Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[CH3:30])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48](I)=[CH:47][CH:46]=2)=[CH:41][CH:40]=1>[Cu].ClC1C=CC=CC=1Cl>[Br:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([N:22]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[CH3:30])[C:19]3[CH:20]=[CH:21][C:16]([C:13]4[CH:12]=[CH:11][C:10]([N:9]([C:3]5[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=5[CH3:1])[C:31]5[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=5)=[CH:15][CH:14]=4)=[CH:17][CH:18]=3)=[CH:47][CH:46]=2)=[CH:41][CH:40]=1
Reactant: Brc1ccc(-c2ccc(I)cc2)cc1
Reactant: Cc1ccc(N(c2ccc(-c3ccc(Nc4ccc(C)cc4C)cc3)cc2)c2ccc(C)cc2C)cc1
Agent: [Cu]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(N(c2ccc(-c3ccc(N(c4ccc(-c5ccc(Br)cc5)cc4)c4ccc(C)cc4C)cc3)cc2)c2ccc(C)cc2C)cc1
Temperature: 25 °C

Procedure:
Into a 2 liter three-necked reaction vessel fitted with an air-cooling tube and a mechanical stirrer, 48.3 g (0.1 mol) of N4,N4′-bis(2,4-dimethylphenyl)-N4-p-tolylbiphenyl-4,4′-diamine, 39.5 g (0.11 mol) of 4′-bromo-4-iodobiphenyl, 20 g of copper powder and 200 mL of o-dichlorobenzene were introduced and heated for 12 hours in an oil bath. After the reaction was completed, the reaction mixture was left to cool to room temperature, followed by removing solid matter by filtration, and thereafter extraction with toluene/water. Then, the solvent was distilled away from the organic layer under reduced pressure, followed by purification with a silica gel column (developer solvent: hexane/toluene=2:1) to give the desired N4′-(4′-bromobiphenyl-4-yl)-N4,N4′-bis(2,4-dimethylphenyl)-N4-p-tolylbiphenyl-4,4′-diamine. The compound obtained was in a yield of 45.0 g corresponding to 63%. The compound obtained was measured with the same elementary analyzer as the above.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[S:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2)(=[O:26])=[O:24]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(Cc2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.6 %

Procedure:
To a solution of ethyl 1-((6-hydroxynaphthalen-2-yl)methyl)piperidine-4-carboxylate (1 g, 3.19 mmol) and TEA (0.64 g, 6.38 mmol, 2 eq) in DCM (20 mL) was added Tf2O (1.8 g, 6.38 mmol, 2 eq) dropwise at 0° C. The mixture was stirred at room temperature for 12 h. The reaction was quenched with water at 0° C., washed with sat. NaHCO3 (10 mL) and brine (5 mL×3). The organic layer was dried over Na2SO4 and concentrated to afford ethyl 1-((6-(((trifluoromethyl)sulfonyl)oxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate as a brown solid (350 mg, yield: 90%). ESI-MS: 446.1 (M+H)+. 1HNMR (400 MHz, CDCl3) δ: 7.88 (d, J=9.2 Hz, 1H), 7.84-7.82 (m, 2H), 7.79 (s, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.35 (d, J=9.2 Hz, 1H), 4.13 (q, J=7.6 Hz, 2H), 3.66 (s, 2H), 2.89-2.86 (m, 2H), 2.32-2.28 (m, 1H), 2.11-2.07 (m, 2H), 1.88-1.78 (m, 4H), 1.26 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:4].[ClH:13].Cl.[CH2:15]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:1].[ClH:13].[ClH:1].[CH2:15]([N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([NH:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[O:4])[CH2:26][CH2:25]1)[C:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17]
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: O=C(CCl)NCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCN(CC(=O)c2ccccc2)CC1)NCc1ccccn1

Procedure:
A mixture of 2-chloro-N-(pyridin-2-ylmethyl)acetamide (1.3 mmol), N-phenacyl piperazine dihydrochloride (1 mmol), and K2CO3 (8.75 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-31), 0.7 g (60.45%), M+ 381.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F:9][CH:10]([F:27])[O:11][C:12]1[CH:17]=[CH:16][C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH:10]([F:27])[F:9])=[CH:13][CH:14]=2)=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: FC(F)Oc1ccc(-c2cnc(Cl)nc2)cc1
Temperature: 150 °C

