Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC[C:3]1[C:8]([CH2:9][NH:10][C:11]2[NH:12][C:13](=[O:20])[C:14]3[NH:15][CH:16]=[N:17][C:18]=3[N:19]=2)=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(C)=O.C(#N)C.C([O-])(=O)C.C([NH+](CC)CC)C>O>[CH2:9]([NH:10][C:11]1[NH:12][C:13](=[O:20])[C:14]2[NH:15][CH:16]=[N:17][C:18]=2[N:19]=1)[C:8]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1CNc1nc2nc[nH]c2c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: CC[NH+](CC)CC
Solvent: CS(C)=O
Solvent: O
Solvent: CC#N
Product: O=c1[nH]c(NCc2ccccc2)nc2nc[nH]c12
Reaction time: 1 h

Procedure:
Introduced into a 1.5 ml Eppendorf tube were 100 μl of a solution containing 10 mmol·l−1 of 6-aminomethylbenzylguanine in anhydrous dimethylsulfoxide (1 μmol) and 100 μl of a solution containing 10 mmol·l−1 of Tb(KR)-NHS in anhydrous dimethylsulfoxide (1 μmol). The mixture was stirred for one hour. The reaction was monitored by HPLC on a Merck Lichrospher RP °18, 5 μm, 125×4.6 column with a gradient of acetonitrile in water containing 25 mM of triethylammonium acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C(=O)([O-])[O-].[K+].[K+].I[CH2:33][CH3:34]>CC(=O)CC>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([O:22][CH2:33][CH3:34])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 64.7 %

Procedure:
3.0 g (9 millimoles) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzoic acid, 4 g (30 millimoles) of potassium carbonate and 2.9 g (18.9 millimoles) of iodoethane in 27 ml of butan-2-one were refluxed until conversion was complete (monitored by thin layer chromatography). When the mixture had cooled, the solid was filtered off, the filtrate was evaporated down and the residue was recrystallized from methanol to give 2.1 g (65%) of the title compound of melting point 137°-138° C.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].O1CCCC1>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: COC(=O)N1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)N1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C

Procedure:
A mixture of methyl 4-(7-acetyl-5-chloroquinolin-8-yl)piperazine-1-carboxylate (0.018 g, 0.052 mmol) and ammonium acetate (0.0399 g, 0.518 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.13 mL, 0.13 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C17H22ClN4O2 (M+H)+: m/z=349.1; Found: 349.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[ClH:12].Cl.[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][SH:29])[CH2:22][CH2:21]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[OH2:2].[ClH:14].[ClH:12].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[SH:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:31][CH:30]=3)[CH2:21][CH2:22]2)[OH:11])=[CH:7][CH:8]=1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: COc1ccc(N=C=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(O)=[SH]CCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Product: O
Yield: 48.9 %

Procedure:
The procedure described in Example 2 was followed, using 0.9 g of 4-methoxyphenyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.72 g (25% of theory) of N-(4-methoxyphenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride monohydrate as an off-white crystalline solid, M.p. 235°-237° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](OS(C)(=O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:10])([F:11])[F:1])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(F)(F)F)CC1
Temperature: 60 °C
Yield: 33.8 %

Procedure:
To a stirred solution of 2-trifluoromethyl-phenol (1 g, 0.00617 mole) in DMF (10 mL) was added cesium carbonate (4.01 g, 0.0123 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.72 g, 0.00616 mole). The reaction mixture was heated at 60° C. overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (0.1% ethyl acetate in hexane) to afford 0.72 g (34%) of 4-(2-trifluoromethyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 346.16 (M+1)+, 94.42%. A solution of 4-(2-trifluoromethyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.72 g, 0.00208 mole) in dichloromethane was stirred at 0-5° C. To the cold solution was added TFA (1 mL) dropwise and stirring was continued at 10° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with ether and dried to afford 0.22 g (99%) of 4-(2-trifluoromethyl-phenoxy)-piperidine trifluoracetate. LCMS: 360.1 (M+1)+, 99.3%, 1H NMR (CDCl3): δ 8.9-8.5 (bd, 2H), 7.62-7.6 (d, 1H), 7.56-7.46 (t, 1H), 7.1-7.02 (t, 1H), 7.0-6.94 (d, 1H), 5.0-4.8 (m, 1H), 3.5-3.3 (s, 4H), 2.3-2.2 (s, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:12]1([CH3:27])[CH:17]=[CH:16][C:15]([C:18]2[N:22]=[C:21]([CH2:23][C:24](O)=[O:25])[O:20][N:19]=2)=[CH:14][CH:13]=1.N1CCCCC1>C(O)C>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:23]([C:21]3[O:20][N:19]=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([CH3:27])=[CH:13][CH:14]=4)[N:22]=3)[C:24](=[O:25])[O:1]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2noc(CC(=O)O)n2)cc1
Reactant: COc1ccc(C=O)c(O)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc2cc(-c3nc(-c4ccc(C)cc4)no3)c(=O)oc2c1

