Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[NH:54]1[CH:58]=[N:57][C:56]([C:59](O)=[O:60])=[N:55]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:59]([C:56]2[N:57]=[CH:58][NH:54][N:55]=2)=[O:60])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)c1nc[nH]n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)c2nc[nH]n2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 68 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1H-1,2,4-triazole-3-carboxylic acid as the starting materials in 68% yield. LCMS for C26H26ClN10O2 (M+H)+: m/z=545.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N12CCCN=C1CCCCC2.Cl>ClCCl>[C:25]([Si:22]([CH3:24])([CH3:23])[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccc(O)cc12
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(N3C(=O)c4ccccc4C3=O)c2c1
Yield: 79.6 %

Procedure:
To a suspension of 32.26 g (0.115 mol) of 2-(5-hydroxy-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione in 320 ml of dichloromethane, a solution of 43.54 g (0.288 mol) of TBDMS chloride in 150 ml of dichloromethane was added. The resulting mixture was treated dropwise with 35.5 ml (0.23 mol) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature, obtaining a clear solution. After 3 hours the reaction mixture was poured in 300 ml of a solution 0.1 N of hydrochloric acid. The aqueous layer was separated and extracted with 200 ml of dichloromethane. Organic extracts were dried over sodium sulfate and the solvent evaporated under vacuum. The raw product was purified by flash chromatography over silica gel eluiting with dichloromethane-cyclohexane-ethyl acetate (4:4:2). 36.03 g of product as white solid were obtained. Yield=79.2%. mp=225-228° C. HPLC r.t. 8.3 [M+H]+=394 [2M+H]+=787
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([O:13][CH2:14][CH2:15][NH2:16])=[CH2:12].C1C=CC=CC=1.[BH4-].[Na+]>O>[CH:11]([O:13][CH2:14][CH2:15][NH:16][CH:8]([CH3:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:12]
Reactant: CC(=O)Cc1ccccc1
Reactant: C=COCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: C=COCCNC(C)Cc1ccccc1
Yield: 64 %

Procedure:
A solution of 40.2 g. (0.3 mole) of phenylacetone, 26.2 g. (0.3 mole) of 2-aminoethyl vinyl ether and 200 cc. of anhydrous benzene were heated under reflux under a DeanStart water separator until the theoretical amount of water was removed (ca. 4 hours). At the end of this time, the benzene was removed under vacuum and the resulting crude imine was taken up in 450 cc. of dry methanol. To this solution was added 22.6 g. (0.6 mole) of sodium borohydride in small portions over a period of 1/2 hour. After the addition was complete, the reaction mixture was refluxed for 3 hours. The methanol was removed under vacuum and 300 cc. of water, 150 cc. of 20% potassium hydroxide and 60 g. of potassium hydroxide were added successively and the resulting oil was extracted with ether. After drying the ether solution over anhydrous magnesium sulfate, filtering and concentrating the resulting oil, it was distilled. 32.5 g. (64% yield) of the product as a colorless oil was obtained, b.p. 100°-102°/1.5 mm; ND25 1.5070.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.Br[CH2:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=1)=O>C(O)C>[Br:1][C:2]1[C:3]([C:14]2[S:16][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[N:15]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: Cn1cc(C(=O)CBr)cn1
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Solvent: CCO
Product: CCNC(=O)Nc1cc(-c2nc(-c3cnn(C)c3)cs2)c(Br)cn1
Temperature: 80 °C
Yield: 99.5 %

