Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([OH:29])[C@H:14]([CH3:30])[O:13][C:12]1=[O:31])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:40]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:40]1([C:45]([O:29][C@@H:15]2[C@@H:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:17][CH2:18][CH2:19][C@H:11]([N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:32])[CH2:8][O:9][CH3:10])[C:12](=[O:31])[O:13][C@H:14]2[CH3:30])=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=C(Cl)C1CCCC1
Reactant: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](O)[C@H](C)OC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](OC(=O)C2CCCC2)[C@H](C)OC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A 20 mL vial was charged with tert-butyl((3S,7R,8R,9S)-8-hydroxy-7-(4-methoxybenzyl)-9-methyl-2-oxooxonan-3-yl)(methoxymethyl)carbamate (200 mg, 0.443 mmol), CH2Cl2 (2215 μl), NEt3 (185 μl, 1.329 mmol) and DMAP (5.41 mg, 0.044 mmol). The reaction mixture was cooled to 0° C. in an ice bath under N2 and cyclopentanecarbonyl chloride (76 mg, 0.576 mmol) was added in one portion. The reaction became dark brownish-yellow. After stirring for 2 h, the reaction mixture was quenched by the addition of saturated aqueous NaHCO3. The mixture was extracted with CH2Cl2 (3×) and the combined organic layers were washed with brine, dried over MgSO4, concentrated, and purified by column chromatography on SiO2 (0→100% EtAOx/hexanes) to provide the title compound as a yellow solid (85 mg, 35.0%): 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J=8.5 Hz, 4H), 6.81 (d, J=8.4 Hz, 4H), 5.06-4.85 (m, 3H), 4.77 (d, J=11.6 Hz, 1H), 4.57 (dd, J=10.7, 6.0 Hz, 0H), 4.29-4.17 (m, 1H), 3.78 (s, 3H), 3.38-3.26 (m, 3H), 2.74 (p, J=8.0 Hz, 1H), 2.61 (dd, J=13.7, 3.7 Hz, 1H), 2.31 (dd, J=13.7, 11.1 Hz, 1H), 2.20-2.07 (m, 1H), 1.99-1.52 (m, 8H), 1.51-1.40 (m, 9H), 1.27 (d, J=5.8 Hz, 3H), 1.15-0.96 (m, 1H), 0.97-0.87 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 176.26, 173.56, 157.94, 155.49, 131.94, 129.59, 113.80, 81.21, 75.54, 72.72, 58.52, 55.43, 55.22, 44.32, 44.04, 35.77, 30.09, 30.00, 29.58, 28.20, 26.48, 25.72, 25.70, 19.09, 17.56; ESIMS m/z 570.5 ([M+Na]+).
Reaction SMILES: Cl.[OH:2][NH2:3].C[O-].[Na+].[C:7]([C:11]1[N:12]=[C:13]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=4[O:29][CH:30]([CH2:33][CH2:34][CH3:35])[C:31]#[N:32])=[CH:21][C:19]=3[CH:20]=2)[S:14][CH:15]=1)([CH3:10])([CH3:9])[CH3:8]>CS(C)=O.CO>[C:7]([C:11]1[N:12]=[C:13]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=4[O:29][CH:30]([CH2:33][CH2:34][CH3:35])[C:31](=[N:3][OH:2])[NH2:32])=[CH:21][C:19]=3[CH:20]=2)[S:14][CH:15]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: CCCC(C#N)Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(N)=NO
Temperature: 25 °C
Yield: 110.8 %

Procedure:
Hydroxyamine hydrochloride (174 mg) was dissolved in dimethylsulfoxide (2 ml) and 28% solution of sodium methoxide in methanol (0.125 g) was added into it. The mixture was stirred for ten minutes at room temperature. 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}-pentanenitrile (224 mg) was added into the solution and the resulting mixture was stirred at 80° C. for an hour. The reaction mixture was collected and diluted with water and was extracted with ethyl acetate. The organic layer was washed with brine and was dried over magnesium sulfate. Concentration gave 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanamide oxime as an amorphous solid (266 mg).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O-:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].C([N+](CCCC)(CCCC)CCCC)CCC.I[CH2:31]/[CH:32]=[CH:33]/[B:34]1[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]1>ClCCl>[CH3:39][C:37]1([CH3:40])[C:36]([CH3:41])([CH3:42])[O:35][B:34](/[CH:33]=[CH:32]/[CH2:31][O:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]=3[CH:11]=2)[O:38]1
Reactant: N#Cc1nc2ccc([O-])cc2s1
Reactant: CC1(C)OB(/C=C/CI)OC1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC1(C)OB(/C=C/COc2ccc3nc(C#N)sc3c2)OC1(C)C
Temperature: 80 °C

Procedure:
