-2-carboxylic acid (Intermediate 1) (3 g, 11.2 mmol) was added diazomethane solution in diethyl ether upon cooling in an ice-water bath. After stirring for 3 hr, the reaction mixture was concentrated and chromatographed on silica gel eluting with a gradient solvent mixture of AcOEt and hexanes to give the title compound (2.74 g).
Reaction SMILES: [C:1]1(=O)CCCCC1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:18][CH2:19][C:20]2([O:26][CH3:27])[CH2:25][CH2:24]O[CH2:22][CH2:21]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1>>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:18][CH2:19][C:20]2([O:26][CH3:27])[CH2:25][CH2:24][CH2:1][CH2:22][CH2:21]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C1CCCCC1
Reactant: COC1(COS(=O)(=O)c2ccc(C)cc2)CCOCC1
Product: COC1(COS(=O)(=O)c2ccc(C)cc2)CCCCC1

Procedure:
This compound was synthesized from cyclohexanone following the procedure described for (4-methoxytetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (Intermediate O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)O.[ClH:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([Cl:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: OC(c1ccc(F)cc1)c1ccc(Cl)cc1Cl
Reactant: Cl
Product: Fc1ccc(C(Cl)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 22 parts of 2,4-dichloro-α-(4-fluorophenyl)benzenemethanol and 240 parts of hydrochloric acid solution 12 N is stirred for 40 hours at room temperature. The reaction mixture is poured onto ice-water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is distilled, yielding 13.2 parts of 2,4-dichloro-1-[chloro-(4-fluorophenyl)methyl]benzene; bp. 146° C. at 0.15 mm. pressure.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([C:14]([CH3:21])([CH3:20])[C:15]([O:17]CC)=[O:16])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>>[CH2:1]([NH:8][C:9]([NH:11][N:12]([C:14]([CH3:21])([CH3:20])[C:15]([OH:17])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)N(C)NC(=O)NCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CN(NC(=O)NCc1ccccc1)C(C)(C)C(=O)O
Yield: 36.8 %

Procedure:
According to the procedure described in the synthesis method of Compound VI-4, ethyl 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)-2-methylpropanoate (Compound V-2) (2.932 g, 10 mmol) was reacted with lithium hydroxide monohydrate (839.2 mg, 20 mmol) to obtain the title compound (975.1 mg, 37%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1(/[CH:13]=[CH:14]/[C:15]2[CH:16]=[C:17]([CH:20]([OH:24])[CH2:21][C:22]#[N:23])[O:18][CH:19]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.N.CO.C(Cl)Cl>>[NH2:23][CH2:22][CH2:21][CH:20]([C:17]1[O:18][CH:19]=[C:15](/[CH:14]=[CH:13]/[CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:16]=1)[OH:24]
Reactant: N#CCC(O)c1cc(/C=C/C2CCCCC2)co1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: NCCC(O)c1cc(/C=C/C2CCCCC2)co1

Procedure:
LiAlH4 reduction of (E)-3-(4-(2-cyclohexylvinyl)furan-2-yl)-3-hydroxypropanenitrile following the method used in Example 1 gave after flash chromatography purification (2%-20% 7N NH3/MeOH—CH2Cl2 gradient) Example 22 as a colorless oil. Yield (0.07 g, 53%); 1H NMR (400 MHz, CD3OD) δ 7.34 (s, 1H), 6.41 (s, 1H), 6.17 (d, J=17.2 Hz, 1H), 5.88 (dd, J=7.3, 16.1 Hz, 1H), 4.67 (t, J=6.9 Hz, 1H), 2.67-2.80 (m, 2H), 2.00-2.10 9m, 1H), 1.90-2.00 (m, 2H), 1.63-1.81 (m, 5H), 1.10-1.40 (m, 5H); RP-HPLC tR=10.42 min; ESI-MS m/z 232.2 [M−H2O+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:39])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:39][CH2:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])cc2ccoc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(CBr)c2occc2c1
Temperature: 80 °C
Reaction time: 0.05 h