Procedure:
In a 25 mL flask 5-bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 6, 478 mg, 1.58 mmol) and 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethanone (Intermediate 96, 352 mg, 1.73 mmol) were suspended in ethanol (10 mL). The reaction mixture was heated at 80° C. for 12 h, cooled to room temperature and concentrated to one half the volume under reduced pressure. The resulting solids were filtered and washed with acetonitrile. Isolation gave 640 mg of the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]I)([CH3:4])([CH3:3])[CH3:2].[I-].[CH2:13]([O:20][C:21]1[CH:26]=[C:25](I)[CH:24]=[CH:23][C:22]=1[N:28]1[S:32](=[O:34])(=[O:33])[N:31]([CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:30](=[O:41])[CH2:29]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O.[Zn]>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][C:25]1[CH:24]=[CH:23][C:22]([N:28]2[CH2:29][C:30](=[O:41])[N:31]([CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[S:32]2(=[O:34])=[O:33])=[C:21]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: CC(C)(C)OC(=O)NCCI
Agent: [I-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc dust (3 g, 46 mmol) is placed in a flask and heated under vacuum to remove traces of water. DMF (25 mL) is then added under nitrogen atmosphere. Dibromoethane (cat. 0.25 mL) is added and the mixture heated until effervescence occurs. The reaction is allowed to cool to RT over 30 min and chlorotrimethylsilane (cat 0.3 mL) is added, followed after 30 min with (2-iodoethyl)-carbamic acid tert-butyl ester (4.5 g, 16.5 mmol) dissolved in 10 mL of DMF. After 30 min, TLC indicates the iodide has been consumed and Pd2(dba)3 (0.20 g) and tri-o-tolylphosphine (0.30 g) are added, followed by the dropwise addition of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (5 g, 9.2 mmol) dissolved in 25 mL of DMF. The reaction mixture is stirred for 14 h and then diluted with EtOAc and filtered through Celite. The filtrate is washed with 1M HCl, brine and water, dried over MgSO4, filtered through a short plug of silica and concentrated to afford the title compound as a light yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15](OC)=[CH:14][CH:13]=2)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6](O)=[CH:7][C:8]=2O)[O:3]1.COC1C=CC(C2C(=O)C3C(=CC(O)=CC=3O)OC=2)=CC=1.OC1C(C2C=CC(O)=CC=2)C(=O)C2C(=CC(O)=CC=2O)O1.N[C@H](C(=O)O)CC[S+](C)C[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O>COCCO>[OH:1][CH:2]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1
Reactant: COc1ccc(C2C(=O)c3c(O)cc(O)cc3OC2O)cc1
Agent: COc1ccc(-c2coc3cc(O)cc(O)c3c2=O)cc1
Agent: C[S+](CC[C@H](N)C(=O)O)C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: O=C1c2c(O)cc(O)cc2OC(O)C1c1ccc(O)cc1
Solvent: COCCO
Product: O=C1c2ccccc2OC(O)C1c1ccccc1

Procedure:
The assay of 2,5,7-trihydroxy-4′-methoxyisoflavanone dehyderatase (biochanin A synthetase) was carried out as follows. 2,5,7,4′-tetrahydroxyisoflavanone (10 nmol) dissolved in 2-methoxyethanol was incubated together with licorice HI4′OMT (1 μg) and 1 μmol of S-adenosyl-L-methionine (SAM) at 30° C. for 15 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)[C:7]=2[CH:29]=1.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:8]2[C:7]3[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[S:11][CH2:10][C:9]2=[O:12])[CH2:20][CH2:19]1
Reactant: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CS2
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CS2

Procedure:
tert-Butyl {1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 51) (750 mg, 1.78 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([OH:24])[CH2:22][CH3:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:24][C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][N:27]=2)[CH2:22][CH3:23])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(Oc1ccc(C#N)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Yield: 73 %