Procedure:
4.5 parts of 2-hydroxy-4-methoxy benzaldehyde and 7.38 parts of the ethyl ester of 3-p-tolyl-1,2,4-oxadiazol-5-acetic acid (melting point: 56° C) are dissolved in 80 parts of ethanol. 0.3 part of piperidine is added and the mixture is heated for 1 hour under reflux. After cooling, the crystalline precipitate obtained is filtered and washed in ethanol. Thus 8.5 parts of 7-methoxy-3-(3-p-tolyl-1,2,4-oxadiazol-5-yl) coumarin are obtained which melts at 227° C.
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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.[Cu]I>[F:6][C:7]1[C:8]([C:4]#[C:3][C@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@@H](C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-but-3-yn-2-ol (37 mg, 0.53 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and CuI (2 mg) in a mixture of DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after a silica gel column with a 0-70% EtOAc in hexanes gradient and trituration with petroleum ether. (Yield 21 mg, 48%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[CH:18]3)=[N:8][CH:9]=1)=[S:3].Br[CH2:31][C:32](=O)[CH2:33][CH3:34]>C(O)C>[CH2:33]([C:32]1[N:1]=[C:2]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[CH:18]4)=[N:8][CH:9]=2)[S:3][CH:31]=1)[CH3:34]
Reactant: COC(=O)C(C)n1ccc2cc(OCCCOc3ccc(C(N)=S)cn3)ccc21
Reactant: CCC(=O)CBr
Solvent: CCO
Product: CCc1csc(-c2ccc(OCCCOc3ccc4c(ccn4C(C)C(=O)OC)c3)nc2)n1
Temperature: 80 °C
Yield: 98.4 %

Procedure:
A mixture of methyl 2-[5-(3-{[5-(aminocarbonothioyl)-2-pyridinyl]oxy}propoxy)-1H-indol-1-yl]propanoate (Example 68, 0.1 g, 0.24 mmol) and 1-bromo-2-butanone (0.05 g, 0.29 mmol) in ethanol (8.90 mL) was heated under argon at 80° C. for 3 h. The resulting mixture was concentrated. The title compound (0.11 g, 98%) was isolated by column chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 8.69 (dd, 1H), 8.13 (dd, 1H), 7.25-7.10 (m, 3H), 6.90-6.81 (m, 3H), 6.47 (d, 1H), 5.12 (qt, 1H), 4.58 (t, 2H), 4.20 (t, 2H), 3.71 (s, 3H), 2.85 (qt, 2H), 2.36-2.24 (m, 2H), 1.82 (d, 3H), 1.35 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:2]([CH3:1])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]1)[N:10]=[C:9]2[N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cccc(C)c1CNc1cc2c(N3CCCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI): predicted mass calcd. for C25H25FN6O2, 460.2
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:15]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[NH2:35])[C:30]#[N:31].C1N2CCN(CC2)C1>CN1C(=O)CCC1>[CH3:13][C:12]1[C:4]([CH2:3][C:2]2[NH:35][C:34]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=3[N:26]=2)=[C:5]2[C:9](=[C:10]([CH3:14])[CH:11]=1)[N:8]([S:15]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:16])=[O:17])[CH:7]=[CH:6]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=C(Br)Br)c(C)cc(C)c32)cc1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: C1CN2CCN1CC2
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cc4nc5cc(C#N)ccc5[nH]4)c(C)cc(C)c32)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(2,2-dibromovinyl)-5,7-dimethyl-1-tosyl-1H-indole (130 mg, 0.269 mmol), 3,4-diaminobenzonitrile (46.6 mg, 0.350 mmol), and DABCO (75 mg, 0.673 mmol) in NMP (0.5 mL) was stirred at 100° C. for 19 h. The reaction mixture was cooled to room temperature. The reaction mixture was concentrated and purified by silica gel flash column chromatography (heptanes/EtOAc=1/3 to 0/1) to give the title compound. MS (ESI+) m/z 455.2 (M+H).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH:10]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)=[CH2:11].C(N(CC)C(C)C)(C)C>CC(C)=O>[CH:10]([C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)=[CH:14][CH:13]=1)=[CH2:11]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C=Cc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: C=Cc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 18.4 g (0.1 mole) of cyanuric chloride in 150 ml of acetone being stirred at 0°-5° C. was added dropwise over a 1/2 hr. period a solution of 11.9 g (0.1 mole) of 4-vinylaniline and 12.9 g (0.1 mole) of N,N-di-iso-propylethylamine. After the addition was complete, the solution was stirred at room temperature for 15 min., and then poured into 1 liter of ice water to isolate the product. The product was collected by filtration, washed with 200 ml of water, and dried in vacuo at room temperature to give 25 g. Recrystallization from 75 ml. of benzene gave 15.0 g (56%) (mp 152°-154°).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)[S:7][C:8]=1[C:9]1[NH:13][CH:12]=[N:11][N:10]=1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[CH2:1]([O:3][C:4]1[N:5]=[C:6]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)[S:7][C:8]=1[C:9]1[N:13]=[CH:12][N:11]([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][O:36]2)[N:10]=1)[CH3:2]
Reactant: CCOc1nc(-c2ccnc(NC(C)=O)c2)sc1-c1nnc[nH]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOc1nc(-c2ccnc(NC(C)=O)c2)sc1-c1ncn(C2CCCCO2)n1
Yield: 59.7 %

