Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH:14]=[O:15])=[O:4].[O-:16]Cl=O.[Na+].OO.Cl>C(#N)C.CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14]([OH:16])=[O:15])=[O:4]
Reactant: [O-][Cl+][O-]
Reactant: COC(=O)c1ccc2[nH]nc(C=O)c2c1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)c1ccc2[nH]nc(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.7 %

Procedure:
To a solution of 5 g 3-Formyl-1H-indazole-5-carboxylic acid methyl ester in 100 mL acetonitrile and 8 mL DMF a solution of 4.4 g NaH2PO4 in 90 mL water was added dropwise at RT within 1 h. Then a solution of 4.2 g NaClO2 (80%) in 90 mL water followed by 5.3 mL H2O2 (30%) was added dropwise at 0° C. After stirring for 16 h at RT the reaction mixture was cooled to 0° C. followed by addition of 180 mL half-concentrated aqueous hydrochloric acid. The precipitated product was collected by filtration to yield 2.3 g pure product. The filtrate was extracted with ethyl acetate (3×150 mL), the combined organic layers were dried over MgSO4. After removal of the solvent under reduced pressure further 3.42 g of product were obtained. The combined product fractions were used without further purification. Yield: 5.7 g.
Reaction SMILES: [B-].[Na+].[CH2:3]1[O:13][C:6]2([CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)[O:5][CH2:4]1.Cl>CO>[CH2:4]1[O:5][C:6]2([CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2)[O:13][CH2:3]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [B-]
Agent: [Na+]
Solvent: CO
Product: OC1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
Sodium borohydrate (2.4 g, 64 mmol) was added in portions to a stirred ice cold solution of 1,4 cyclohexanedione monoethylene ketal 38 (20 g, 128 mmol) in 60 mL of methanol (Step 35). After addition was complete, 1N HCl was added to the solution dropwise until a pH of 8 was obtained and then the solvent was removed by roto-evaporation. The product 39 (16.8 g, 84%) showed a single spot on TLC (Rf=0.4, ethyl acetate/hexane 20:80 solvent system, visualization was with acidic vanillin ethanol solution) and was used without further purification. 1H NMR (CDCl3) δ1.6-1.9 (m, 8H, ring-CH2), 3.8 (m, 1H, CH--O), 4.0 (s, 4H, ketal-CH2), 5.3 (s, 1H, OH).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:17][C:16]([NH2:18])=[N:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:19][O:20][C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)=[O:22].O>N1C=CC=CC=1>[CH3:19][O:20][C:21](=[O:22])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:18][C:16]2[S:17][C:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:8][CH:9]=3)=[N:14][N:15]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CCCCCOc1ccc(-c2nnc(N)s2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCOc1ccc(-c2nnc(NC(=O)c3ccc(C(=O)OC)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of 5-(4-pentyloxyphenyl)-1,3,4-thiadiazol-2-yl-amine (20 g) in pyridine (200 ml) was added 4-methoxycarbonylbenzoylchloride (15 g) and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration and dried to give N-[5-(4-pentyloxyphenyl)-1,3,4-thiadiazol-2-yl]terephthalamic acid methyl ester (30.3 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[CH:6]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1.Br[CH2:28][C:29]([N:31]([CH3:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>CN(C=O)C>[CH3:3][C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:28][C:29]([N:31]([CH3:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:30])[C:7](=[O:15])[CH:6]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1
Reactant: CC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2ccccc21
Reactant: CN(C(=O)CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=NC(NC(=O)OCc2ccccc2)C(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc21
Reaction time: 0.5 h
Yield: 39 %

Procedure:
80% Sodium hydride in oil (102 mg) was added to a solution of phenylmethyl [2,3-dihydro-5-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]carbamate (1.00 g) in dry DMF (10 ml) under nitrogen. The mixture was stirred for 0.5 h at 23° and was treated with a solution of 2-bromo-N-methyl-N-phenylacetamide (707 mg) in dry DMF (1 ml). The mixture was stirred at 23° for 1 h, partitioned between phosphate buffer solution (pH6.5) and EA, the organic phase was washed with water and dried. The solvent was evaporated in vacuo and the residue was purified by chromatography on alumina. Elution with MeOH-DCM (1:50) gave the title compound (568 mg).
Reaction SMILES: Cl.[C:2]([N:5]([CH2:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=1)[CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:8]2[CH:19]=[CH:20][C:21]([N:23]=C(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:22][C:7]1=2)(=[O:4])[CH3:3]>O1CCCC1.C(OCC)(=O)C>[C:2]([N:5]([CH2:37][C:38]1[CH:39]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:41]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:43]=1)[CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:8]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:7]1=2)(=[O:4])[CH3:3]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(N=C(c3ccccc3)c3ccccc3)cc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(N)cc21
Reaction time: 0.25 h
Yield: 75 %

