Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:32])[CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21]([OH:31])([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1>[O-2].[O-2].[O-2].[Cr+6].O>[OH:31][C:21]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)=[O:32])[CH2:19][CH2:20]1
Reactant: Cc1ccc(C2(O)CCN(CCCC(O)c3ccc(F)cc3)CC2)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(C2(O)CCN(CCCC(=O)c3ccc(F)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
One gram of chromium trioxide was added with stirring to 40 ml of pyridine cooled to 0°C. The mixture was stirred at room temperature for 1 hour, and then again cooled to 0°C. Into the said mixture was added 1.1 g of 1-(p-fluorophenyl)-4-[4-hydroxy-4-(p-methylphenyl)-piperidino]-1-butanol, and the mixture was stirred for 1 hour under cooling with ice. The reaction mixture was poured into 300 ml of cold water to separate an oily substance. The oily substance is extracted with ethyl acetate, and the ethyl acetate layer was washed 4 times with each 60 ml of water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was recrystallized from aqueous acetone to obtain γ-(4-hydroxy-4-p-methylphenylpiperidino)-p-fluorobutyrophenone, melting at 119° - 120°C.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:30][N:31]=[C:32]=[O:33]>C1COCC1>[CH3:30][NH:31][C:32]([N:12]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:29])[F:27])=[CH:16][CH:15]=2)[CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:33]
Reactant: CN=C=O
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Solvent: C1CCOC1
Product: CNC(=O)N1CCN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was made in the following manner: 55 mg of 3-phenyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 2 equiv. methylisocyanate were added. The reaction was shaken at room temperature overnight. The solvent was removed in vacuo, the residue was dissolved in DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as free base. Addition of 1 equiv. of 1M HCl in dioxane and concentratation in vacuo afforded 33 mg of the title compound as hydrochloride salt. Yield 48% ES MS m/z 454
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[CH:16][N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C@H:6]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:5]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:3])[CH3:2].C1C(=O)N([Br:43])C(=O)C1>C(O)C>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[C:16]([Br:43])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][CH2:19][CH2:20][O:21][CH3:22])[C@H:6]([O:23][C:24](=[O:29])[C:25]([CH3:26])([CH3:27])[CH3:28])[C@H:5]1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:3])[CH3:2]
Reactant: COCCO[C@@H]1c2ccn3cc(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCO
Product: COCCO[C@@H]1c2ccn3c(Br)c(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Reaction time: 1 h

Procedure:
To a of 0° C. cooled solution of 2.20 g (4.60 mmol) (7R,8R,9R)-10-acetyl-7-(2-methoxyethoxy)-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydroimidazo(1.2-h][1.7]naphthyridine in ethanol (20 ml) is added 0.84 g (4.60 mmol) NBS and the mixture is stirred for 1 h. Afterwards the reaction is quenched by adding of saturated aqueous sodium hydrogen carbonate solution and it is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by crystallisation (cyclohexane) to give 1.60 g (2.86 mmol/62%) of the title compound as a colourless solid with a melting point of 166–167° C. (cyclohexane).
Reaction SMILES: C([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(OC(C)(C)C)=O.C(Cl)Cl>CN(C)C=O>[NH2:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reaction time: 0.17 h

