Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].[CH3:11][O:12][CH2:13][CH2:14][Br:15]>>[BrH:15].[CH3:11][O:12][CH2:13][CH2:14][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][C:2]1=[NH:10]
Reactant: COCCBr
Reactant: Nc1nc2ccccc2s1
Product: Br
Product: COCCn1c(=N)sc2ccccc21
Temperature: 85 °C
Yield: 82 %

Procedure:
Benzothiazol-2-ylamine (10.0 g, 66.6 mmol) and 2-bromoethyl methyl ether (9.39 mL, 99.9 mmol) were combined and heated at 85° C. for 6 hours. The dark solid was triturated with EtOH then filtered and dried under vacuum to afford the title compound (15.8 g, 82%). 1H NMR (DMSO-d6, 300 MHz) δ ppm 3.23 (s, 3H), 3.69 (t, J=5.1 Hz, 2H), 4.51 (t, J=5.1 Hz, 2H), 7.42 (dt, J=1.0, 8.0 Hz, 1H), 7.56 (m, 1H), 7.72 (d, J=8.0 Hz, 1H), 8.00 (dd, J=1.1, 8.0 Hz, 1H), 10.16 (br s, 2H); MS (DCI/NH3) m/z 209 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:28])[N:14]([CH3:27])[C:15]([CH2:24][C:25]#N)=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:29].[K+].Cl.[Si](C=[N+]=[N-])(C)(C)C.[CH2:39]([OH:41])C>O>[CH2:1]([N:8]1[C:12]2[C:13](=[O:28])[N:14]([CH3:27])[C:15]([CH2:24][C:25]([O:41][CH3:39])=[O:29])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: [OH-]
Reactant: Cn1c(CC#N)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c1=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC(=O)Cc1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
A suspension of 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetonitrile (3 g, 7.04 mmol) in Ethanol (60 mL) and Water (20 mL) was treated with KOH (3.95 g, 70.4 mmol) and then heated to 140° C. in a sealed tube for 24 hours. The mixture was cooled to 0° C. and then treated with 4N HCl until pH<2. The mixture was partly concentrated and then extracted with Ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and then concentrated. The residue was dissolved in Methanol (60.0 mL), cooled to 0° C. and then treated with TMS-diazomethane (35.2 mL, 70.4 mmol). The mixture was warmed to ambient temperature and then stirred for 20 minutes. Upon reaction completion, the mixture was cooled to 0° C., quenched with acetic acid and then concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford methyl 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (2.3 g, 5.46 mmol, 78% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.40-7.44 (m, 2H) 7.25-7.35 (m, 7H) 7.00-7.04 (m, 1H) 5.88-5.94 (m, 1H) 5.80-5.88 (m, 2H) 3.74 (s, 3H) 3.63 (s, 2H) 3.59 (s, 3H); LCMS (m/z) ES+=421 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:13]([Cl:27])[C:12]2=[O:28])=[C:6]([F:29])[CH:5]=1.C(N(CC)CC)C.[NH:37]1[CH:41]=[C:40]([C:42](O)=[O:43])[N:39]=[CH:38]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[Cl:27][C:13]1[C:12](=[O:28])[N:11]([C:7]2[C:6]([F:29])=[CH:5][C:4]([CH2:3][NH:2][C:42]([C:40]3[N:39]=[CH:38][NH:37][CH:41]=3)=[O:43])=[CH:9][C:8]=2[F:10])[CH:16]=[CH:15][C:14]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: O=C(O)c1c[nH]cn1
Reactant: NCc1cc(F)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1cc(F)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1)c1c[nH]cn1
Reaction time: 8 h

