Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:13])[CH:2]=[CH2:3].C>C(O)C.[Rh]>[CH2:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:13])[CH2:2][CH3:3]
Reactant: C=CCc1cccc2c1CCC2=O
Agent: [Rh]
Solvent: CCO
Product: CCCc1cccc2c1CCC2=O
Yield: 94.6 %

Procedure:
1.63 g of 4-(2-propenyl)-1-indanone is dissolved in 300 ml of anhydrous ethanol and 400 mg of rhodium at 5% on active charcoal and hydrogenated at ambient temperature and ambient pressure for 3/4 hour. After filtering on celite, the filtrate is washed with ethanol and evaporated to dryness, and 1.56 g of expected product is obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:6][C:7]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:8][CH:9]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:29](=[O:38])[CH:28]=2)=[CH:21][N:20]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[O:6][C:7]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:29](=[O:38])[CH:28]=3)=[CH:21][N:20]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CN(C)CCn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Solvent: c1ccncc1
Product: CN(C)CCn1ccc(Cc2cnc(NCCSCc3ccc(CN(C)C)o3)[nH]c2=O)cc1=O

Procedure:
2-(2-Dimethylaminomethyl-5-furylmethylthio)ethylamine (4.00 g) and 2-nitroamino-5-[1-(2-dimethylaminoethyl)-2-oxopyridin-4-yl-methyl]pyrimidin-4-one (7.14 g) were refluxed in pyridine (50 ml) for 24 hours. The reaction mixture was evaporated under reduced pressure and the residue subjected to medium pressure column chromatography (Kieselgel 60 silica mesh - main column) using ethyl acetate:methanol (80:20→70:30) gradient elution. The fractions containing the desired title product were evaporated in vacuo and treated with maleic acid (1.79 g) in isopropanol. The solvent was evaporated under reduced pressure and the residue washed with acetone and cold isopropanol. On standing at 5° C. the residue crystallised from ethanol-methanol to yield 2-[2-(2-dimethylaminomethyl-5-furylmethylthio)ethylamino]-5-[1-(2-dimethylaminoethyl)-2-oxopyridin-4-ylmethyl]pyrimidin-4-one as a maleate salt (0.79 g), m.p. 123°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][N:22](C(OCC3C=CC=CC=3)=O)[CH:21]([CH3:35])[CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:44])[N:13]2[C:36]1[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:43].Br.CC(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH:21]([CH3:35])[CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:44])[N:13]2[C:36]1[C:37]([Cl:43])=[CH:38][CH:39]=[CH:40][C:41]=1[Cl:42]
Reactant: CC1CN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1CN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CCN1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}-2-methylpiperazine-1-carboxylate (105 mg, 0.16 mmol) in methylene chloride (2 mL) at 0° C. was added 30% HBr/HOAc (0.32 mL, 1.62 mmol) slowly. The resulting reaction mixture was stirred at 0° C. for 30 min, and then at rt for 30 min. The reaction was quenched with water, then added 5N NaOH solution to pH ˜1, and extracted with methylene chloride (50 mL×3) and ethyl acetate (50 mL×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by preparative thin layer chromatography using 8% of 2N ammonium in methanol/methylene chloride as eluent provided 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(3-methylpiperazin-1-yl)methyl]-3,4-dihydroquinazolin-2(1H)-one as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.06 (d, 3H, J=4.8 Hz), 1.72 (m, 1H), 2.06 (m, 1H), 2.69 (m, 2H), 2.82 (t, 2H, J=9.3 Hz), 2.98 (d, 1H, J=11.9 Hz), 3.40 (m, 2H), 4.34 (abq, 2H, J=14.4 Hz), 5.10 (s, 1H), 6.17 (s, 1H), 6.84 (s, 1H), 7.30-7.60 (m, 7H). MS (API-ES+): 517 (M+H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[NH2:15][CH2:16][CH2:17][CH2:18][OH:19]>CO.[Pd]>[OH:19][CH2:18][CH2:17][CH2:16][NH:15][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: NCCCO
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(NCCCO)C1

Procedure:
A mixture of tert-butyl 3-oxo-1-piperidinecarboxylate (5.0 g, 25.1 mmol) and 3-amino-1-propanol (5.66 mL, 73.8 mmol) in MeOH (75 mL) was hydrogenated over 10% Pd on C (200 mg) for 1 day (Yokoyama et al., Bioorg. Med. Chem. 2008, 16, 7968) to give tert-butyl 3-[(3-hydroxypropyl)amino]-1-piperidinecarboxylate as an oil: 1H NMR (CDCl3) (rotamers) δ 3.80 (t, J=5.1 Hz, 2H), 3.80 (br, 1H), 3.65 and 3.67 (2t, J=4.7 Hz, 1H), 3.06-2.86 (m, 4H), 2.62-2.56 (m, 1H), 1.90-1.86 (m, 1H), 1.72-1.62 (m, 3H), 1.50-1.30 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]1([C:26]([OH:28])=O)[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:26](=[O:28])[C:17]1[CH:18]=[CH:19][C:20]([C:23]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:25])=[CH:21][CH:22]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1ccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)cc1
Yield: 71.8 %