Procedure:
Add 2 N hydrochloric acid (2 mL) to a solution of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-(benzhydrylideneamino)-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (example 6b) (0.920 g, 1.32 mmol) in tetrahydrofuran (10 mL) at room temperature and stir for 15 min. Dilute the mixture with ethyl acetate (20 mL) and wash with saturated sodium hydrogen carbonate solution and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (1:1), to provide the title compound as an off-white solid (0.526 g, 75%); APCI MS 531 (M+H).
Reaction SMILES: [CH2:1]([N:4]1[C:16]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][CH3:3].CN([CH:26]=[O:27])C.O=P(Cl)(Cl)Cl>O>[CH2:1]([N:4]1[C:16]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:13]([CH:26]=[O:27])=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][CH3:3]
Reactant: CCCn1c2ccccc2c2cccc(-c3ccccc3)c21
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCn1c2ccccc2c2cc(C=O)cc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a 500 ml, three neck round bottom flask equipped with mechanical stirrer, thermometer, and addition funnel were added N-propylphenylcarbazole (56g, 0.2 mol) (prepared as described in the procedure used to prepare Compound (6)) and DMF (300 ml). The flask was placed in an ice/salt bath. When the temperature inside the flask reached 0° C., POCl3 (21 ml, 0.22 mol) was added slowly by the addition funnel. The inside temperature was not allowed to rise above 5° C. during the addition of the POCl3. When the addition of POCl3 was completed, the flask was placed on a steam bath for 2 hr. The flask was cooled to room temperature, then added slowly to a large excess of water (2 liters in a 4.5 liter beaker). The solution was stirred at room temperature for 3 hr, the solid was filtered off, washed repeatedly with water, and followed by washing with ethanol (20 ml). The product was recrystallized once from THF/water and dried at 60° C. in a vacuum oven for 6 hr. to produce 50 g (79% yield) of N-propylphenyl-3-formylcarbazole. 1H-N MR and IR spectra confirmed the structure of the product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[CH2:11][CH2:10][CH2:9][NH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])(=O)=O.O>ClCCl>[Si:26]([NH:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[CH2:11][CH2:10][CH2:9][NH:8][C:6]=2[N:7]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Nc1nc(Cl)c2c(n1)NCCC2
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Nc1nc(Cl)c2c(n1)NCCC2
Temperature: -37 °C
Reaction time: 1.5 h
Yield: 100000000 %

Procedure:
To a solution of 69 g (370 nmol) of 2-amino-4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine in anhydrous dichloromethan (450 ml) was added 70 ml (500 mmol) of triethylamine, and then cooled to -37° C. Then, under inert gas atmosphere, to the reaction mixture was dropwise added 102 ml (450 mmol) of tertbutyldimethylsilyl trifluoromethanesulfonate over a period of 30 minutes, and the mixture was stirred at that temperature for 1.5 hours. The suspension turned to a red-colored solution. The reaction solution was poured into 300 ml of water. After usual work up, the product was extracted with 300 ml of dichloromethane. The combined dichloromethane layer was dried over potassium carbonate, and then the solvent was evaporated from the filtrate. To the resulting oily residue was added 300 ml of hexane, then heated to 80° C. with stirring. An insoluble oily residue then removed by decantation. The target compound was extracted with 200 ml of hexane from the oily residue. The combined hexane layer was evaporated to give 112 g (370 mmol) of 2-tert-butyldimethylsilylamino-4-chloro-5,6,7,8tetrahydropyrido[2,3-d]pyrimidine in the form of white crystals. (Yield 99%)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]1=[S:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]1=[S:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=S)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: S=C1CNCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a solution of 1-benzyl-4-(tert-butyloxycarbonyl)piperazin-2-thione (925 mg, 3.02 mmol) in CH2Cl2 (25 mL) was added trifluoroacetic acid (2.5 mL). The mixture was stirred at room temperature, under nitrogen, for 2 h. The solvent was evaporated and the residue azeotroped with toluene (2×10 mL). The residue was partitioned between CH2Cl2 (2×50 mL) and Na2CO3 solution (10% (w/v), 40 mL). The combined organic layers were dried Na2SO4) and evaporated. The residue was chromatographed on silica, eluting with CH2Cl2 :MeOH (95:5) to afford the title compound (539 mg, 87%) as a pale orange solid. mp. 70-73° C. 1H NMR (250 MHz, CDCl3) δ3.11-3.16 (2H, m), 3.29-3.33 (2H, m), 4.10 (2H, s), 5.31 (2H, s), 7.30-7.37 (5H, m). MS (ES+) (207, M+1).
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([CH2:25][O:26]C(=O)C)=[N:16][CH:15]([NH:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[C:14]1=[O:41])=[O:11])[CH2:2]2.[OH-].[Na+]>C(O)C>[CH:5]12[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:10]([CH2:12][N:13]1[C:19]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([CH2:25][OH:26])=[N:16][CH:15]([NH:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[C:14]1=[O:41])=[O:11])[CH2:4]2
Reactant: CC(=O)OCC1=NC(NC(=O)OCc2ccccc2)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c(C)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc2c1N(CC(=O)N1CC3CCC(CC3)C1)C(=O)C(NC(=O)OCc1ccccc1)N=C2CO
Temperature: 25 °C