Procedure:
1-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one hydrochloride (150 mg, 0.334 mmol) is dissolved in a solution of 4 ml tetrahydrofuran and triethylamine (35 mg, 0.35 mmol). 4-imidazolecarboxylic acid (62 mg, 0.56 mmol), 1-hydroxybenzotriazole hydrate (90 mg, 0.67 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (128 mg, 0.668 mmol), and triethylamine (100. mg, 0.989 mmol) were combined in 5 ml tetrahydrofuran and stirred under nitrogen. The solution containing 1-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(1H)-one hydrochloride was added in one portion, rinsing with 2 ml tetrahydrofuran. Stirring was continued at room temperature overnight, then the reaction was poured into 90 ml of icewater, and the product collected by filtration and dried in vacuo (254 mg, 94%). 1H-NMR (400 MHz, DMSO-d6) δ 12.55 (br s, 1H), 8.73 (t, J=6.57 Hz, 1H), 7.90 (d, J=7.87 Hz, 1H), 7.75 (s, 1H), 7.67 (m, 2H), 7.35, (dt, J=10.04, 2.54 Hz, 1H), 7.21 (m, 3H), 6.78 (d, J=8.04 Hz, 1H), 5.39 (s, 2H), 4.47 (m, 2H). 19F-NMR (400 MHz, DMSO-d6) δ −109.26 (quintet, J=7.87 Hz, 1F), −113.52 (quartet, J=9.30 Hz, 1F), −120.59 (d, J=9.21 Hz, 2F). LC/MS tr=4.48 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 507 (M+H). ES-HRMS m/z 507.0818 (M−H calcd for C23H16ClF4N4O3 requires 507.0842).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:56]=[CH:57][CH:58]=1)[O:5][C:6]1[CH:33]=[C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH2:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH2:43][C:42]=3[C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=3)[CH2:36][CH2:35]2)[CH:31]=[CH:30][C:7]=1[C:8]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1)(=[O:13])=[O:12])=[O:9].[CH:59]1([CH:62]=O)[CH2:61][CH2:60]1.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:56]=[CH:57][CH:58]=1)[O:5][C:6]1[CH:33]=[C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH2:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH2:43][C:42]=3[C:49]3[CH:50]=[CH:51][C:52]([Cl:55])=[CH:53][CH:54]=3)[CH2:36][CH2:35]2)[CH:31]=[CH:30][C:7]=1[C:8]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:62][CH:59]3[CH2:61][CH2:60]3)[CH2:23][CH2:22]2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1)(=[O:12])=[O:13])=[O:9]
Reactant: O=CC1CC1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCNCC5)c([N+](=O)[O-])c4)c(Oc4cccc(Cl)c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCN(CC6CC6)CC5)c([N+](=O)[O-])c4)c(Oc4cccc(Cl)c4)c3)CC2)=C(c2ccc(Cl)cc2)C1

Procedure:
A suspension of EXAMPLE 187B (50 mg), cyclopropanecarbaldehyde (100 mg) and MP-CNBH3 resin (0.2 g, 2.43 mmol/g) in dichloromethane (4 mL)/methanol (3 mL) was shaken for 16 hours at room temperature. The product was filtered, washed with dichloromethane/methanol and concentrated. The crude product was purified by RP HPLC(C8, 30%-100% CH3CN/water/0.1% TFA) to yield the product. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 8.35 (s, 1H), 8.10 (s, 1H), 7.67-7.75 (m, 1H), 7.60 (d, 1H), 7.36 (d, 2H), 7.15 (t, 1H), 7.07 (d, 3H), 6.89 (d, 1H), 6.73 (dd, 1H), 6.63 (s, 1H), 6.60 (s, 1H), 6.40 (s, 1H), 3.86 (s, 1H), 3.12 (s, 5H), 2.71-2.80 (m, 3H), 2.13-2.28 (m, 9H), 1.98 (s, 3H), 1.79 (s, 1H), 1.41 (t, 2H), 0.99-1.11 (m, 2H), 0.94 (s, 6H), 0.84 (d, 1H), 0.63 (d, 2H), 0.33 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11]C(=O)OC(C)(C)C)[CH:6]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 4-(2-methyl-4-nitrophenoxy)pyridin-2-ylcarbamate (1.0 g, 2.90 mmol) in dichloromethane (28 mL) was added TFA (4 mL). After stirring at room temperature for 6 hours, the reaction mixture was concentrated under reduced pressure to provide the crude product that was used without further purification.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]>ClCCl>[Br:1][C:11]1[CH:12]=[CH:13][C:4]([OH:3])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc(O)c1
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1cc(O)ccc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
Bromine (6.74 mL) was added to a solution of methyl 3-hydroxybenzoate (20.0 g) in dichloromethane (200 mL) and stirred at room temperature for 4 hours. The reaction solution was concentrated, diisopropyl ether (40 mL) was added and the solid separated out therefrom was filtered to give the aimed compound (28.3 g, 93%) as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([S:27][CH2:28][CH:29]([CH3:35])[C:30]([O:32]CC)=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:14]=1)(=[O:3])[CH3:2].[OH-].[Na+].CC(O)=O>CO.C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([S:27][CH2:28][CH:29]([CH3:35])[C:30]([OH:32])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C)CSC(CCc1ccccc1C(C)=O)c1cccc(COC2CCCCO2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)c1ccccc1CCC(SCC(C)C(=O)O)c1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the ester of Step 7 (6.67 mmol) and 1.0N NaOH (13 mL) in 55 mL of MeOH:THF 3:2 was stirred at r.t. for 24 hours. 25% Aq NH4OAc was then added and the mixture was acidified with HOAc. The title acid was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica with acetone:toluene:HOAc.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[C:11]([C:12]([OH:14])=O)=[CH:10][NH:9][N:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH:15]([N:18](C(C)C)CC)([CH3:17])[CH3:16].C(N)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH:15]([NH:18][C:12]([C:11]1[C:7]([CH2:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:8][NH:9][CH:10]=1)=[O:14])([CH3:17])[CH3:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OCc1n[nH]cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)N
Product: CC(C)NC(=O)c1c[nH]nc1COC(C)(C)C
Temperature: 70 °C