Procedure:
To a solution of (RS)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-propan-1-ol (described herein above) (21.0 mg, 0.0576 mmol) and 6-chloro-nicotinonitrile (9.6 mg, 0.069 mmol) in 1 mL of DMF was added sodium hydride (60%, 10 mg, 0.25 mmol) at room temperature. The mixture was stirred over night and quenched by an addition of aq. ammonium chloride solution. The mixture was extracted with ethyl acetate and the separated organic layer was washed with water two times and brine subsequently. The organic phase was dried over anhydrous sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by TLC (heptane/ethyl acetate 2:1) yielding the titled compound(19.6 mg, 73% yield) as a light yellow oil. ES-MS m/e: 466.1 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:4]=1[C:5](OC)=[O:6].[NH3:14]>C1COCC1.CO>[Br:13][C:10]1[CH:9]=[C:4]2[C:3]([CH2:2][NH:14][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: N
Reactant: COC(=O)c1cc(Br)ccc1CBr
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NCc2ccc(Br)cc21

Procedure:
Methyl 2-bromomethyl-5-bromobenzoate (0.1 mol) was dissolved in THF/methanol (200 ml) (1:1) and the solution obtained was saturated with dry ammonia gas. The solvent was removed and the residue was triturated with water, diethyl ether and hexane and then recrystallised from ethanol/dichloromethane to obtain 6-bromo-2,3-dihydro-isoindol-1-one (12.5 g). 1H NMR (400 MHz, d6 DMSO) δ 8.70 (1H, bs), 7.78 (1H,s), 7.77 (1H, d, J=7 Hz), 7.55 (1H, d, J=7 Hz), 4.35 (2H,s). m/z (ES+) 212 (M+). b) 5-Bromo-3-methoxy-1H-isoindolium trifluoromethanesulfonate Prepared in a similar manner to that of Example 1a using 6-bromo-2,3-dihydro-isoindol-1-one. 1H NMR (360 MHz, CDCl3) δ 12.5 (1H, brs), 8.05 (1H,d, J=1 Hz), 7.94 (1H, dd, J=7 and 1 Hz), 7.66 (1H, dd, J=7 and 1 Hz), 5.07 (2H, s), 4.60 (3H, s). m/z (ES+) 226 (M+). c) (6-Bromo-3H-isoindol-1-yl)hydrazine 5-Bromo-3-methoxy-1H-isoindolium trifluoromethanesulfonate (3.7 g) was dissolved in THF (35 ml) and triethylamine (2.8 ml) was added followed by hydrazine (1 M in THF, 35 ml). After an hour the solid which had precipitated was filter off and dried to give title compound (2.8 g) 1H NMR (360 MHz, CDCl3) δ 12.5 (1H, brs), 7.85 (1H,d, J=1 Hz), 7.51 (1H, dd, J=7 and 1 Hz), 7.25 (1H, dd, J=7 and 1 Hz), 4.49 (2H, s). m/z (ES+) 226 (M+). d) 8-Bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (6-Bromo-3H-isoindol-1-yl)hydrazine (2.8 g) was stirred in 10% trifluoroacetic acid in dichloromethane (40 ml) and 5-methyl-3-phenyl-4-isoxazole carboxaldehyde was added (2.33 g) and the reaction was stirred for 0.5 hours. The solvent was removed and the residue was partitioned between ethyl acetate and water and the organic layer was washed with saturated sodium hydrogen carbonate, dried, filtered and evaporated. The residue was taken up into methanol and dichloromethane, sodium acetate was added and the stirred suspension was treated dropwise with bromine (0.5 ml). The reaction was diluted with water and extracted into dichloromethane and dried, filtered and evaporated. The product was purified by silica chromatography using ethyl acetate as eluant to yield the title compound (1.46 g).
Reaction SMILES: [OH:1][CH:2]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:30][CH:29]=1)[CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=1)[C:4]([O:6]CC1C=CC=CC=1)=[O:5].[H][H]>C(O)C.[Pd]>[OH:1][CH:2]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:30][CH:29]=1)[CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(OCc1ccccc1)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2cccnc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2cccnc2)cc1
Reaction time: 1 h