A reaction vial was charged with tetrabutylammonium 2-cyanobenzo[d]thiazol-6-olate (209 mg, 1.19 mmol), (E)-2-(3-iodoprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (386 mg, 1.31 mmol) and 15 mL of dry dichloromethane. The vial was sealed, and the solution was heated in an oil bath at 80° C. overnight (˜16 hours). The crude reaction mixture was added to 1 gram of celite, and the solvent was evaporated under vacuum. The product was purified by silica gel chromatography using an increasing gradient of ethyl acetate in dichloromethane as eluent. This gave 166 mg of (E)-6-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)benzo[d]thiazole-2-carbonitrile as a colorless oil that crystallized to a white solid upon standing at ambient temperature.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[NH:8][CH2:9][CH2:10][C:4]2=[N:3][N:2]=1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C>ClCCl>[CH:1]1[N:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[N:8]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=4[CH3:15])=[CH:29][CH:28]=3)=[O:26])[CH2:9][CH2:10][C:4]2=[N:3][N:2]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)NCCc1nncn1-2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3nncn3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5 mmol of 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and then 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 hours and then washed with water, aqueous NaHCO3 and brine. The solution is dried (Na2SO4) and the solvent removed in vacuo to give a solid. The solid is purified by chromatography on silica gel with ethyl acetate-hexane as solvent to give the desired product as a glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:17][NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[C:28](Cl)=[O:29].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:17][NH:18][C:28]([C:20]3[O:19][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH:21]=3)=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1cc2ccccc2o1
Reactant: COc1ccc(C2(CN)CCCCC2)cc1OC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CNC(=O)c3cc4ccccc4o3)CCCCC2)cc1OC
Yield: 44.3 %

Procedure:
C-[1-(3,4-Dimethoxy-phenyl)-cyclohexyl]-methylamine (276 mg, 1.12 mmol) and Benzofuran-2-carbonyl chloride (223 mg, 1.23 mmol) were dissolved in 6 mL of 1,4-dioxane containing triethylamine (312 μL, 2.24 mmol) at 0° C. The reaction mixture was evaporated to dryness, redissolved in dichloromethane, and extracted with 1M hydrochloric acid, 1M sodium hydroxide, and a saturated aqueous solution of sodium chloride. The organic layer dried over sodium sulfate and evaporated to dryness. The crude product was then purified by column chromatography on silica gel using a gradient of 0-20% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (195 mg, 0.496 mmol, 44.2%). ESI-MS m/z calc. 393.2, found 394.2 (M+1)+. Retention time of 2.96 minutes. 1H NMR (400 MHz, CD3CN) δ 1.45-2.20 (m, 10H), 3.48 (d, J=6.5 Hz, 2H), 3.80 (s, 3H), 3.83 (s, 3H), 6.68 (s, 1H), 6.92-7.02 (m, 3H), 7.30-7.38 (m, 2H), 7.42-7.49 (m, 1H), 7.51-7.55 (m, 1H), 7.72 (d, J=7.8 Hz, 1H)
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:20].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:20])[C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cn1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2sccc2-c2[nH]nc(-c3ccc(Br)nc3)c21
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of 6-(6-Bromo-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.32 g, 1.0 mmol) and Cs2CO3 (3.26 g, 10.0 mmol) in DMF (10 mL) was stirred under molecular oxygen at ambient temperature. The reaction mixture was stirred for 12 hr. Afterward, the mixture was poured into ice water, followed by aqueous wash and evaporation of the solvent, which provided the corresponding 6-(6-Bromo-pyridin-3-yl)-4H-1-thia-4,5-diaza-cyclopenta[a]pentalen-7-one (0.31 g, 0.92 mmol) as orange solid in 92% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C:10]([C:12]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH:13]=1)=[O:11]>ClCCl>[CH3:8][NH:9][C:10]([C:12]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:13]=1)=[O:11]
Reactant: CNC(=O)C1=CC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)C1=CC2(CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 146 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a stirred solution of tert-butyl 3-(methylcarbamoyl)spiro[indene-1,4′-piperidine]-1′-carboxylate (C5) (0.45 g, 1.30 mmol) in dichloromethane (5 mL) and the solution was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and dried under high vacuum for 18 h to provide N-methylspiro[indene-1,4′-piperidine]-3-carboxamide (C6) as an oil (0.46 g). LC/MS (10-90% over 3 min with 0.9% FA) m/z 243 (M+1), Rt 1.2 minutes.