Procedure:
Using General Procedure A with 5.8 g (24.0 mmol) D-Proline benzyl ester hydrochloride and 2.0 g (12.0 mmol) benzene-1,4-dioic acid afforded, after flash chromatography (EtOAc), 4.66 g (72%) of the title compound as a yellow oil. MS m/e (%): 558 (M+NH4+, 100), 541 (M+H+, 95).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[O:8].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+].[NH4+:21].[OH-]>O>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH2:21])=[O:1]
Reactant: O=CCCCCCO
Reactant: [NH4+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)CCCCCO
Temperature: 90 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
5.26 Grams (45 mmols) of 6-hydroxyhexanal was charged to a 100 milliliter Schlenk flask and dissolved in 10 milliliters of deionized water by heating to 85-95° C. in a water bath. The resulting solution was charged to the Parr autoclave containing 0.484 grams of Na2S2O8 and 35 milliliters of NH4OH. The reactor was placed under 400 psi air, heated to 80° C. and a 500 psi air purge was established. The reaction was allowed to proceed for 3 hours. At that time, reaction conversion was virtually complete and 6-hydroxycaproamide was formed in 40% yield.
Reaction SMILES: [I:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Cl[Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].O>O1CCCC1>[I:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Ic1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)ncnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.6 %

Procedure:
4-Iodo-7H-pyrrolo[2,3-d]pyrimidine (352 mg, 1.44 mmol) in tetrahydrofuran (15 mL) cooled to 0° C. was mixed with sodium hydride (55 wt % dispersion in mineral oil, 75.5 mg, 1.73 mmol) and chlorotriisopropylsilane (0.37 mL, 1.7 mmol) and stirred at room temperature for 45 minutes. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/1 (v/v)) to give the title compound as a pale yellow oil (431 mg, yield 74%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:12]=[N:13][CH:14]=1.[C:23]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29])#[CH:24]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]([C:24]#[C:23][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])[CH:12]=[N:13][CH:14]=1
Reactant: C#Cc1cccc(C#N)c1
Reactant: O=S(=O)(Oc1cncc(F)c1)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1cccc(C#Cc2cncc(F)c2)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
Add triethylamine (0.79 mL, 5.64 mmol), copper (I) iodide (15.43 mg, 0.08 mmol) and bis(triphenylphosphine)palladium (II) dichloride (49.48 mg, 0.07 mmol) to a solution of trifluoromethanesulfonic acid 5-fluoropyridin-3-ylester, (prepared as described in PREPARATION 6), (345 mg, 1.41 mmol) and 3-ethynylbenzonitrile, prepared as described in PREPARATION 8), (230 mg, 1.41 mmol) in ethyl acetate (2 mL). Stir in a sealed tube at 70° C. for 18 h. Concentrate and purify by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate, to give the title compound (109 mg, 35%).
Reaction SMILES: [C:1]([OH:10])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:11][O:12][C:13](=[O:20])[C@@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:15]>>[CH3:18][CH:17]([CH3:19])[CH2:16][C@@H:14]([NH:15][C:1](=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:13]([O:12][CH3:11])=[O:20]
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: CCCCC/C=C/C(=O)O
Product: CCCCC/C=C/C(=O)N[C@H](CC(C)C)C(=O)OC

Procedure:
Prepared in a similar manner as described in example 4 from (E)-oct-2-enoic acid and D-leucine methyl ester. MS (M+H, 270).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][S:5][C:6]=1[NH:7][C@H:8]([C:13]([O:15]C)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11].[OH-].[Li+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[N:4][S:5][C:6]=1[NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)[C@H](CC(C)C)Nc1sncc1Br
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](Nc1sncc1Br)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.1 %