Procedure:
To a solution of benzyl (2RS,3RS)-3-hydroxy-3-[4-(pyridin-3-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (3.00 g, 5.38 mmol) in ethanol (200 ml) was added 10% palladium/carbon (containing water by 50%, 300 mg), and the mixture was stirred under a 1 atm hydrogen stream for 1 hr. The reaction solution was filtered with celite and the filtrate was concentrated to give the objective substance (2.8 g, 100%, crude). The present compound was used for, the next reaction as a crude compound.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[CH:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][C:48]=1[C:57](O)=[O:58].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(N(CC)CC)C>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:57]([C:48]1[CH:49]=[CH:50][C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:47]=1)=[O:58])=[O:43]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2ccc3ccccc3c2)s1
Reaction time: 8 h
Yield: 19.6 %

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (3.70 g) was dissolved in dimethylformamide (20 ml). Naphthalene-2-carboxylic acid (0.95 g) and diphenylphosphoryl azide (1.29 ml) were added under ice-cooling and dissolved in the solution. A solution of triethylamine (2.24 ml) in dimethylformamide was dropwise added, and the mixture was allowed to stand overnight at room temperature. Then, a 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 0.53 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)naphthalene-2-caboxamide.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:12][C:11]([C:13]([O:15]C)=[O:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:17]>>[ClH:17].[N:1]1([CH2:7][C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CN2CCOCC2)s1
Agent: Cl
Product: O=C(O)c1ccc(CN2CCOCC2)s1
Temperature: 100 °C

Procedure:
A mixture of 3.01 g of methyl 5-(morpholin-4-ylmethyl)thiophene-2-carboxylate and 30 mL of 6.0 M hydrochloric acid was subjected to heating under reflux overnight at 100° C. The reaction mixture was concentrated under reduced pressure, and the residue was washed with acetonitrile, thereby obtaining 3.05 g of 5-(morpholin-4-ylmethyl)thiophene-2-carboxylic acid hydrochloride.
Reaction SMILES: BrC1C(C(N[C@H]2CCC[C@@H]2NC2C=NC(C(F)(F)F)=CN=2)=O)=NC=CC=1.Cl.[F:28][C:29]([F:44])([F:43])[C:30]1[N:31]=[CH:32][C:33]([NH:36][C@H:37]2[CH2:41][CH2:40][CH2:39][C@@H:38]2[NH2:42])=[N:34][CH:35]=1.[CH2:45]([O:47][C:48]1[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][C:49]=1[C:50](O)=[O:51])[CH3:46]>>[CH2:45]([O:47][C:48]1[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][C:49]=1[C:50]([NH:42][C@H:38]1[CH2:39][CH2:40][CH2:41][C@@H:37]1[NH:36][C:33]1[CH:32]=[N:31][C:30]([C:29]([F:28])([F:43])[F:44])=[CH:35][N:34]=1)=[O:51])[CH3:46]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: CCOc1ccc(C)cc1C(=O)O
Agent: Cl
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1Br
Product: CCOc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
Prepared according to the procedure for 3-bromo-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide (Example 28) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 75 mg, 0.27 mmol) and 2-ethoxy-5-methylbenzoic acid (CAS number 854645-34-4; 57 mg, 0.32 mmol) and was then purified by column chromatography (silica, 40-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: NCCC1C=CC(O)=C(O)C=1.C[N:13]1[C@H:17]2[C@@H:18]([C:28](OC)=O)[C@@H:19]([C:21]3[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=3)[CH2:20][C@@H]1CC2.[ClH:32].[ClH:33].FC1C=CC(C(C2C=CC(F)=CC=2)OCCN2CCN(CCCC3C=CC=CC=3)CC2)=CC=1.C1N(CCCC2C=CC=CC=2)CCN(CCOC(C2C=CC(F)=CC=2)C2C=CC(F)=CC=2)C1>>[ClH:32].[Cl:32][C:25]1[CH:26]=[C:21]([C:19]23[CH2:28][CH:18]2[CH2:17][NH:13][CH2:20]3)[CH:22]=[CH:23][C:24]=1[Cl:33]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(F)cc2)C[C@@H]2CC[C@H]1N2C
Agent: Cl
Agent: Fc1ccc(C(OCCN2CCN(CCCc3ccccc3)CC2)c2ccc(F)cc2)cc1
Agent: NCCc1ccc(O)c(O)c1
Product: Clc1ccc(C23CNCC2C3)cc1Cl