Procedure:
While maintaining the nitrogen gas atmosphere, 3 fold molar excess of Boc-L-Tyrosine (Vega, supra.) dissolved in dimethylformamide and adjusted to 15 ml. with the addition of methylene chloride is added to the product of Step (F) above and the resulting mixture shaken. After about 10 minutes, 3 fold molar excess of N,N-dicyclohexylcarbodiimide is added and the resulting mixture is shaken for 4.5 to 5 hours at room temperature. At the end of this period, the reaction mixture is filtered and the residue washed with dimethylformamide. The washed residue is dried.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:17]4[S:18][C:19]([C:28]([O:30]CC)=[O:29])=[C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:21]=4)=[C:14]([CH3:16])[N:15]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:17]4[S:18][C:19]([C:28]([OH:30])=[O:29])=[C:20]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=4)=[C:14]([CH3:16])[N:15]=3)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1sc(-c2c(C)nc3ccc(C4CCCCC4)cn23)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2ccc(C3CCCCC3)cn2c1-c1nc(-c2ccccc2)c(C(=O)O)s1
Temperature: 50 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A mixture of ethyl 2-(6-cyclohexyl-2-methylimidazo[1,2-a]pyridin-3-yl)-4-phenyl-1,3-thiazole-5-carboxylate (204 mg, 0.458 mmol) obtained above in THF (5 mL) and MeOH (5 mL), was added 2N aqueous sodium hydroxide (750 μL), and the mixture was stirred at 50° C. for 12 h. The mixture was allowed to cool to rt and then neutralized by the addition of 1N aqueous hydrochloric acid (1.5 mL). The resulting precipitate was collected by filtration and then washed with water and diethyl ether to give the title compound (159 mg, 83%) as a gray solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([S:8][C:9]([CH3:27])([CH3:26])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])([OH:17])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1>C(#N)C>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C:10]([OH:17])([C:9]([CH3:27])([S:8][C:5]1[N:6]=[N:7][C:2]([N:28]2[CH:32]=[N:31][CH:30]=[N:29]2)=[CH:3][CH:4]=1)[CH3:26])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: CC(C)(Sc1ccc(Cl)nn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: c1nc[nH]n1
Solvent: CC#N
Product: CC(C)(Sc1ccc(-n2cncn2)nn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 93 %

Procedure:
A mixture consisting of 3.0 g (7.3 mmol) of (+)-3-(6-chloropyridazin-3-ylthio)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol 2.0 g(29 mmol) of 1,2,4-triazole, and 1.5 ml of acetonitrile was heated at reflux for 19 hours. After allowing the mixture to cool, the solvent was removed by distillation under reduced pressure, and the residue was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The organic layer was washed successively with water and a saturated sodium chloride aqueous solution and dried. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using a mixed solvent of chloroform and methanol (100:1). The solvent was removed from the effluent by distillation under reduced pressure, and the residue was recrystallized from a mixed solvent of chloroform and diethyl ether to obtain 3.0 g (93%) of (+)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-3-(6-(1H- 1,2,4-triazol-1-yl)pyridazin-3-ylthio)butan-2-ol as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH:7]1[CH2:9][O:8]1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][CH:7]([OH:8])[CH2:9][N:14]1[CH2:15][CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13]1
Reactant: Brc1cccc(OCC2CO2)c1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CO
Product: OC(COc1cccc(Br)c1)CN1CCc2ccccc2C1

Procedure:
To a solution of 2-((3-bromophenoxy)methyl)oxirane (1.5 g, 6.55 mmol) in MeOH (15 mL) was added 1,2,3,4-tetrahydroisoquinoline (1.0 g, 7.86 mmol) at 20° C. The mixture was heated at reflux temperature for 16 h, until the reaction was shown to be complete. The mixture then was concentrated to provide the crude which was purified using column chromatography on silica gel producing the desired 1-(3-bromophenoxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (1.8 g, 78.3%) as colorless oil. LCMS (m/z): 362.1 (M+1).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[OH:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[Cl:23])[CH:15]=2)=[O:13])[CH2:8]1>>[Cl:23][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:15]=[C:14]([C:12]([N:9]3[CH2:10][CH2:11][C@@H:7]([O:6][CH2:2][CH:3]4[CH2:5][CH2:4]4)[CH2:8]3)=[O:13])[S:22][C:21]=12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Reactant: BrCC1CC1
Product: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](OCC2CC2)C1

Procedure:
The title compound was prepared from bromomethyl-cyclopropane and (3R)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone by a procedure analogous to Example 67B. MS: 337.2/339.2 (MH+); HPLC Rf: 5.232 min.; HPLC purity 85%.
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([C:31](=[O:34])[NH:32][CH3:33])[CH:26]=[CH:25]3)[CH:18]=[CH:17][N:16]=1)[C:3](=O)[O:4]C1C=CC([N+]([O-])=O)=CC=1.[NH3:35]>CN(C)C=O>[CH3:33][NH:32][C:31]([N:27]1[C:28]2[C:24](=[CH:23][C:22]([O:21][C:19]3[CH:18]=[CH:17][N:16]=[C:15]([N:2]([CH3:1])[C:3]([NH2:35])=[O:4])[CH:20]=3)=[CH:30][CH:29]=2)[CH:25]=[CH:26]1)=[O:34]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C)C(=O)Oc4ccc([N+](=O)[O-])cc4)c3)ccc21
Reactant: N
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(N(C)C(N)=O)c3)ccc21
Temperature: 25 °C
Reaction time: 10.5 h
Yield: 48 %