Procedure:
To a solution of 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid [1.520 g, Reference Example 17(d)], hydroxybenzatriazole (3.110 g) and diisopropyl ethylamine (4.010 ml) in dimethyl formamide (130 ml) was added isopropylamine (1.960 ml) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.420 g). The mixture was heated at 70° C. for 2.5 hours, then diluted with ethyl acetate, then washed with water, then with brine, then dried over magnesium sulfate and then evaporated. The residue was triturated with a mixture of ethyl acetate and petrol to yield 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide (652 mg) as an off-white solid. LC-MS (METHOD B): 2.99 minutes; 240 (M+H)+. (b) 3-tert-Butyloxymethyl-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:15]([CH:18]=[CH:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)([O-])=O.[CH2:25](N)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:15]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:19]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[CH:18]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])C=Cc1cccs1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: c1ccc(Cn2cc(-c3cccs3)c3c2CCNC3)cc1

Procedure:
The title compound (136.8 mg) was prepared from 0.53 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 300 μL of benzylamine, and 0.41 g of 2-(2-nitro-vinyl)-thiophene. MS (ESI): exact mass calculated for C18H18N2S, 294.12; found, m/z 295.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.36-7.32 (m, 2H), 7.30-7.26 (m, 1H), 7.22 (dd, J=5.2, 1.1 Hz, 1H), 7.18-7.15 (m, 2H), 7.12 (s, 1H), 7.02 (dd, J=5.2, 3.6 Hz, 1H), 6.94 (dd, J=3.6, 1.1 Hz, 1H), 5.13 (s, 2H), 4.34 (s, 2H), 3.49 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54](/[CH:57]=[CH:58]/[CH2:59][C:60]([OH:62])=[O:61])=[CH:53][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:63]([O:70][CH2:71][CH2:72]O)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54](/[CH:57]=[CH:58]/[CH2:59][C:60]([O:62][CH2:72][CH2:71][O:70][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[O:61])=[CH:53][CH:52]=2)[CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCOCc1ccccc1
Reactant: Cc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cn(Cc3ccc(/C=C/CC(=O)O)cc3)c12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cn(Cc3ccc(/C=C/CC(=O)OCCOCc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a mixture of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-[4-((1E)-3-carboxyprop-1-enyl)benzyl]-7-methyl-1H-indole (0.10 g), 2-(benzyloxy)ethanol (22 mg), 4-dimethylaminopyridine (7 mg) and dichloromethane (0.5 mL) was added dicyclohexylcarbodiimide (37 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was directly purified by column chromatography on silica gel (eluent: n-hexane/ethylacetate=4/1-2/1) to give 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-(4-{(1E)-3-[2-(benzyl-oxy)ethoxycarbonyl]prop-1-enyl}benzyl)-7-methyl-1H-indole (48 mg). This material was dissolved in a mixed solvent of methanol (1 mL) and tetra hydrofuran (1 mL). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=12/1-8/1) to give the title compound (14 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)C)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:1][NH:8][CH2:10][CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cccc(OCC(Cc2ccccc2)CN(C)Cc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CNCC(COc1cccc(OC)c1)Cc1ccccc1

