Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=O)[C:7](=[CH:19][N:20](C)[CH3:21])[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.C(O)(=O)C.C(N)=[NH:31]>C(N)=N>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:31]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N+:9]([O-:18])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: N=CN
Reactant: CN(C)C=C1C[N+]([O-])=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Solvent: CC(=O)O
Product: [O-][N+]1=C(c2ccccc2Cl)c2cc(Cl)ccc2-c2ncncc2C1

Procedure:
A mixture of 0.4 g (1.1 mmol) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one 2-oxide and 1.0 g (9.6 mmol) of formamidine acetate in 20 ml of formamidine was heated on a steam bath for 7 hr. The mixture was poured over ice and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was triturated with ether to give an off-white solid, mp 215°-217° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)=[CH:17][C:10]=23)=[C:5]([O:31][CH3:32])[CH:4]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[CH3:32][O:31][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][C:16]([CH:18]3[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]3)=[CH:17][C:10]=12)[C:1]#[N:2]
Reactant: COc1cc(C#N)ccc1-c1ccnc2[nH]c(C3CCCN(C(=O)OC(C)(C)C)C3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)ccc1-c1ccnc2[nH]c(C3CCCNC3)cc12

Procedure:
A solution of Example 137A (75 mg, 0.17 mmol) in dichloromethane (3 mL) was treated with trifluoroacetic acid (1 mL) for 10 minutes and was concentrated. The residue was purified by reverse phase HPLC, eluted with 10-70% acetonitrile in 0.1% trifluoroacetic acid/water to afford the title compound. LCMS: 333.11 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 1.63-1.80 (m, 2H) 1.88 (d, 1H) 2.11 (d, 1H) 2.77-2.89 (m, 1H) 3.02-3.12 (m, 1H) 3.14-3.22 (m, 1H) 3.29 (d, 1H) 3.81 (s, 3H) 6.05 (d, 1H) 7.07 (d, 1H) 7.54 (s, 2H) 7.67 (s, 1H) 8.21 (d, 1H) 8.70 (d, 1H) 8.87 (s, 1H) 11.83 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]1([CH:16]2[NH:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH2:20][NH:21][CH:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17]2)=[CH:4][CH:3]=1
Reactant: c1ccc(C2CNCCN2)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(CN2CCNC(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
1.54 g of 4-Bromobenzyl bromide and 1 g of 3-Phenylpiperazine in 20 mL of acetonitrile were stirred at room temperature and 0.85 g of potassium carbonate was added. The reaction was stirred at room temperature overnight. The solution was filtered through Celite and concentrated in vacuo. Purification was done by flash chromatography to afford 1.13 g of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:18])=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1
Reactant: CCCc1nc(OC)c(NC(=O)Oc2ccccc2)cc1C
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: CCCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C
Yield: 57 %

Procedure:
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[Br:13][C:14]1[S:18][C:17]2=[N:19][C:20]([C:22](O)=[O:23])=[CH:21][N:16]2[CH:15]=1>>[Br:13][C:14]1[S:18][C:17]2=[N:19][C:20]([C:22]([NH:7][C:6]3[CH:8]=[CH:9][CH:10]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)=[O:23])=[CH:21][N:16]2[CH:15]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: O=C(Nc1cccc(OC(F)(F)F)c1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using 3-(trifluoromethoxy)aniline and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:11]1.CI.[Cl-].[NH4+]>O1CCCC1>[CH3:1][CH:19]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([CH3:9])[CH:11]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1cn(C)c2ccccc12
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of lithium diisopropyl amide, LDA, (5.5 millimole) in 10 mL of dry tetrahydrofuran at -78° C. was added dropwise a solution of methyl 2-(1-methyl-3-indolyl)acetate (1.02 g) in 3 mL of dry tetrahydrofuran. This mixture was stirred for one hour, then 1.42 g of methyl iodide was added and the mixture was warmed to room temperature and stirred for an additional 30 minutes. The mixture was poured into a solution of aqueous saturated ammonium chloride and then extracted with diethyl ether. The ether extract was dried over magnesium sulfate and concentrated to an oil by evaporation. The residue was subjected to silica gel chromatography using a developing solution of hexanes/ethyl acetate (6:1 by volume) to give 1.04 g of the product.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]=O.C(Cl)(Cl)Cl>CO.[Pt]=O>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:14][C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1ccccc1Oc1ccccc1
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(CNc2ccccc2Oc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
In 60 ml of methanol were dissolved 3.70 g of 2-aminodiphenyl ether and 3.70 g of 2,4-dimethoxybenzaldehyde, and then 70 mg of platinum oxide was added, followed by stirring at room temperature under a hydrogen stream overnight. To the reaction mixture was added 30 ml of chloroform for dissolving the precipitate, and the catalyst was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to give 5.06 g of N-(2,4-dimethoxybenzyl)-2-phenoxyaniline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])([CH3:13])([CH3:12])[CH3:11]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[N:17]\[S:14]([C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:16])=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CC(C)(C)S(N)(=O)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)(=O)/N=C\c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-bromo-benzaldehyde (1.27 mL, 10.8 mmol) in THF (50 mL) were added titanium(IV) ethoxide (0.786 mL, 21.6 mmol) and tert-butylsulfonamide (1.31 g, 10.8 mmol), and stirring was continued for 16 h at 65° C. After cooling to RT, volatiles were evaporated, and the residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 3:1) to afford the title compound. MS (LC/MS): 289 [M+H]+; tR (HPLC conditions f): 2.35 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1>C1CCCCC1.[Rh].[O-2].[Al+3].[O-2].[O-2].[Al+3]>[CH3:1][C:2]1([CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:14]([CH3:15])[CH3:16])[NH:4][CH2:3]1
Reactant: CC(C)C1CC=CCCC=CCC(C)(C)C=N1
Agent: [Rh]
Agent: [Al+3]
Agent: [O-2]
Solvent: C1CCCCC1
Product: CC(C)C1CCCCCCCCC(C)(C)CN1