Procedure:
7-Methyl-5-nitro-1-benzofuran (2.1 g, 12 mmol; Intermediate 63) was dissolved in CCl4 and heated to 80° C. Benzoyl peroxide (0.43 g, 1.6 mmol) was added followed by NBS (2.1 g, 12 mmol) that was added in small portions. The reaction mixture was heated at reflux overnight with stirring. Additional benzoyl peroxide (0.08 mmol) and NBS (0.2 mmol) were added and the reaction mixture was stirred for one additional night. After this time, the mixture was filtered and concentrated. The crude was redissolved in DCM and washed with water. The organic solvent was dried (MgSO4) and evaporated. The residue was purified using preparative HPLC with a gradient of 45-70% MeCN. This afforded 0.7 g (22%) of 7-(bromomethyl)-5-nitro-benzofuran as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.78 (s, 2H) 6.96 (d, J=2.3 Hz, 1H) 7.84 (d, J=2.3 Hz, 1H) 8.28 (d, J=2.3 Hz, 1H) 8.49 (d, J=2.3 Hz, 1H). HPLC Rt=1.9 min (System A; 30-80% MeCN over 3 min ACE column).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([CH3:11])[C:3]=12.[CH3:12][C:13]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)([CH2:23][CH3:24])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[CH3:12][C:13]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][N:9]=[C:10]([CH3:11])[C:3]=23)[CH:30]=1)([CH2:23][CH3:24])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21]
Reactant: Cc1n[nH]c2nccc(I)c12
Reactant: CCC(C)(CNC(=O)OC(C)(C)C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(C)(CNC(=O)OC(C)(C)C)c1cccc(-c2ccnc3[nH]nc(C)c23)c1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
4-iodo-3-methyl-1H-pyrazolo[3,4-b]pyridine (150 mg, 0.5790 mmol), tert-butyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butylcarbamate (225.4 mg, 0.5790 mmol), Na2CO3 (868.5 μL of 2 M, 1.737 mmol) and Pd(PPh3)4 (66.91 mg, 0.05790 mmol) were placed in a microwave tube and Dioxane (1.500 mL) was added. The resulting suspension was stirred at 150° C. in the microwave (using a 10 minute ramp and nitrogen cooling) for 45 minutes. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow gum. The mixture was purified by column chromatography (75% EtOAc in hexanes, ˜75 mL silica) to give a slightly yellow gum (203 mg, 89% Yield).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6].C([Li])CCC.[CH2:13]([C:15]1([CH3:23])[CH2:20][CH2:19][CH2:18][CH:17]([CH3:21])[C:16]1=[O:22])[CH3:14]>O1CCCC1.CCCCCC>[CH2:13]([C:15]1([CH3:23])[CH2:20][CH2:19][CH2:18][CH:17]([CH3:21])[C:16]1([C:1]#[C:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6])[OH:22])[CH3:14]
Reactant: CCC1(C)CCCC(C)C1=O
Reactant: C#CC(O)CCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(O)C#CC1(O)C(C)CCCC1(C)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.2 G (0.41M) of 1-hexyn-3-ol in 200 ml of anhydrous tetrahydrofurane (THF) have been placed in a three-necked reaction vessel and cooled to -70°. At this temperature there were added under stirring 390 ml (0.91M) of a 15% solution of butyl-lithium in hexane and the temperature was then raised to about 20° within one night. A solution of 40 g (0.26M) of 2-ethyl-2,6-dimethylcyclohexanone in 90 ml of THF-75/25 isomeric mixture of the following compounds ##STR15## was added dropwise to the reaction mixture cooled again to -70°. After having been kept under stirring for 3 h at -70° and overnight at room temperature, the mixture was poured onto ice, extracted with ether, washed with brine until neutrality, dried over Na2SO4, filtered and concentrated.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2C3CN(C(C4CCCCC4)=O)[CH2:13][C:14](=[O:15])[N:9]3[CH2:8][CH2:7][C:5]=2[CH:6]=1.C1(CCN)C=CC=CC=1.[Cl:33]CC(Cl)=O>>[Cl:33][CH2:13][C:14]([NH:9][CH2:8][CH2:7][C:5]1[CH:4]=[CH:3][CH:2]=[CH:1][CH:6]=1)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: O=C(C1CCCCC1)N1CC(=O)N2CCc3ccccc3C2C1
Agent: NCCc1ccccc1
Product: O=C(CCl)NCCc1ccccc1