Reaction SMILES: C1C2C(COC([C@@H:18]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:19]([NH:21][C:22]3[N:26]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:25]=[C:24]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[CH:23]=3)=[O:20])=O)C3C(=CC=CC=3)C=2C=CC=1.CCCC[N+:50](CCCC)(CCCC)CCCC.[F-].O>C(Cl)Cl>[NH2:50][C@@H:18]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:19]([NH:21][C:22]1[N:26]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH:23]=1)=[O:20]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)Cn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccccc1)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cn1nc(-c2ccncc2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.9 %

Procedure:
To a rt solution of 26.B (341 mg, 0.63 mmol) in CH2Cl2 (5 mL) was added TBAF (available from Aldrich) (1.0 M, 3.2 mL, 3.2 mmol). The resulting mixture was stirred at rt for 12 hr, treated with water (15), and extracted with 30% iPrOH/CHCl3 (3×15 mL). The combined organic layers were washed with water, brine and dried over MgSO4. After removal of organic solvent under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-10% MeOH/CH2Cl2 for elution gave the title product 26.C as colorless solid (141 mg, 71%).
Reaction SMILES: [O-]CC.[Na+].[NH2:5][C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[C:7]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)=O.[C:24](OCC)(=[O:32])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl>C(O)C.O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][C:25]1[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[S:10][C:6]2=[N:5][C:24]=1[OH:32])[CH3:31]
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1c(O)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 100 °C
Yield: 23.5 %

Procedure:
To a solution of sodium ethoxide 21% in ethanol (1.8 mL; 4.8 mmol) in dry ethanol (30 mL) under a nitrogen atmosphere was added (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p-tolyl)methanone (1.09 g; 4 mmol) and diethyl succinate (0.929 mL; 5.6 mmol). The mixture was heated to 100° C. for 24 h. The reaction mixture was dissolved with water (8 ml) and acidified with a solution of hydrochloric acid 1N to pH 1 and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over sodium sulphate and concentrated under reduced pressure. The crude was suspended in dry ethanol (30 mL) and a catalytic amount of concentrated sulfuric acid (10 drops) was carefully added. The reaction mixture was heated to reflux for 21 h. The volatiles were removed under reduced pressure and the remaining residue was purified by flash-chromatography on silica gel using a gradient of methanol (1-20%) in ethyl acetate as eluent to furnish 0.358 g (19.6%) of ethyl[2-hydroxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate as an ochre solid. ESI/APCI(+): 382 (M+H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([CH:28]1[N:33]2[CH2:34][C@H:35]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:36][C@H:32]2[CH2:31][NH:30][CH2:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:45][O:46][C:47]1[CH:54]=[CH:53][C:52]([N:55]2[C:59]([C:60]([F:63])([F:62])[F:61])=[N:58][N:57]=[N:56]2)=[CH:51][C:48]=1[CH:49]=O>ClCCl>[CH:15]([C@H:28]1[N:33]2[CH2:34][C@H:35]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:36][C@H:32]2[CH2:31][N:30]([CH2:49][C:48]2[CH:51]=[C:52]([N:55]3[C:59]([C:60]([F:63])([F:62])[F:61])=[N:58][N:57]=[N:56]3)[CH:53]=[CH:54][C:47]=2[O:46][CH3:45])[CH2:29]1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CNCC(C(c3ccccc3)c3ccccc3)N2C1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1C[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