Procedure:
4-Nitrophenyl N-methyl-(4-(1-methylcarbamoyl-indol-5-yloxy)pyridin-2-yl)carbamate (105 mg, 0.228 mmol) was dissolved in N,N-dimethylformamide (2.5 ml); aqueous ammonia (0.5 ml, 28.0%) was added thereto; the reaction mixture was stirred at room temperature for 10.5 hours. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystals were suspended in ethanol:diethyl ether=1:1 (6 ml), filtered off, washed with diethyl ether, and dried to yield the title compound (37 mg, 0.11 mmol, 48%) as pale yellow crystals.
Reaction SMILES: Cl[S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.N1C=CC=CC=1.Cl>ClC(Cl)C>[CH:9]([C:8]1[CH:11]=[CH:12][C:5]([S:2]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:14]([F:13])([F:23])[F:24])=[CH:17][CH:18]=2)(=[O:4])=[O:3])=[CH:6][CH:7]=1)=[O:10]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: O=Cc1ccc(S(=O)(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.3 %

Procedure:
to a mixture of 610 mg of 4-chlorosulfonylbenzaldehyde (3 mmoles) and 460 mg of 4-trifluoromethoxyaniline (3 mmoles) in 2 ml of dichloroethane is added 2 ml of pyridine (25 mmoles). The reaction mixture is stirred at room temperature for 5 hours and then poured into 100 ml of 10% HCl solution. The mixture is extracted twice with 30 ml of DCM. The combined organic extracts are washed with 30 ml of water, 30 ml of a saturated solution of sodium bicarbonate and brine, and the solution is dried over MgSO4 and concentrated. The crude product is purified on silica gel using DCM/AcOEt 90/10 as eluent. 0.48 g of 4-formyl-N-(4-trifluoromethoxy-phenyl)-benzenesulfonamide is isolated as a white solid (yield=47%). Analytical LC/MS method A:([M+H]+): 346, RT: 5.53 min (gradient 5 to 85% acetonitrile in 7 min).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:16]C.[C:18](Cl)(=[O:21])[CH2:19][CH3:20].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][C:6]=2[CH:5]=[C:4]([C:18](=[O:21])[CH2:19][CH3:20])[C:3]=1[OH:16]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)C1Cc2ccc(OC)c(Cl)c2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)C1Cc2cc(C(=O)CC)c(O)c(Cl)c2O1

Procedure:
To 1,2-dichloroethane (50 ml) were added ethyl 7-chloro-2,3-dihydro-6-methoxybenzofuran-2-carboxylate (1b) (4.25 g, 0.01656 mol) and propionyl chloride (2.58 ml, 0.03311 mol). The solution was stirred on an ice bath and treated with anhydrous aluminum chloride (6.62 g, 0.04967 mol) at 0°-5° C. for 45 minutes. An additional portion of aluminum chloride (2.21 g, 0.01656 mol) was added and the mixture left to stir overnight.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27](OCC)=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27]([NH:33][CH2:34][CH:35]([OH:37])[CH3:36])=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)(=O)=O)c1=O
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)(=O)=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methylsulfonyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-amino-2-propanol employing methods similar to those described in Example 202 and was obtained as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.33 (t, J=5.1 Hz, 1 H), 8.56 (s, 1 H), 7.67 (s, 1 H), 7.21 (dd, J=8.2, 5.4 Hz, 2 H), 7.01 (t, J=8.5 Hz, 2 H), 4.37 (t, J=7.7 Hz, 2 H), 4.12 (s, 2 H), 4.08 (m, 2 H), 3.62 (m, 1 H), 3.35 (m, 1 H), 3.14 (t, J=6.7 Hz, 2 H), 2.95 (s, 3 H), 2.19 (m, 2 H), 1.27 (d, J=6.4 Hz, 3 H); HRMS C23H26FN3O6S (M+H)+ calcd 492.1526, found 492.1623.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[C:10]3[N:26]([CH3:27])[CH:25]=[CH:24][C:11]3=[N:12][C:13]=2[C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[CH2:3]1.[C:28]1(=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](=[O:37])[NH:29]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:38]=[C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](=[O:37])[N:29]1[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[C:10]3[N:26]([CH3:27])[CH:25]=[CH:24][C:11]3=[N:12][C:13]=2[C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH3:15])[CH2:3]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1N1CCCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1N1CCCC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Yield: 24.8 %