Procedure:
466.8 g (2 mols) of 3,3-dimethyl-12-isopropyl-1-aza-1,5,9-cyclododecatriene is dissolved in 4 liters of cyclohexane, and the solution is hydrogenated at 20°-25° C. under an initial pressure of 100 bars, in the presence of 80 g of rhodium/aluminium oxide, for 4 hours in a steel autoclave. The solvent is then distilled off to obtain, as main fraction, 425 g 1.79 mols) of 3,3-dimethyl-12-isopropyl-1-aza-cyclododecane; b.p. 92°-94° C./4 Pa; nD20 =1.4706.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=1)[C:10]([CH2:12][NH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:18][CH2:17]1)=[O:11])=[O:6].[OH:41][C:42]1[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[OH:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=2)[C:10]([CH2:12][NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18][CH2:17]2)=[O:11])=[O:6])=[CH:44][CH:43]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NCCNC(=O)c1cccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(CCNCC(=O)c2cccc(C(=O)NCCNCc3ccc(O)cc3)c2)CC1

Procedure:
A solution of biphenyl-2-ylcarbamic acid 1-(2-{-[3-(2-aminoethylcarbamoyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (9.31 g, 17.1 mmol; prepared as described in Preparation 8) and 4-hydroxybenzaldehyde (2.30 g, 18.8 mmol, 1.1 eq) in 125 mL MeOH was stirred at room temperature for 2 hours. Na(OAc)3BH (7.26 g, 34.2 mmol, 2.0 eq) was added to the reaction at room temperature in two portions separated in one hour interval. The reaction was stirred for an additional hour before being concentrated under vacuum. The residue was taken up in 100 mL DCM and stirred with 100 mL of 1.0 N HCl for 1 hour. The aqueous phase was adjusted to pH 9 using 10.0 N NaOH. The mixture was stirred for an additional 10 minutes. The organic phase was separated, dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified using silica gel chromatography (7% MeOH in CH2Cl2 with 1% NH4OH as eluent). The title compound was obtained as an off-white solid (8.08 g, 73%). MS m/z: [M+H+] calcd for C38H43N5O5, 650.34; found, 650.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH2:13])[CH2:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][C:23](=[O:25])[CH3:24])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)CC(N)CC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CC(NC(C)=O)CC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 7-methoxy-1,2,3,4-tetrahydronapthalen-2-ylamine (2.54 g; 14.3 mmol) in CH2Cl2 (20 mL) was added DIEA (3.4 mL) and the reaction mixture was cooled to 0° C. Acetyl chloride (1.22 mL; 17.1 mmol) was added dropwise at 0° C. and the reaction was allowed to warm to room temperature, then stirred for 18 h. The reaction mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4, filtered and the solvent removed under reduced pressure to yield a crude solid. Purification by flash chromatography (SiO2) eluting with hexanes-EtOAc yielded N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide as a white solid.
Reaction SMILES: NC1C=CC=CC=1NC(=O)C1C=CC(CNC2N=C(C3C=CC(OCCN(C)C)=CC=3)C=CN=2)=CC=1.C(OC(=O)[NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][C:51](=[O:66])[C:52]1[CH:57]=[CH:56][C:55]([CH:58]=[C:59]2[S:63][C:62](=[O:64])[NH:61][C:60]2=[O:65])=[CH:54][CH:53]=1)(C)(C)C>>[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][C:51](=[O:66])[C:52]1[CH:53]=[CH:54][C:55]([CH:58]=[C:59]2[S:63][C:62](=[O:64])[NH:61][C:60]2=[O:65])=[CH:56][CH:57]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=C2SC(=O)NC2=O)cc1
Agent: CN(C)CCOc1ccc(-c2ccnc(NCc3ccc(C(=O)Nc4ccccc4N)cc3)n2)cc1
Product: Nc1ccccc1NC(=O)c1ccc(C=C2SC(=O)NC2=O)cc1
Yield: 37 %