Procedure:
A solution of N-benzyl-N-methyl-2-benzyl-3-(3-methoxyphenoxy)propylamine (7.0 g) in ethanol (100 ml) is hydrogenated at room temperature and atmospheric pressure until uptake ceases, using 10% palladium on charcoal (2.0 g) as catalyst. The catalyst is filtered off (Hi-flo) and the solvent removed under reduced pressure to give N-methyl-2-benzyl-3-(3-methoxyphenoxy)propylamine as an oil, which is converted with oxalic acid in ether of N-methyl-2-benzyl-3-(3-methoxyphenoxy)propylamine oxalate, m.p. 127°-129° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]2[CH2:16][NH:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Br:17][C:18]1[S:26][C:21]2[S:22][C:23]([Br:25])=[CH:24][C:20]=2[C:19]=1[CH2:27]Br>>[Br:17][C:18]1[S:26][C:21]2[S:22][C:23]([Br:25])=[CH:24][C:20]=2[C:19]=1[CH2:27][N:15]1[CH2:16][CH:13]([CH2:12][S:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:14]1
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Reactant: BrCc1c(Br)sc2sc(Br)cc12
Agent: Cl
Product: O=S(=O)(CC1CN(Cc2c(Br)sc3sc(Br)cc23)C1)c1ccc(F)cc1

Procedure:
Prepared from 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (Example 1 Step 4) and 2,5-dibromo-3-(bromomethyl)thieno[2,3-b]thiophene (Step 3) according to the method of Example 1 Step 5. 1H NMR (500 MHz, CDCl3) δ 7.90–7.88 (2H, m), 7.33 (1H, s), 7.26–7.23 (2H, m), 3.60 (2H, s), 3.40 (2H, t, J=7.4 Hz), 3.35 (2H, d, J=7.3 Hz), 2.90 (2H, t, J=7.0 Hz), 2.84–2.77 (1H, m); m/z (ES+) 540 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][OH:17].[OH-:19].[Na+].O>C(Cl)Cl>[C:1]([O:11][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])(=[O:19])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:17][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])=[O:7])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CN(C)CCO
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN(C)CCOC(=O)c1ccc(C(=O)OCCN(C)C)cc1

Procedure:
A solution of 40.60 g (0.20 mol) of terephthaloyl chloride in 200 ml methylene chloride was gradually added to a solution of 35.66 g (0.40 mol) of 2-dimethylaminoethanol, 16.0 g (0.40 mol) of sodium hydroxide and 200 ml of water and stirred rapidly. The reaction was exothermic and achieved reflux. The mixture was stirred for another 1.75 hours after which the organic layer was separated, washed with water, dried over MgSO4 and concentrated to an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:4].NC1SC=CC=1C(=O)C1C=CC=CC=1Cl.[Br:35]CC(Br)=O.BrBr>N.N1C=CC=CC=1.C(O)(=O)C.C(O)CCC>[Br:35][C:8]1[S:7][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:1]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:10]=2[CH:9]=1
Reactant: NCC(=O)Nc1sccc1C(=O)c1ccccc1Cl
Reactant: O=C(Br)CBr
Agent: BrBr
Agent: N
Agent: Nc1sccc1C(=O)c1ccccc1Cl
Solvent: CC(=O)O
Solvent: CCCCO
Solvent: c1ccncc1
Product: O=C1CN=C(c2ccccc2Cl)c2cc(Br)sc2N1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
220 g (0.746 mol) of 2-amino-N-[3-(2-chlorobenzoyl)thiophen-2-yl]acetamide (prepared by reacting 2-amino-3-(2-chlorobenzoyl)thiophene with bromoacetylbromide and subsequently piping in gaseous ammonia) are added at 110° C. to a mixture of 1.8 l of n-butanol and 150 ml of glacial acetic acid. The mixture is refluxed for 1 hour, cooled to ambient temperature and 330 ml of pyridine and 57 ml (178.8 g, 1.12 mol) of bromine are added with cooling. Then the mixture is stirred for another 0.5 to 2 hours, cooled to 5 to 10° C. and stirred for a further 2 hours at this temperature. The product that crystallises out is isolated by filtration, washed with 50% ethanol and dried overnight in vacuo at 60° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13]Br>C(Cl)(Cl)Cl.[Fe]>[Br:13][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: BrBr
Reactant: c1ccc(-c2ccccn2)cc1
Agent: [Fe]
Solvent: ClC(Cl)Cl
Product: Brc1ccccc1-c1ccccn1
Temperature: 0 °C
Yield: 35.4 %