Procedure:
Using N-{4-[4-ethoxy-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (6.2 g, 19 mmol) produced in Example 8-B (v), p-toluenesulfonic acid monohydrate (4.3 g, 23 mmol), 3,4-dihydro-2H-pyran (7.9 g, 94 mmol) and tetrahydrofuran (188 mL) as starting materials and in the same manner as in Example 4-B(i), the title compound (4.7 g, 60%) was obtained as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:13]1[S:17][C:16]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=3)[N:19]=2)=[C:15]2[CH2:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH2:34][C:14]=12)[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([C:13]1[S:17][C:16]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=3)[N:19]=2)=[C:15]2[CH2:31][CH2:32][C:33]([CH3:35])([CH3:36])[CH2:34][C:14]=12)[CH3:12]
Reactant: CCc1sc(-c2nc(-c3ccc(CO)cc3)no2)c2c1CC(C)(C)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCc1sc(-c2nc(-c3ccc(C=O)cc3)no2)c2c1CC(C)(C)CC2
Temperature: -40 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
To a cold solution (−70° C.) of oxalyl chloride (169 mg, 1.34 mmol) and DMSO (209 mg, 2.67 mmol) in DCM (4 mL) a solution of {4-[5-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methanol (410 mg, 1.11 mmol) in DCM (5 mL) is added. The mixture is warmed to −40° C. within 30 min and then triethylamine (394 mg, 3.89 mmol) is added. Stirring is continued at −40° C. for 1 h, then at rt. The reaction is quenched by adding water and the mixture is extracted with diethyl ether. The organic extract is dried over MgSO4, filtered and the solvent of the filtrate is evaporated. The crude product is purified by chromatography on prep. TLC plates with heptane:EA 3:1 to give 4-[5-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,2,4]oxadiazol-3-yl]-benzaldehyde (180 mg) as a white solid; LC-MS: tR=1.24 min, [M+1]+=367.24.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH:23]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37])([O-:33])=[O:32]>ClCCl>[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH:23]=1)=[O:37])([O-:33])=[O:32]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3ccccc3[N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (200 mg, 647 μmol) in dichloromethane (15 mL) was added triethylamine (200 μL, 1.43 μmol) and 2-nitrobenzoyl chloride (190 μL, 1.43 mmol). The solution was stirred at room temperature for 96 hours, and was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=5.12 min, MH+ 459].
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[CH:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])=[CH2:7].O>C(OCC)(=O)C>[O:13]=[C:9]1[CH2:10][CH2:11][CH2:12][N:8]1[CH:6]([C:5]1[N:4]=[CH:3][NH:2][N:1]=1)[CH3:7]
Reactant: C=CN1CCCC1=O
Reactant: c1nc[nH]n1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(c1nc[nH]n1)N1CCCC1=O
Yield: 63 %

Procedure:
This product is synthesised, in 63% yield, from 1,2,4-triazole and 1-vinyl-2-pyrrolidinone by a similar method described in Example 1. On account of the higher water solubility of this product, ethyl acetate (3×50 ml) is used to extract it from the aqueous phase during washing. The product distils as a pale yellow oil, bp 150°/0.05 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=[CH2:13].[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:13][CH:12]([CH3:14])[C:11]([OH:16])=[O:15])=[CH:5][CH:4]=1
Reactant: C=C(C)C(=O)O
Reactant: COc1ccc(CS)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CSCC(C)C(=O)O)cc1