Sodium triacetoxyborohydride (163 mg) was added to a mixture of bis(acetic acid) salt of (7R,8aS)-4-benzhydryl-7-[(tert-butyldimethylsilyl)oxy]octahydropyrrolo[1,2-a]pyrazine (0.38 g) and 2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzaldehyde (210 mg) in dichloromethane, and the whole was stirred for 3 hours at room temperature. The mixture was washed with aqueous sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1). The later eluting fractions were collected and evaporated under reduced pressure to give colorless oil of (4R,7R,8aS)-4-benzhydryl-7-[(tert-butyldimethylsilyl)oxy]-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]-octahydropyrrolo[1,2-a]pyrazine (0.18 g).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:24][CH2:23]1>>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[C:28]([N:25]4[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]4)[CH:29]=3)[N:20]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: COc1ccccc1CNc1cccn2nc(Cl)nc12
Product: COc1ccccc1CNc1cccn2nc(Nc3cccc(N4CCN(C)CC4)c3)nc12

Procedure:
N(8)-(2-Methoxy-benzyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methoxy-benzyl)-amine (100.00 mg, 0.34634 mmol) and 3-(4-methylpiperazin-1-yl)aniline (74.2 mg, 0.388 mmol) in a manner analogous to Example 2d. Product isolated as a brown foam (39.14 mg, 25.4%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.12 (s, 1H), 7.96 (d, J=6.4 Hz, 1H), 7.25 (m, 4H), 7.09 (t, J=15.9, 7.8 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 6.88 (t, J=15.0, 7.9 Hz, 1H), 6.73 (t, J=14.5, 7.4 Hz, 1H) 6.46 (d, J=8.6 Hz, 1H), 6.32 (d, J=8.1 Hz, 1H), 6.10 (m, 1H), 4.48 (d, J=5.2 Hz, 2H), 3.87 (s, 3H), 3.12 (s, 4H), 2.45 (s, 4H), 2.22 (s, 3H). MS=444 (MH)+.
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][CH:22]2[CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[N-]=C=O>CN(C=O)C.C(O)(=O)C>[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[C:36]([N:24]1[CH2:25][CH:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:22]([CH2:21][N:13]([CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:23]1)=[O:37]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [N-]=C=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(c1cccc2ccccc12)N(CC1CN(C(=O)c2ccccc2Cl)CC1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
A mixture of 9.9 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[4-phenylpyrrolidin-3-yl]methyl}carbamate, 4.9 mg of 2-chlorobenzaldehyde, 50 μl of acetic acid and 0.5 ml of DMF was mixed at room temperature with 75 mg of MP-Triacetoxyborohydride (mfd. by Argonaut Technologies, USA) and stirred for 15 hours. At room temperature, the reaction solution was mixed with 50 mg of PS-Isocyanate (mfd. by Argonaut Technologies, USA) and stirred for 4 hours, and the reaction solution was filtered. The filtrate was concentrated under a reduced pressure to obtain tert-butyl {[1-(2-chlorobenzoyl)-4-phenylpyrrolidin-3-yl]methyl}[1-(1-naphthyl)ethyl]carbamate as a crude product. A 0.5 ml methanol solution of the thus obtained crude product was mixed with 0.5 ml of 4 M hydrogen chloride/ethyl acetate solution at room temperature and stirred for 4 hours. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a fractional high performance liquid chromatography (methanol-0.1% formic acid aqueous solution) to obtain 3.3 mg of N-{[1-(2-chlorobenzoyl)-4-phenylpyrrolidin-3-yl]methyl}-1-(1-naphthyl)ethanamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:10][C:11]1[N:16]=[CH:15][CH:14]=[CH:13]N=1)[CH2:7][C:8]#C)=[O:5])[CH3:2]>C1(C)C(C)=CC=CC=1>[N:16]1[CH:15]=[CH:14][CH:13]=[C:8]2[CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][C:11]=12
Reactant: C#CCN(Cc1ncccn1)C(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)N1Cc2cccnc2C1

Procedure:
7.7 g (35 mmol) of 2-(N-ethoxycarbonyl-N-propargylaminomethyl)-pyrimidine are refluxed for 40 hours in 150 ml of xylene. The mixture is concentrated, and the residue is recrystallised from ligroin.