Procedure:
To a solution of (3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-5-acetoxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (1.9 g) in ethanol (40 ml) was added 1N-sodium hydroxide solution (7 ml) under stirring at ambient temperature. The mixture was stirred for 20 minutes under the same conditions. After removal of the solvent water was added into the mixture, which was adjusted to pH 4 with a diluted hydrochloric acid and extracted with ethyl acetate twice. The combined extract was washed with water and dried over magnesium sulfate. Removal of the solvent gave (3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-3-benzyloxycarbonylamino-5-hydroxymethyl-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one as an amorphous mass (1.68 g, 95.3%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.[Cl:43][C:44]1[C:52]2[O:51][CH:50]=[CH:49][C:48]=2[C:47]([CH2:53][CH2:54][CH2:55]O)=[CH:46][CH:45]=1>C1COCC1>[Cl:43][C:44]1[C:52]2[O:51][CH:50]=[CH:49][C:48]=2[C:47]([CH2:53][CH2:54][CH2:55][N:36]2[C:32](=[O:42])[C:33]3[C:34](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:35]2=[O:37])=[CH:46][CH:45]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCc1ccc(Cl)c2occc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc(Cl)c2occc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
Diethylazodicarboxylate (0.35 ml) was added dropwise to a solution of triphenylphosphine (587 mg) and phthalimide (329 mg) in dry THF (10 ml) at 0° under nitrogen. A solution of 3-(7-chloro-benzofuran-4-yl)-propan-1-ol (364 mg) in THF (5 ml) was then added and the mixture allowed to warm to room temperature and stirred for 2 h. The solvent was evaporated and the residue purified by column chromatography, eluting with cyclohexane/ether 3:1 gave the title compound as a colourless solid (521 mg)
Reaction SMILES: Br[CH2:2][C:3](=[O:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@@H:11]([CH2:12][C@H:13]([OH:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[OH:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C1COCC1>[OH:23][C@@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:24])[CH2:2][O:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:12]1
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Reactant: Oc1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)COc3ccncc3)CC[C@@H]12
Temperature: 25 °C
Yield: 7.7 %

Procedure:
A solution of 21-bromo-3α-hydroxy-5β-pregnan-20-one (500 mg, 1.26 mmol), 4-hydroxypyridine (144 mg, 1.51 mmol), and triethyl amine (200 μL) in 10 mL of THF was heated under reflux for 4 h. The mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was washed with sat. aq. NaCl, dried with MgSO4 and concentrated in vacua. The crude residue was subjected to flash column chromatography. Elution with 50% acetone in CH2Cl2 yielded 3α-hydroxy-21-(pyrid-4-yloxy)-5β-pregnan-20-one (40 mg) as an oily solid; TLC Rf (acetone:CH2Cl2 1:1)=0.28.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([S:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=O)=[CH:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:5]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([S:21][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:13]1[Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(c1ccccc1)c1cn(Cc2ccccc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1c(Sc2ccccc2)c2ccccc2n1Cc1ccccc1
Temperature: 0 °C