Procedure:
KR2002076486 describes a process for preparation of praziquantel by reacting phenylethylamine with chloroacetyl chloride to obtain 2-chloro-N-phenethylacetamide. The compound 2-chloro-N-phenethylacetamide is then reacted with pthalimide to give 2-pthalimido-N-phenethylacetamide, which is then treated with hydrazine monohydrate to give 2-amino-N-phenylethylacetamide. On further treatment with bromoacetal, 2-amino-N-phenylethylacetamide gives 2-[2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide. This compound on further cyclization and acylation using cyclohexanoylchloride forms praziquantel.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH2:24][NH:23][CH2:22][CH2:21]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH2:24][N:23]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH2:22][CH2:21]2
Reactant: O=[N+]([O-])c1ccc(OCCCBr)cc1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(CCCOc1ccc([N+](=O)[O-])cc1)CC2
Yield: 79.2 %

Procedure:
A mixture of 1-(3-bromopropoxy)-4-nitrobenzene (10 g), 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride (8.8 g) and potassium carbonate (10.6 g) in DMF (100 ml) was heated at 100° for 16 h. The mixture was then filtered and the filtrate evaporated. The residue was taken up in water and extracted with dichloromethane. The organic layer was washed with water, dried, and evaporated to give an oil which crystallised in ether to give the title compound (11.3 g), m.p. 100°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][O-:12].[Na+].CO>CO.C(Cl)Cl.O>[Br:1][C:2]1[CH:9]=[C:8]([O:12][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C=O)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-fluorobenzaldehyde (50 g, 246 mmol), in MeOH (500 mL) in a 15° C. water bath was added a 25% solution of NaOMe/MeOH (88 mL). The mixture was stirred at r.t. for 1 hour followed by 2 hours at reflux. The solid was filtered and the filtrate was concentrated to dryness to give a second crop of solid. Both crops were taken up in CH2Cl2/H2O. After washing with H2O, the organic phase was dried (MgSO4), filtered, and evaporated to give an off-white solid (52.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cu][C:20]#[N:21].[OH-].[NH4+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[N:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: N#C[Cu]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#N)cc1
Temperature: 170 °C
Yield: 15933 %

Procedure:
A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (500 mg, 1.60 mmol) in N,N-dimethylformamide (4.01 mL) was treated with copper(I) cyanide (144 mg, 1.60 mmol). The mixture was heated at 170° C. for 1 h. At this time, the reaction was cooled to 25° C. and poured into aqueous ammonium hydroxide (5 mL). The solution was diluted with water (25 mL) and extracted with ethyl acetate (3×35 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid methyl ester (65.6 g, 15.8%) as a clear oil: EI-HRMS m/e calcd for C16H19NO2 (M+) 257.1415 found 257.1406.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:39][C@H:40]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:41][CH2:42][OH:43]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:39][C@H:40]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:41][CH2:42][OH:43])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: N[C@@H](CCO)c1ccccc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](CCO)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 81 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (S)-3-amino-3-phenylpropan-1-ol: yield 81%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:34]C)[C:10](=[O:33])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][O:24][CH2:25][C:26]4C=CC=CC=4)[C:16](=[O:32])[C:12]3=2)[C:7]1=[O:36].Br.C(O)(=[O:44])C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:34])[C:10](=[O:33])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][O:24][C:25](=[O:44])[CH3:26])[C:16](=[O:32])[C:12]3=2)[C:7]1=[O:36]
Reactant: COc1c2c(c3n(c1=O)CCCCN(CCOCc1ccccc1)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: CC(=O)O
Agent: Br
Solvent: C1COCCO1
Product: CC(=O)OCCN1CCCCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-[2-(benzyl-oxy)ethyl]-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (120 mg, 0.21 mmol) and 33% hydrogen bromide in acetic acid (1 mL) in dioxane (1 mL) was stirred at room temperature for 1 hour. The product mixture was concentrated under vacuum. The residue was subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: [CH2:1]([O:8][N:9]=[CH:10][C:11]1([C:17]([OH:19])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl.CCC1(CC)C(=O)NC(=O)OC1.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:8][NH:9][CH2:10][C:11]1([C:17]([OH:19])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1(C=NOCc2ccccc2)CCCCC1
Agent: CCC1(CC)COC(=O)NC1=O
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Solvent: CO
Product: O=C(O)C1(CNOCc2ccccc2)CCCCC1
Temperature: 0 °C