Procedure:
Following the procedure described for the synthesis of compound 117 (scheme 28) but substituting the amide 116 by the amide 348, title compound was obtained in 37% yield. 1H NMR: (400 MHz, DMSO-d6, δ (ppm): 9.72 (s, 1H), 8.06 (d, j=8.2 Hz, 2H), 7.79 (s, 1H), 7.69 (d, J=8.4, 2H), 7.14 (d (dd) J=7.8, 1H), 6.95 (d (dd), J=1.6 Hz, J=9.0, 1H), 6.75 (dd, J=1.2 Hz, J=8.0 Hz, 1H), 6.56 (t (dd), J=7.2 Hz 1H). LRMS: 339.4 (calcd.), 340.4 [MH]+ (found).
Reaction SMILES: C(=S)(OCC)[S:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][CH3:11])[CH:4]=1.[OH-].[Na+]>C(O)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([SH:2])=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: CCOC(=S)Sc1ccc(Cl)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(S)ccc1Cl
Temperature: 25 °C

Procedure:
To an ethanol (5 ml) solution of O-ethyl S-(4-chloro-3-methoxyphenyl) dithiocarbonate (394 mg, 1.50 mmol) was added a 1N aqueous solution of sodium hydroxide (5 ml). The resulting mixture was heated under reflux for 1 hour. After the reaction mixture was cooled to room temperature, ethanol was distilled off under reduced pressure. The residue was washed with dichloromethane. The water layer was acidified with acetic acid. The product thus obtained was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 4-chloro-3-methoxybenzenethiol as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)=[N:23]2)=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([S:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH:32]([NH:35][C:11]([C:8]4[CH:7]=[C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)[O:10][N:9]=4)=[O:13])[CH2:33][CH2:34]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: O=C(O)c1cc(-c2cccs2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4cc(-c5cccs5)on4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.8 %

Procedure:
5-Thiophen-2-yl-isoxazole-3-carboxylic acid (43 mg, 0.22 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (70 mg, 0.22 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed by 1-hydroxybenzotriazole (32 mg, 0.24 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (47 mg, 0.25 mmol, 1.15 eq) and N,N-diisopropylethylamine (83 μL, 0.48 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 5-thiophen-2-yl-isoxazole-3-carboxylic acid {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amide as an orange solid (15 mg, 13% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](Cl)=[O:11].[NH2:13][CH2:14][C:15]1[N:19]([C:20]2[S:21][C:22]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:23][C:24]=2[C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:18]([CH3:39])=[N:17][N:16]=1>>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([C:24]1[CH:23]=[C:22]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[S:21][C:20]=1[N:19]1[C:18]([CH3:39])=[N:17][N:16]=[C:15]1[CH2:14][NH:13][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11])=[O:33]
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Product: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2cc3ccccc3[nH]2)s1

Procedure:
Indole-2-carbonyl chloride and methyl (2-(3-aminomethyl-5-methyl[1,2,4]triazol-4-yl)-3-(2-chlorobenzoyl)thiophen-5-yl)acetate are reacted to give methyl (3-(2-chlorobenzoyl)-2-(3-(2-indolecarbonylaminomethyl)-5-methyl[1,2,4]triazol-4-yl)thiophen-5-yl)acetate.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH3:14][O:15][C:16]([CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])=[O:17]>>[CH3:1][N:2]([C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:16]([O:15][CH3:14])=[O:17])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: CNCCc1c[nH]c2ccccc12
Reactant: COC(=O)CCCC(=O)Cl
Product: COC(=O)CCCC(=O)N(C)CCc1c[nH]c2ccccc12
Yield: 92.9 %