Procedure:
p-Methoxy-α-toluene thiol (15.4 g., 0.1 mol.) is added to a solution of methacrylic acid (8.6 g., 0.1 mol.) in 50 ml. 2N sodium hydroxide. The mixture is heated on the steam bath for 3 hours, then refluxed for two hours and cooled. The mixture is extracted with ether, then the aqueous layer is acidified with concentrated HCl and extracted with dichloromethane. The acidic extracts are washed with brine, dried (MgSO4) and evaporated in vacuo. The resulting semi-solid is taken up in 50 ml. of dichloromethane, diluted with 50 ml. hexane, and chilled. 3-[(4-methoxyphenyl)methylthio]-2-methylpropanoic acid is collected as a white crystalline solid, m.p. 74°-82° (5.5 g.).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]3(OCC[O:13]3)[CH2:10]2)=[CH:5][CH:4]=1)#[CH:2]>C1COCC1.Cl.C(OCC)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[CH2:10]2)=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc2c(c1)CC1(CC2)OCCO1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#Cc1ccc2c(c1)CC(=O)CC2
Reaction time: 2 h
Yield: 46.7 %

Procedure:
A solution of 7′-ethynyl-3′,4′-dihydrospiro[1,3-dioxolane-2,2′(1′H)-naphthalene] (0.85 g, 3.9 mmol ) in THF (15 ml ) and 1N HCl (5 ml) was stirred overnight at room temperature. Concentrated HCl (2×0.5 ml) was then added in two aliquots 2 hours apart. After stirring a further 2 hours the solution was diluted with diethyl ether, the aqueous phase was separated, and the solution dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (15 g) eluting with diethyl ether:hexane (1:9→1:4) to give 7-ethynyl-2-tetralone as a solid (0.31 g). 1H NMR (CDCl3, 200 MHz) δ: 2.54 (t, J=7 Hz, 2H, CH2), 3.05 (s, 1H, ethynyl H), 3.06 (t, J=7 Hz, 2H, CH2), 3.56 (s, 2H, CH2), 7.18 (d, J=8 Hz, 1H, Ar), 7.26 (s, 1H, Ar), 7.34 (d, J=8 Hz, 1H, Ar).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][S:13][C:7]=3[CH2:6][C:5]=12.[CH2:14](O)[CH3:15]>C(O)(=O)C.[Pd]>[CH3:3][N:4]1[CH2:15][CH2:14][CH:7]([CH:6]2[C:7]3[S:13][CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][N:1]3[N:2]=[CH:3][N:4]=[C:5]23)[CH2:6][CH2:5]1
Reactant: C1=Cn2cnnc2Cc2sccc21
Reactant: CCO
Agent: [Pd]
Solvent: CC(=O)O
Product: CN1CCC(C2c3sccc3CCn3ncnc32)CC1
Yield: 76 %

Procedure:
A mixture of compound (10) (0.00342 mol) and compound (9) (0.00342 mol) was hydrogenated in acetic acid (1.65 ml) and ethanol (150 ml) with palladium on activated carbon (2 g) as a catalyst at 50° C. overnight under a 3 bar pressure in a Parr apparatus. The catalyst was filtered through celite and the filtrate was evaporated till dryness. The residue was taken up in dichloromethane and washed with potassium carbonate 10%. The organic layer was dried (MgSO4), filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 90/10/1) (15-40 μm). The pure fractions were collected and evaporated. The residue (1.5 g) was crystallized from 2,2'-oxybispropane, yielding 0.92 g (76%) of (±)-6,10-dihydro-10-(1-methyl-4-piperidinyl)-5H-thieno[2,3-d][1,2,4]triazolo[1,5-a]azepine; mp. 123.4° C. (comp. 11).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][N:14]([CH3:28])[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][CH:18]2[CH2:17][CH2:16][C:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([N:14]([CH3:28])[CH3:13])[CH2:20][CH2:19]2)=[CH:5]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(NCCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Tryptamine (320 mg) was dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 4-dimethylamino-4-phenylcyclohexanone (435 mg), glacial acetic acid (229 μl) and sodium triacetoxyborohydride (550 mg), the suspension was stirred for 3 days at RT. For working up, water (20 ml) was added to the reaction mixture. The organic phase was separated off and the aqueous phase was extracted once with ether and then rendered strongly alkaline with sodium hydroxide solution. The aqueous phase was milky-cloudy at pH 10. It was extracted with ethyl acetate (4×10 ml), the extracts were combined, dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained (674 mg) was recrystallized twice from ethyl acetate (5 ml). 22 mg of the nonpolar diastereoisomer of N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained (m.p. 134-138° C.).