Procedure:
3 g (19.3 mmol) of 2-phenylpyridine and 40 mg (0.716 mmol) of an iron powder were mixed and stirred. 4.0 g (25 mmol) of bromine was dropped paying attention to heat generation while stirring and cooling the mixture to 0° C., and the mixture was heated up to 90° C. and stirred for 10 hours. After completion of the reaction, this reaction mixture was dissolved in chloroform, and washed with a 5% aqueous sodium thiosulfate solution. The chloroform solution was dried over sodium sulfate, then, concentrated, and the residue was purified by silica gel column chromatography, to obtain the intended 2-(bromophenyl)pyridine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:25][CH:26]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)=[N:11][N:12]=1.[CH3:31][NH2:32]>C1COCC1.CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:25][CH:26]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:32][CH3:31])=[CH:15][CH:14]=2)=[N:11][N:12]=1
Reactant: CN
Reactant: CCC(=O)N1CC=C(c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)CC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCC(=O)N1CC=C(c2cnc(N)c(-c3nnc(-c4ccc(CNC)cc4)o3)n2)CC1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A solution of 1-[4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]propan-1-one (20 mg, 0.04 mmol) and a solution of methanamine (107 μL of 2 M, 0.21 mmol) in THF was heated at 65° C. for 6 h. The reaction mixture was allowed to cool to room temperature and the solvents were evaporated under reduced pressure. The crude material obtained was dissolved in DMF (1 mL), filtered and purified by mass directed reverse phase LC/MS (1-99% ACN/H2O (5 mM HCl)) to yield 1-[4-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]propan-1-one (9 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 2H), 8.58 (s, 1H), 8.18 (d, J=7.7 Hz, 2H), 7.80 (d, J=8.0 Hz, 2H), 7.63 (s, 2H), 6.66 (s, 1H), 4.30-4.13 (m, 4H), 3.70 (dt, J=16.2, 5.4 Hz, 2H), 2.71 (s, 1H), 2.59 (t, J=5.2 Hz, 4H), 2.41 (dt, J=21.8, 7.3 Hz, 2H), 1.03 (q, J=7.0 Hz, 3H). LC/MS m/z 420.5 [M+H]+.
Reaction SMILES: [CH2:1]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Li][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH2:1]([C:7]1[CH:11]=[C:10]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[S:9][C:8]=1[Sn:21]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCCCCCc1ccsc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCc1cc([Sn](CCCC)(CCCC)CCCC)sc1[Sn](CCCC)(CCCC)CCCC
Temperature: -80 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
The dried THF (100 mL) is added with the 3-hexylthiophen (1 g, 5.94 mmol), cooled at −80° C., and slowly added with n-BuLi (5.94 mL, 14.85 mmol, 2.5 M in hexane) by one drop for 60 minutes. The reaction mixture is agitated at −80° C. for 3 hours. The reaction mixture is slowly added with tributyltin chloride (4.56 mL, 14.85 mmol) by one drop for 30 minutes. After the reaction mixture is agitated at −80° C. for 30 minutes, the reaction mixture rises to room temperature and is additionally agitated for 2 hours and is quenched with the NH4Cl aqueous solution. The reaction mixture is extracted with ethylacetate and then the organic layer is washed with water and dried with anhydrous sodium sulfate. The solvent was evaporated and the mixture before being purified was purified by the flash column chromatography using the silica gel quenched with triethylamine to obtain the desired compound 17 (4.21 g, 95% yield). 1H NMR (400 MHz, CDC13): δ=7.06 (s, 1H, CH—C-hexyl), 2.76-2.73 (t, J=12 Hz, 2H, ArCH2-, hexyl), 1.62 (m, 14H, ArCH2CH2-, hexyl+6×—(CH2)2-CH2-, butyl), 1.44-1.40 (m, 24H, 6×—(CH2)2-CH2-, butyl), 1.25-1.15 (m, 6H, CH3 (CH2)3-, hexyl), and 0.99-0.91 (m, 21H, CH3, hexyl+6×CH3, butyl) ppm. 13C NMR (100 MHz, CDC13): δ=144.30, 136.80, 136.05, 125.58, 31.64, 30.91, 29.25 29.09, 27.54, 27.37, 22.77, 14.12, 13.74, 10.78 ppm. C34H68SSn2 (746.39): calcd. C, 54.71; H, 9.18; S, 4.30; Sn, 31.81. found C, 54.59; H, 9.23; S, 4.40.