Procedure:
A mixture of tert-butyl ((1S)-1-(6-(3-hydroxypiperidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (300 mg, 0.802 mmol), isoindoline-1,3-dione (165 mg, 1.12 mmol) and PPh3 (377 g, 1.44 mmol) in THF (2 mL) was stirred at 0° C. Next, diethyl azodicarboxylate (251 mg, 1.44 mmol) was added dropwise at 0° C., and the mixture was stirred at 20° C. for 16 hours. The solvent was evaporated in vacuo, and the residue was purified by preparative TLC to give the title compound as a white solid (100 mg, 35.2%). ESI-MS m/z [M+H]+ calc'd for C28H33N5O4, 504. found 504.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].Cl[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=1>>[Cl:27][C:26]1[C:21]([N:17]2[CH2:18][CH2:19][CH:14]([S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:12])=[O:13])[CH2:15][CH2:16]2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1cccnc1Cl
Reactant: O=S(=O)(c1ccc2ccccc2c1)C1CCNCC1
Product: O=S(=O)(c1ccc2ccccc2c1)C1CCN(c2ncccc2Cl)CC1
Yield: 48.8 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-(2-naphthylsulfonyl)piperidine (Example 11, Step 3, 175 mg, 0.63 mmol) was reacted with 2,3-dichloropyridine (188 mg, 1.3 mmol) to afford the title compound (119 mg), a white solid, in 48% yield.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:46][N:47]1[CH:51]=[CH:50][C:49]([NH2:52])=[N:48]1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12]2)[C:8]([NH:52][C:49]2[CH:50]=[CH:51][N:47]([CH3:46])[N:48]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1nc(Oc2ccccc2)ccc1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cn1ccc(NC(=O)C(CC2CCCC2)n2nc(Oc3ccccc3)ccc2=O)n1
Temperature: 25 °C
Reaction time: 1.8 h
Yield: 21 %

Procedure:
A solution of 3-cyclopentyl-2-(6-oxo-3-phenoxy-6H-pyridazin-1-yl)-propionic acid (0.30 g, 0.91 mmol) in methylene chloride (9.0 mL, 0.10M) at 25° C. was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (164 μL, 0.92 mmol) and 1-hydroxybenzotriazole (0.13 g, 0.96 mmol). The solution was stirred at 25° C. for 1.8 h. After this time, the reaction was treated with a solution of 1-methyl-1H-pyrazol-3-ylamine in methylene chloride at 25° C. The reaction was stirred at 25° C. for 5 d. After this time, the reaction was diluted with methylene chloride (100 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×100 mL), a saturated aqueous sodium bicarbonate solution (2×100 mL), water (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with methylene chloride and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 40 g, 50-100% ethyl acetate/hexanes gradient) afforded 3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(6-oxo-3-phenoxy-6H-pyridazin-1-yl)-propionamide (76.7 mg, 21%) as a white solid; ES+-HRMS m/e calcd for C22H25N5O3 [M+H+] 408.2030 found 408.2030. 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.87-0.98 (m, 1H), 1.17-1.31 (m, 1H), 1.35-1.63 (m, 7H), 1.69 (ddd, J=13.1, 9.3, 3.6 Hz, 1H), 1.88-2.00 (m, 1H), 3.73 (s, 3H), 5.29 (dd, J=11.1, 3.6 Hz, 1H), 6.33 (d, J=2.0 Hz, 1H), 7.09 (d, J=9.8 Hz, 1H), 7.17-7.26 (m, 3H), 7.34-7.43 (m, 2H), 7.46 (d, J=9.8 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 10.66 (s, 1H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:9]1([CH3:19])[CH2:14]C[CH:12]([CH:15]([CH3:17])[CH3:16])[CH:11](O)[CH2:10]1>C1(C)C=CC=CC=1>[C:1]([O:7][CH:8]1[CH:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10][CH:9]([CH3:19])[CH2:14]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: COC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OC1CC(C)CCC1C(C)C
Yield: 91 %