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10](=O)[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[NH2:2][C:1]1[S:29][C:10]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])=[N:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)NC(=O)c1c(F)cccc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(-c2c(F)cccc2F)sc1N
Temperature: 95 °C
Reaction time: 48 h

Procedure:
To a solution of the ethyl 2-cyano-2-(2,6-difluorobenzamido)acetate (1 eq) in 10 mL of toluene was added Lawesson reagent. The mixture was stirred at 95° C. for 2 days. Solvents were removed under reduced pressure. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:1) to give the ethyl 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylate, which was dissolved in 5 mL of methanol and 5 mL of THF. Then the mixture was added 1M sodium hydroxide (2 eq). The reaction mixture was stirred at room temperature overnight. The reaction was concentrated to remove most of solvents. The residue was extracted with ethyl acetate. The aqueous layer was acidified to pH=4-5 by 1N HCl. The resulting mixture was extracted by ethyl acetate. The organic layer was separated, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. to give the pure titled compound (34%). LC/MS (m/z): 257.1 (MH+), Rt: 0.61 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][CH2:16][CH2:17][Cl:18].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][Cl:18])[CH2:10][CH2:9]1)([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCCCl)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 4.94 g tert-Butyl-1-piperazine-carboxylate and 12.66 g 1-Bromo-3-chloropropane in 15 ml DMF (dry) was added 4.08 g K2CO3 and the reaction heated to 50° C. for one minute and stirred at room temperature for additional 3 h. The reaction mixture is pored into 200 ml of water and extracted with DCM. The combined organic phases were washed with water and dried over MgSO4 and evaporated in vacuo. The product was purified by flash column chromatography (n-heptane/ethylacetate 1:1, RF=0.3) Yield 3.9 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[N+:19]([O-])=O)=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO>[NH2:19][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(Nc2ccc(F)cc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(Nc2ccc(F)cc2)c(N)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 60c (1.4 g, 4.8 mmol) and SnCl2.2H2O (4.9 g, 21.7 mmol) in EtOH (50 mL) was stirred at 80° C. After 4 h, the mixture was cooled to room temperature and was slowly added to saturated aqueous NaHCO3. The solid was filtered and washed with H2O. The solid was triturated with EtOAc and the filtrate was concentrated. The crude product 60d was used in the next reaction without purification. MS m/z (M+H+) 261.1.
Reaction SMILES: [C:1]1([C:15]([OH:17])=O)[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C[N:19](C=O)C.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+]>C1COCC1>[C:1]1([C:15]([NH2:19])=[O:17])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc2cc3ccccc3cc12
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2cc3ccccc3cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
To a solution of anthracene-1-carboxylic acid (2.5 g, 11.26 mmol) in THF (30 ml) was added DMF (1.75 ml, 22.52 mmol). The solution was cooled to 0° C. and oxalyl dichloride (2M in CH2Cl2, 22.5 ml, 45 mmol) was added dropwise. The reaction solution was stirred at room temperature for 2 hours and then was cannulated into a solution of concentrated ammonium hydroxide (25 ml) in a 3-necked flask cooled at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The white precipitate was filtered and washed with water to give anthracene-1-carboxylic acid amide as an off-white solid (2.58 g, 100% yield). LC/MS (m/z 222.15 (M+H)+); HPLC (Column: Shimadzu VP-0DS, C-18 Ballistic; 10-90% aq CH3OH/0.1% H3PO4, same for compounds hereafter unless noted) Rt: 2.872 min.