Procedure:
A solution composed of methyl N-(4-bromoisothiazol-5-yl)leucinate (98 mg, 0.32 mmol) in methanol (1.5 mL) at 0° C. was treated with a 2.0 M solution of lithium hydroxide (1.0 mL, 2.0 mmol). The mixture was stirred rapidly at rt for 6 h and then recooled to 0° C. prior to acidification to pH 5.5with 2.0 M hydrochloric acid in water. The reaction vessel contents were poured into water, extracted with ethyl acetate (3×) and the combined organics were washed with saturated sodium chloride solution and dried (Na2SO4). Concentration in vacuo gave 92 mg of N-(4-bromoisothiazol-5-yl)leucine as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][C:16](=[O:18])[N:35]2[CH2:36][CH2:37][N:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33][CH2:34]2)[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC(=O)O)CC1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC(=O)N2CCN(c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a colution containing trans-(4-tertbutoxycarbonylamino-cyclohexyl)-acetic acid (15.44 g, 0.06 mol), triethylamine (6.05 g, 0.06 mol) and 1-phenylpiperazine (9.73 g, 0.06 mol) in CH2Cl2 (250 mL) was added EDAC-HCl ((1-ethyl-(3dimethylaminopropyl)-carbodiimide hydrochloride (11.5 g, 0.06 mol)). The reaction mixture was stirred at room temperature 16 hours, then washed with water, 1N NaOH, brine, and dried (MgSO4). The solvent was evaporated, and the residue was chromatographed on a flash silica gel column eluting with CH2Cl2 and then EtOAc. The product fractions were recrystallized from acetonitrile (CH3CN) to yield 12.0 g (50%) of trans-{4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-cylohexyl}-carbamic acid tert-butyl ester as white crystals; mp 197.5-200° C.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH:5]=[CH:4][N:3]=[N:2]1.ClC(OCC)=O.CCN(CC)CC.[K+].[C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH2:30]C([O-])=O.[Mg+2].[Cl-].[Cl-]>CC#N.CCN(CC)CC>[C:36]([O:35][C:29](=[O:34])[CH2:30][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:7]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C(O)c1cccc(-n2ccnn2)c1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
The title compound was prepared from 3-[1,2,3]triazol-1-yl-benzoic acid [prepared by refluxing of methyl 3-azidobenzoate [CAS-No. 93066-93-4] in trimethylsilyl-acetylene, followed by saponification with aqueous NaOH in refluxing EtOH] (10.0 g, 52.86 mmol) by activation with ethyl chloroformate/Et3N and reaction with mono tert.-butyl malonate potassium salt with Et3N and MgCl2 in CH3CN according to general procedure K (method a). Obtained as an orange oil (11.55 g).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[N:4][CH:3]=1.[NH2:10][C@H:11]([CH3:27])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[CH:19]=2)=[N:14]1>>[Cl:26][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][N:13]([CH2:12][C@H:11]([NH:10][C:7]([C:5]3[S:6][C:2]([CH3:1])=[CH:3][N:4]=3)=[O:9])[CH3:27])[N:14]=2)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1cnc(C(=O)O)s1
Product: Cc1cnc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)s1
Yield: 54.6 %

Procedure:
5-Methyl-1,3-thiazole-2-carboxylic acid (55 mg, 0.38 mmol) was coupled with (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (100 mg, 0.38 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: C-18 silica, eluent: 0-100% MeCN in water) to obtain 80 mg (54%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.24 (d, 3H), 2.55 (d, 3H), 4.26 (dd, 1H), 4.45 (dd, 1H), 4.51-4.62 (m, 1H), 6.63 (d, 1H), 7.49 (d, 1H), 7.60 (dd, 1H), 7.68 (d, 1H), 7.79 (dd, 1H), 8.13 (d, 1H), 8.24 (d, HA).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].CO[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=1>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCCCc1ccccc1
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2CCCCCCCCc2ccccc2)=N1
Reaction time: 24 h

Procedure:
8-Phenyloctyl bromide was prepared from 8-phenyloctanol, carbon tetrabromide and triphenylphosphine in methylene chloride. A solution of 8-phenyloctanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 20° C. for 4 hours to give 8-phenyloctanol. To an ice cold solution of the octanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 8-phenyloctyl bromide as an oil. To 8-phenyloctyl bromide and 21.27 mmol of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmol) in tetrahydrofuran (20 ml). After stirring for 24 hours, the reaction mixture was similarly worked up to yield 2-[2-(8-phenyloctyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmol) in methyl iodide (20 ml) as refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 76.5°-78° D.). To an ice cold solution of the iodide (9.46 mmol) in methanol (35 ml) was added in portions sodium borohydride (9.20 mmol). Treatment of the reaction mixture as in Example 1(c) results in the isolation of the desired product as an oil.
Reaction SMILES: [Br:1]Br.[CH2:3]([C@@:7]12[C@H:19]([CH2:20][CH2:21][CH3:22])[C:18](=[O:23])[CH:17]=[C:8]1[C:9]1[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=1[CH2:15]2)[CH2:4][CH2:5][CH3:6].C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:17]1[C:18](=[O:23])[C@@H:19]([CH2:20][CH2:21][CH3:22])[C@@:7]2([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:15][C:14]3[CH:13]=[C:12]([OH:16])[CH:11]=[CH:10][C:9]=3[C:8]=12
Reactant: BrBr
Reactant: CCCC[C@]12Cc3cc(O)ccc3C1=CC(=O)[C@H]2CCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCC[C@]12Cc3cc(O)ccc3C1=C(Br)C(=O)[C@H]2CCC
Temperature: 2.5 °C
Reaction time: 1.17 h