Procedure:
A solution of thionyl chloride (0.03 ml, 0.054 g, 0.45 mmol) in dry dichloromethane (5 ml) was added dropwise to a stirred solution of 1-benzyl-3-phenylsulfinylindole (0.150 g, 0.45 mmol) in dry dichloromethane (20 ml), containing suspended sodium bicarbonate (1 g), maintained at 0° C. One half hour after the addition was completed the reaction was quenched with a saturated solution of aqueous sodium bicarbonate. The organic phase was separated, combined with a dichloromethane extract of the aqueous phase and the combined organic phases were dried and evaporated in vacuo. Crystallization of the residue from dichloromethane/hexane gave the title product.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9](=O)[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.Cl.[CH2:26]([O:28][NH2:29])[CH3:27]>C(O)C>[Br:1][C:2]1[C:3]([C:9](=[N:29][O:28][CH2:26][CH3:27])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: O=C(NCC(=O)c1ncc(Br)cc1Br)c1ccccc1C(F)(F)F
Reactant: CCON
Agent: Cl
Solvent: CCO
Product: CCON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
To 200 mg of N-[2-(3,5-dibromopyridine-2-yl)-2-oxoethyl]-2-(trifluoromethyl)benzamide in 1.4 ml of ethanol, 63 mg of ethoxyamine hydrochloride was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 4 ml of water and extracted with ethyl acetate (4 ml×2), the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 195 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[CH:29]=[CH:28][C:27]([N:30](C)[C:31](=O)OC(C)(C)C)=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[CH:25]=[CH:26][C:27]([NH:30][CH3:31])=[CH:28][CH:29]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(N(C)C(=O)OC(C)(C)C)cc5)cn34)ccnc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CNc1ccc(-c2ccc3nnc(COc4ccnc5cc(OC)ccc45)n3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl(methyl)carbamate (0.067 g, 0.13 mmol) was dissolved in MeOH (1.7 mL) and to the solution was added concentrated HCl (0.50 ml, 6.0 mmol). The reaction mixture was stirred at room temperature overnight. Upon completion, the crude mixture was concentrated in vacuo. The solid that remained after concentration was dissolved in MeOH and to the solution was added triethylamine (0.23 ml, 1.6 mmol). The reaction was allowed to stir for 1 h. The crude mixture was concentrated in vacuo. The compound was purified using via flash chromatography, eluting with 5-8% MeOH/NH4OH in DCM to yield 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-methylbenzenamine as a yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]2[C:17]([O:18][CH3:19])=[CH:16][NH:15][C:14](=[O:20])[CH:13]=2)[CH:5]=1.[CH3:21][O:22][CH2:23][CH2:24][CH:25](OS(C(F)(F)F)(=O)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>O1CCCC1>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]2[C:17]([O:18][CH3:19])=[CH:16][N:15]([CH:25]([CH2:24][CH2:23][O:22][CH3:21])[C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[C:14](=[O:20])[CH:13]=2)[CH:5]=1
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: COCCC(OS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC(C(=O)OC(C)(C)C)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A little at a time, 405 mg (10.1 mmol) of sodium hydride (60% in mineral oil) were added to a suspension of 2.4 g (9.2 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile in 70 ml of tetrahydrofuran, and the mixture was stirred at RT for another 1 h. 4.45 g (13.8 mmol) of tert-butyl 4-methoxy-2-{[(trifluoromethyl)sulphonyl]oxy}butanoate (racemate) as a solution in 20 ml of THF were quickly added dropwise to the resulting reaction solution, and after the addition had ended the mixture was stirred at RT for another 1.5 h. The reaction was terminated by addition of 150 ml of saturated aqueous ammonium chloride solution and 150 ml of methyl tert-butyl ether. The phases were separated and the aqueous phase was extracted three times with 130 ml of methyl tert-butyl ether. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (120 g silica cartridge, 85 ml/min, cyclohexane/ethyl acetate gradient), giving the title compound. Yield: 1.73 g (43% of theory)
Reaction SMILES: [N+:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]#[N:10])[C:5]=1[C:11]1[N:12]=[CH:13][S:14][CH:15]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[NH2:1][C:4]1[S:8][CH:7]=[C:6]([C:9]#[N:10])[C:5]=1[C:11]1[N:12]=[CH:13][S:14][CH:15]=1
Reactant: N#Cc1csc([N+](=O)[O-])c1-c1cscn1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1csc(N)c1-c1cscn1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
To a solution of 5-nitro-4-(thiazol-4-yl)thiophene-3-carbonitrile (0.071 g, 0.31 mmol) in ethyl acetate (3 mL) was added tin (II) chloride dihydrate (0.29 g, 1.27 mmol). The reaction mixture was heated in an oil bath set at 70° C. under condenser. After 20 min. the mixture was cooled to RT and concentrated under reduced pressure. Purification by flash chromatography (silica, 40:60 ethyl acetate/hexane) gave 5-amino-4-(thiazol-4-yl)thiophene-3-carbonitrile (24 mgs, 38%) Retention time (min)=1.837, method [4], MS (ESI) 208.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[OH:6])[CH2:4][CH2:3]1.[Cl:13][C:14]1[C:23](Cl)=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.[H-].[Na+].[Cl-].[NH4+]>C1COCC1.O>[Cl:13][C:14]1[C:23]([O:6][CH:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: CC1(C(O)c2cccnc2)CC1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(Oc2nc3ccccc3nc2Cl)c2cccnc2)CC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 56.7 %

Procedure:
In THF (5.0 mL) were dissolved (1-methylcyclopropyl)(pyridin-3-yl)methanol (130 mg, 0.796 mmol) obtained in Step 2 and 2,3-dichloroquinoxaline (190 mg, 0.956 mmol). To the mixture was added 60% sodium hydride (in oil, 38.2 mg, 0.956 mmol) and the mixture was stirred at 50° C. for 1.5 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=17/3) to give Compound A9 (147 mg, 57% yield).