Procedure:
To a solution of 1-(benzyloxyimino-methyl)-cyclohexanecarboxylic acid (1.59 g, 6.08 mmol) in methanol (40 mL) at 0° C. under a nitrogen atmosphere was added a trace amount of methyl orange. A solution of saturated methanolic HCl was added until a persisten red color was observed. Sodium cyanoborohydride (0.42 g, 6.69 mmol) was added portionwise alternately with methanolic HCl to maintain the red color. The reaction mixture was maintained at 0° C. for an additional 3 h and the volatiles were removed in vacuo to yield the title compounds as a pale, yellow oil that was used without further purification. MH+264.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[N:7]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[O:17])[C:8]3=[N:9]2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][NH:18][C:16]([C:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:24])[N:7]2[CH:15]=[CH:14][CH:13]=1)=[CH:4][CH:3]=[C:2]([C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1)[CH:11]=3)=[O:17]
Reactant: CN(C)CCNC(=O)c1cccn2c(=O)c3ccc(Br)cc3nc12
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCNC(=O)c1cccn2c(=O)c3ccc(-c4cccnc4)cc3nc12

Procedure:
The procedure of Example 6 was used with the product of Example 14 (39 mg, 0.1 mmol), product of Example 4 (123 mg, 1.0 mmol), tetrakis(triphenylphospine)palladium(0) (29 mg, 0.025 mmol), 2 M sodium carbonate solution (0.5 ml, 1.0 mmol), and toluene (5 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1.S(=O)(=O)(O)[OH:16].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:11][CH2:12][CH2:13][N:14]1[OH:16]
Reactant: Clc1cccc(Cl)c1N=C1NCCN1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: ON1CCNC1=Nc1c(Cl)cccc1Cl

Procedure:
2.30 g. of 2-[(2,6-dichlorophenyl)imino]-imidazolidine are dissolved in 10 ml. of concentrated sulfuric acid, and 2.97 g. of potassium persulfate are added in portions at room temperature. The temperature is kept below 50° with a cooling bath. The dark solution is diluted with water and rendered highly alkaline with concentrated caustic soda solution. The unreacted starting material is extracted with ether. The aqueous solution is adjusted to pH 7 with glacial acetic acid and then with sodium bicarbonate. The residue is filtered off from the solution and a potassium carbonate solution is added to the filtrate up to pH 10.5. The product which has precipitated is extracted with ethyl acetate and recrystallized twice from acetonitrile, whereupon 2-[(2,6-dichlorophenyl)-imino]-1-hydroxyimidazolidine of melting point 215°, which is identical to the product obtained in Example 3, is obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:21]2[CH2:20][CH2:19][C@H:18]3[C@H:14]([CH2:15][C:16](=O)[NH:17]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.O.[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[C:21]2[CH2:20][CH2:19][C@H:18]3[C@H:14]([CH2:15][CH2:16][NH:17]3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc2c1CC[C@@H]1NC(=O)C[C@H]21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1CC[C@@H]1NCC[C@H]21
Yield: 95.4 %