Procedure:
A mixture of 1 equivalent of methyl acetoacetate, 1 equivalent of menthol and 100 mg of sulfated tin oxide catalyst prepared according to example 1 above, in 20 ml of toluene was heated to 110° C. in a two necked round bottom flask provided with a distillation condenser to remove methanol. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction (about 6 hours), the catalyst was filtered and the filtrate was concentrated and chromatographed on a silica gel column (95% petroleum ether and 5% ethyl acetate) to afford menthyl acetoacetate as a viscous colorless liquid in 91% yield.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:30])[C:18]=2[CH:17]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:46][P-:47]([F:52])([F:51])([F:50])([F:49])[F:48].[K+]>O.ClCCl>[F:46][P-:47]([F:52])([F:51])([F:50])([F:49])[F:48].[C:9]1([S+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:22]2[CH:23]=[CH:24][C:25]3[S:26][C:27]4[C:18](=[CH:17][C:16]([Cl:15])=[CH:29][CH:28]=4)[C:19](=[O:30])[C:20]=3[CH:21]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: O=c1c2ccccc2sc2ccc(Cl)cc12
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=c1c2cc(Cl)ccc2sc2ccc([S+](c3ccccc3)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 7 %

Procedure:
To 320 ml of dichloromethane were suspended 20.2 g (0.1 mol) of diphenylsulfoxide and 24.6 g (0.1 mol) of 2-chlorothioxanthene-9-one, and 28.2 g (0.1 mol) of trifluoromethanesulfonic anhydride was added dropwise thereto at −70 to −60° C., followed by gradually warming to room temperature and reacting with stirring for 3 hours. After completion of the reaction, the obtained reaction solution was washed with water (320 ml×5 times) and 18.4 g (0.1 mol) of potassium hexafluorophosphate and 200 ml of water were added to the obtained dichloromethane layer, followed by stirring at room temperature for 2 hours and fractionating the solution. Then, 9.2 g (0.05 mol) of potassium hexafluorophosphate and 100 ml of water were further added to the obtained dichloromethane layer, followed by stirring at room temperature for 2 hours and fractionating the solution. Then the obtained dichloromethane layer was washed with 200 ml of water and concentrated to dryness under reduced pressure. The obtained crude product was purified by column chromatography to obtain 4.0 g of objective substance as pale yellow glassy substance (yield: 7%).
Reaction SMILES: [N-]=[N+]=[N-].[N:4]([C@H:7]1[CH2:12][CH2:11][CH2:10][C@:9]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])([CH3:13])[C@@H:8]1[OH:22])=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:4][C@H:7]1[CH2:12][CH2:11][CH2:10][C@:9]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])([CH3:13])[C@@H:8]1[OH:22]
Reactant: CC(C)(C)[Si](C)(C)O[C@]1(C)CCC[C@H](N=[N+]=[N-])[C@H]1O
Reactant: [H][H]
Agent: [Pd]
Agent: [N-]=[N+]=[N-]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@]1(C)CCC[C@H](N)[C@H]1O

Procedure:
A solution of azide, 50d, (0.25 g; 0.89 mmol) in 20 mL of ethyl acetate was hydrogenated with Degussa palladium (20 mole %) under 1 atmosphere of hydrogen overnight. The reaction mixture was filtered over celite and the celite was eluted with 2×10 mL of EtOAc. The filtrate was concentrated in vacuo to afford 230 mg of an oil that was used directly for the next step without further purification.