Procedure:
The dopamine uptake transporter binding assay was performed according to the methods described in Madras et al., 1989, Mol. Pharmacol. 36(4):518–524 and Javitch et al., 1984, Mol. Pharmacol. 26(1):35–44. The receptor source was guinea pig striatal membranes; the radioligand was [3H]WIN 35,428 (DuPont-NEN, Boston, Mass.) (60–87 Ci/mmol) at a final ligand concentration of 2.0 nM; the non-specific determinant 1 μM 1-[2-[bis(4-Fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride (“GBR 12909”), a high-affinity dopamine uptake inhibitor; reference compound was also GBR 12909. (−)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl was obtained according to the method of Example 5, above. Reactions were carried out in 50 mM TRIS-HCl (pH 7.4), containing 120 mM NaCl and at 0° C. to 4° C. for two hours. The reaction was terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped in the filters was determined and compared to control values in order to ascertain the interactions of the test compound with the dopamine uptake site. The data are reported in Table 1 below.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[OH:13])([O-:3])=[O:2].N.[Cl-].[NH4+].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].Cl>O>[NH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:13]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1O
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: O
Product: Nc1cccc([N+](=O)[O-])c1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
A suspension of 2,6-dinitrophenol (5 g), ammonia (3 ml) and ammonium chloride (14.30 g) in water (30 ml) was heated to 70° C. A solution of sodium sulphide nonahydrate (24.19 g) in water (23 ml) was added and the resulting mixture stirred at 70° C. for 2 hours. The reaction was cooled to room temperature, acidified (pH 3.2) with 2N HCl, and the brown precipitate isolated by filtration. The filtrate was extracted with chloroform (6×75 ml), the organic extracts combined with the precipitate, and evaporated in-vacuo to yield a dark brown solid. The solid was purified by flash chromatography (SiO2; dichloromethane) to yield the title compound (2.86 g, 68%) as a brown solid. δH (250 MHZ;d6DMSO), 6.75 (1H,td,ArH), 6.90 (2H,bs,ArNH2), 6.92 (1H,m,ArH), 7.14 (1H,m,ArH).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)=O.CC(C[AlH]CC(C)C)C.CO>C1COCC1.CCOCC.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>[OH:2][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(NCc2cccnc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(NCc2cccnc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a −78° C. solution of N-(4-methoxycarbonylphenyl) pyrid-3-ylmethylamine (105 g, 0.433 moles, leg) in THF (17 volumes) was added slowly DIBAl-H (1M in toluene, 1084 mL, 1.084 moles, 2.5 eq,) and held cold for 1 hour. The reaction was then allowed to warm to 0° C. for 2 h. The reaction was carefully quenched with methanol (1.8 eq). It was then diluted with ether (62 volumes) and Saturated Rochelle's salt (37 volumes) and stirred vigorously overnight. The layers were separated and the aqueous extracted with EtOAc. The combined organics were washed with brine, dried with MgSO4, filtered, and concentrated to give N-(4-hydroxymethylphenyl)pyrid-3-ylmethylamine (88.2 g, 95% Yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][C:16]#[N:17]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[C:15](=[CH:4]/[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])/[C:16]#[N:17])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccccc1F
Product: COc1ccc(/C(C#N)=C/c2ccccc2F)cc1OC
Yield: 39.9 %

Procedure:
2-Fluorobenzaldehyde (620 mg) and 3,4-dimethoxybenzyl cyanide (880 mg) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (562 mg, yield: 40%).