Procedure:
A suspension of 25 g (0.66 mol) of lithium aluminum hydride in 2 l of tetrahydrofuran was treated portionwise with 71.5 g (0.33 mol) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one. The mixture was boiled at reflux overnight, cooled to about -10° and then hydrolyzed by the successive dropwise addition of 25 ml of water, 25 ml of 15 percent sodium hydroxide solution and 75 ml of water. The solid residue was filtered off and rinsed with methylene chloride. The organic phases were concentrated. The residue was dissolved in methylene chloride and the solution was dried with sodium sulphate. After distillation of the solvent in a vacuum and crystallization in a refrigerator there were obtained 64.0 g (96%) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole as grey crystals.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C@H:9]2[C@H:13]([CH2:14][O:15]C3CCCCO3)[O:12][C:11](=[O:22])[NH:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:25][C:26]1[CH:39]=[CH:38][C:29]([O:30][C:31]2[CH:36]=[N:35][C:34](Br)=[CH:33][N:32]=2)=[CH:28][CH:27]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+].C1(C)C(S(O)(=O)=O)=CC=CC=1>CO.[Cu]I.C(#N)C>[Cl:25][C:26]1[CH:39]=[CH:38][C:29]([O:30][C:31]2[N:32]=[CH:33][C:34]([N:10]3[C@@H:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=4)[C@H:13]([CH2:14][OH:15])[O:12][C:11]3=[O:22])=[N:35][CH:36]=2)=[CH:28][CH:27]=1
Reactant: O=C1N[C@@H](c2cccc(C(F)(F)F)c2)[C@H](COC2CCCCO2)O1
Reactant: Clc1ccc(Oc2cnc(Br)cn2)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Solvent: CC#N
Product: O=C1O[C@@H](CO)[C@H](c2cccc(C(F)(F)F)c2)N1c1cnc(Oc2ccc(Cl)cc2)cn1
Temperature: 110 °C

Procedure:
(4S,5R)-4-(3-(trifluoromethyl)phenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-oxazolidin-2-one (prepared as in Example 64, Steps A and B) (54 mg, 0.16 mmol) was added to a 10 mL reaction vessel with a screw cap and charged with acetonitrile (0.5 mL), 2-(4-chlorophenoxy)-5-bromopyrazine (47 mg, 0.16 mmol), copper (I) iodide (14 mg, 0.074 mmol), N,N′-dimethylethylenediamine (0.014 mL, 0.15 mmol), and potassium carbonate (44 mg, 0.32 mmol). The vessel was sealed, evacuated and back-filled with nitrogen twice, and then heated to 110° C. in a microwave for 30 min. The reaction mixture was cooled to room temperature, quenched with 1 M HCl, and extracted with ethyl acetate. The organic layer was dried, filtered and concentrated to give the crude intermediate which was immediately dissolved in methanol (5 mL) and treated with excess toluenesulfonic acid for 1 h. The reaction was quenched with 1 mL triethylamine, then concentrated to dryness and purified on silica gel (30% ethyl acetate/hexanes) to give the title compound as a white solid. 1H NMR (acetone-d6) 600 MHz δ (ppm) 8.91 (d, J=1.3 Hz, 1H), 8.05 (d, 1.3 Hz, 1H), 7.83 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 5.86 (d, J=5.0 Hz, 1H), 4.61 (ddd, J=5.4, 3.5, 3.0, 1H), 4.58 (t, J=5.7 Hz, 1H), 4.02 (ddd, J=12.4, 5.5, 3.5 z, 1H), 3.94 (ddd, J=12.3, 5.9, 3.5 Hz, 1H); HPLC-MS calculated C21H15ClF3N3O4S (M+H+): 466.1, found 466.1.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[N:8][S:7][N:6]=1.[CH3:18][NH:19][CH2:20][CH2:21][CH3:22]>C(COC)OC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[C:9]1[C:5]([O:4][CH2:3][CH2:2][N:19]([CH3:18])[CH2:20][CH2:21][CH3:22])=[N:6][S:7][N:8]=1
Reactant: CCCNC
Reactant: Clc1cccc(Cl)c1-c1nsnc1OCCBr
Solvent: COCCOC
Product: CCCN(C)CCOc1nsnc1-c1c(Cl)cccc1Cl
Yield: 58.4 %

Procedure:
In dimethoxyethane, were mixed and stirred 0.35 g of 3-(2-bromoethoxy)-4-(2,6-dichlorophenyl)-1,2,5-thiadiazol e, 0.3 g methylpropylamine at 50° C. for 6 hours. The reaction mixture was concentrated, and was purified by silica gel chromatography to obtain 0.2 g of 3-(2,6-dichlorophenyl)-4-[2-(N-methyl-N-propylamino)ethoxy]-1,2,5-thiadiazole.