Procedure:
10.3 g of N-methyl-tryptamine (i.e., 3-(2-methylaminoethyl)-indole) and 11.7 g of 4-methoxycarbonylbutyryl chloride were treated in the same manner as described in Example 1. 16.6 g of N-methyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-methyl-4-methoxycarbonylbutanamido)ethyl]indole) were therby obtained. Yield: 92.8%
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4cc[nH]c4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using 1H-indole-6-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 6.62 (ddd, J=3.0, 1.9, 0.8 Hz, 1 H), 7.62-7.71 (m, 2 H), 7.76-7.89 (m, 2 H), 8.27-8.33 (m, J=1.4 Hz, 1 H), 8.46 (dt, J=8.2, 1.9, 1.7 Hz, 1 H), 8.82 (dd, J=4.7, 1.7 Hz, 1 H), 9.27 (dd, J=2.2, 0.8 Hz, 1 H), 11.66 (s, 1 H) ppm; MS (DCI/NH3) m/z 263 (M+H)+.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.CCCCCC.C([Li])CCC.[C:20]1(=[O:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.C(OCC)(=O)C>C(OCC)C.O>[OH:29][C:20]1([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: Brc1ccncc1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1(c2ccncc2)CCc2ccccc21
Reaction time: 3 h

Procedure:
4-Bromopyridine hydrochloride (1.9 g, 10 mmol) was dried and then suspended in diethyl ether (30 ml), and the suspension was mixed with n-butyl lithium hexane solution (1.6 M, 12 ml, 19 mmol) at −60° C. and stirred for 3 hours. The reaction solution was mixed with 1-indanone (2.0 g, 15 mmol) and then the reaction solution was stirred for 18 hours while gradually returning to room temperature. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution to extract the reaction product, and the ethyl acetate layer was washed with water and then dried with anhydrous sodium sulfate. The solvent was removed by evaporation from the extract under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 420 mg (2.0 mmol, 20% in yield) of the title compound.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[O:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][N:6]=2)[CH2:9][CH2:10]1
Reactant: Nc1ccc(O)cc1
Reactant: Fc1nccnc1C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2nccnc2C2CCOCC2)cc1

Procedure:
To a round-bottomed flask was added 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyrazine (1.1147 g, 6.12 mmol), 4-aminophenol (0.801 g, 7.34 mmol), and cesium carbonate (5.98 g, 18.35 mmol) in DMSO (20.39 mL) at 110° C. to stir. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide 4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline. MS (ESI, pos. ion) m/z: 272.1.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:10](OCC)(OCC)[O:11][CH2:12][CH3:13].C(OC(=O)C)(=O)C>>[CH2:12]([O:11][CH:10]=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=CC(=O)CC(=O)OCC
Yield: 70 %

Procedure:
Using the procedure of Crombie et al., Journ. of Chem. Soc. Perkin Trans. 1, 464-471 (1979), a solution of ethyl acetoacetate (26 g, 0.20 mol), triethyl orthoformate (29.6 g, 0.20 mol) and acetic anhydride (41 g, 0.40 mol) was refluxed for 90 minutes. Distillation under reduced pressure gave the product (1): 26 g, 70% yield; bp=85°-98° C. at 0.5 mm Hg (The following value is reported in the Crombie et al. publication: bp=85° C. at 0.25 mm Hg); NMR (CDCl3) δ 1.2-1.5 (m, 6H), 2.4-2.5 (d,3H), 4.0-4.6 (m,4H), 7.7 (d,1H). The signals were split into pairs of closely spaced lines indicative of the cis and trans isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:8][CH2:7]1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(N(CC)CC)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH2:10][CH2:11]1
Reactant: Nc1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2N2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1

Procedure:
2-[4-(3,4-dichlorobenzyl)-piperazin-1-yl]-phenylamine (45 mg) was dissolved in a solution of triethylamine in dichloromethane (3 mL, 0.29 M in triethylamine). This solution was added to a test tube containing p-toluenesulfonyl chloride (60 mg). After standing at ambient temperature for several days, the reaction was directly passed through a small pad of silica and eluted with 10% ethyl acetate in hexanes, then with 50% ethyl acetate in hexanes. Solvent removal left 57.5 mg of the product: MS m/z 489 (M)+.