Procedure:
Bromine (0.0072 mL, 0.14 mmol) was added to an ice-cold mixture of (rac)-(1S,8aR)-8a-butyl-6-hydroxy-1-propyl-8,8a-dihydrocyclopenta[a]inden-2(1H)-one (40 mg, 0.14 mmol) and NaHCO3 (59 mg, 0.70 mmol) in CCl4 (0.48 mL). The resulting mixture was sonicated for 20 seconds and then stirred at 0-5° C. for 70 minutes. The mixture was diluted with CH2Cl2 (30 mL) and washed with water (30 mL), and the aqueous phase was back-extracted with CH2Cl2 (2×10 mL). The combined organics were washed with saturated aqueous Na2S2O3, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 12S (1.2×7.5 cm) silica gel column, eluting with 10:1 hexane-EtOAc, to give a clear oil. This material was further purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing twice with 5:1 hexane-EtOAc. The major UV visible band provided (rac)-(1S,8aR)-3-bromo-8a-butyl-6-hydroxy-1-propyl-8,8a-dihydrocyclopenta[a]inden-2(1H)-one as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>CS(C)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([CH2:2][N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)=[CH:4][CH:5]=2)=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: C1CSCCN1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CN2CCSCC2)cc1

Procedure:
4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) was dissolved in DMSO (1 mL) and stirred for 1 h with thiomorpholine. The reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiomorpholinomethyl)benzamide. MS (Q1) 424.0 (M)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6](=[O:12])[C:5]2[CH:13]=[C:14]([CH3:16])[S:15][C:4]1=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:27][CH3:28])(=O)=O>CN(C)C=O>[CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:27][CH3:28])=[O:10])[C:6](=[O:12])[C:5]2[CH:13]=[C:14]([CH3:16])[S:15][C:4]1=2)[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(C)sc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2sc(C)cc2c1=O
Temperature: 100 °C

Procedure:
A suspension of 0.237 part of 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylic acid and 0.83 part of pulverized potassium carbonate in 6 parts by volume of dry dimethylformamide is stirred under heating at 100° for 1 hour. To the mixture is then added 0.3 part by volume of diethyl sulfate. The mixture is stirred under heating at 100° C for 1 hour and filtered to remove insoluble material. The filtrate is concentrated to dryness under reduced pressure and the residue is extracted with chloroform. Evaporation of the solvent from the extract gives ethyl 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylate as crystals. Recrystallization from ethyl acetate yields colorless plates melting at 140°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](/[N:8]=[CH:9]/[C:10]2[O:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[N:25]=2)[CH2:20][CH2:19]1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[N:25]=2)[CH2:22][CH2:23]1
Reactant: Cn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)oc1=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1nc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3F)CC2)oc1=O
Yield: 85.8 %

Procedure:
5-[1-(2-Fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (9f, 0.42 g, 1 mmol) on reduction with sodium cyanoboro hydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 5-[1-(2-fluoro-4-[(5-nitro-2-furyl)methyl]aminophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (10f, 358 mg, 86%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:22]=[CH:21][C:10]([O:11][CH:12]([CH3:20])[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:9][CH:8]=2)[C:5]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:4]=2[N:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[N:6]([C:7]2[CH:22]=[CH:21][C:10]([O:11][CH:12]([CH3:20])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[C:5]2[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[CH:26][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCC(C)Oc1ccc(-n2c(C)nc3cc(C(F)(F)F)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cc(C(F)(F)F)ccc2n1-c1ccc(OC(C)CCC(=O)O)cc1

Procedure:
A solution of 2.4 g of 12 and 0.25 g of sodium hydroxide in 50 ml of aqueous ethanol was refluxed for one hour, and extracted with ether. The extract was dried and concentrated. The residue was crystallized from ether-hexane to give 13, as a white solid, m.p.: 67°-68° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4]>CO.[Ni]>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([NH2:10])[C:3]=1[NH2:4]
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1C
Agent: [Ni]
Solvent: CO
Product: Cc1ccc(N)c(N)c1C

Procedure:
A solution of 2,3-dimethyl-6-nitroaniline (83 g, 500 mmol) in methanol (1000 mL) was hydrogenated (H2, 50 psi) over Raney Nickel (5 g). On completion, the reaction mixture was filtered, and the mother liquor was evaporated to dryness to give a dark solid as the product.