Procedure:
To a solution of 5-bromo-2-chloropyrimidine 4 (7.7 mmol) in 1,4-dioxane (1.5 mL) is added 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (8.9 mmol), 1.8M K2CO3 aq. (16.2 mmol) and Pd(PPh3)4 (0.38 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 150° C. for 10 min under microwave. After this time, the reaction mixture is diluted with a saturated solution of NH4Cl and extracted with DCM (3×50 mL). The organic layer is washed with brine, dried over Na2SO4 and concentrated. Purification by short silica gel chromatography using a hexane:EtOAc=3:1 mixture affords 2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine 30. 1HNMR (400 MHz, CDCl3) δ 8.73 (s, 2H), 7.47-7.52 (m, 2H), 7.20-7.24 (m, 2H), 6.52 (t, J=72 Hz, 1H). MS (m/z) (M+1)+: 257.0.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:34][CH3:35])=[C:7]([CH:23]=[C:24]([N:26]2[CH:31]=[CH:30][C:29](=[O:32])[NH:28][C:27]2=[O:33])[CH:25]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[CH2:21][OH:22])([CH3:4])([CH3:3])[CH3:2].I(C1C=CC=CC=1C(O)=O)(=O)=O>CC(N(C)C)=O>[C:1]([C:5]1[C:6]([O:34][CH3:35])=[C:7]([CH:23]=[C:24]([N:26]2[CH:31]=[CH:30][C:29](=[O:32])[NH:28][C:27]2=[O:33])[CH:25]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][C:11]=1[CH:21]=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CO)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CC(=O)N(C)C
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2C=O)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
To a solution of the product from Example 28 (0.60 g, 1.20 mmol) in anhydrous DMA (15 ml) was added 2-iodoxybenzoic acid (336 mg, 1.20 mmol). The mixture was stirred at room temperature for 1 h, and then partitioned between EtOAc (20 ml) and H2O (2×20 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 2% MeOH in CH2Cl2 as the eluent to give the title compound as a colorless solid (395 mg, 66%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.43 (d, J=2.21 Hz, 1H) 10.45 (s, 1H) 10.15 (s, 1H) 8.06 (d, J=16.18 Hz, 1H) 7.97 (d, J=8.82 Hz, 1H) 7.73-7.78 (m, 2H) 7.69 (d, J=2.57 Hz, 1H) 7.51 (dd, J=8.64, 2.39 Hz, 1H) 7.30 (d, J=16.18 Hz, 1H) 7.26 (d, J=2.57 Hz, 1H) 5.66 (dd, J=7.72, 2.21 Hz, 1H) 3.81 (s, 3H) 3.07 (s, 3H) 1.39 (s, 9H).
Reaction SMILES: C[O-].[Na+].CO.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[NH:14][S:15]([C:18]1[N:28]=[C:21]2[CH:22]=[C:23]([Cl:27])[CH:24]=[C:25](Cl)[N:20]2[N:19]=1)(=[O:17])=[O:16].[C:29](O)(=[O:31])C>CS(C)=O.ClCCl.CCCCCC>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[NH:14][S:15]([C:18]1[N:28]=[C:21]2[CH:22]=[C:23]([Cl:27])[CH:24]=[C:25]([O:31][CH3:29])[N:20]2[N:19]=1)(=[O:17])=[O:16]
Reactant: O=S(=O)(Nc1c(Cl)cccc1Cl)c1nc2cc(Cl)cc(Cl)n2n1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc(Cl)cc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn12

Procedure:
Sodium methoxide in methanol (1.1 mL of 25 percent solution, 0.26 g, 0.005 mol) was added to a solution of N-(2,6-dichlorophenyl)-5,7-dichloro[1,2,4]triazolo[1,5-a]pyridine-2-sulfonamide (0.9 g, 0.02 mol) in dimethyl sulfoxide (30 mL) at ambient temperature with stirring. The reaction was complete in a few minutes, but was stirred for 30 min. The mixture was then acidified with acetic acid and diluted with dichloromethane. The resulting organic phase was recovered and washed with water and the volatiles were removed by evaporation under reduced pressure. The residue obtained was mixed with hexane and the insoluble solids were collected by filtration and dried to obtain 0.8 g (90 percent of theory) of the title compound as a light tan powder melting at 232°-234° C.(d).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[S:8][C:9]=1[C:10](O)=[O:11])#[N:2].CCN(CC)CC.[H][H]>C1COCC1>[O:4]1[C:5]2[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=3[S:8][C:9]=2[C:10](=[O:11])[NH:2][CH2:1][CH2:3]1
Reactant: N#CCOc1c(C(=O)O)sc2ccccc12
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NCCOc2c1sc1ccccc21
Yield: 55 %

Procedure:
A mixture of the methyl ester of 3-(cyanomethoxy)benzo [b]thiophene-2-carboxylic acid (405 mg, 1.64 mmols) [J. Hetero. Chem., 12:1037 (1975)], 0.5 mL of Et3N and 0.50 g of RaCo in 50 mL of THF is heated at 100° C. under 1200 psi of hydrogen. The reaction mixture is concentrated in vacuo. Column chromatography eluting with a gradient of 1:1 hexane:ethyl acetate to all ethyl acetate provides 2,3-dihydro-[1]benzothieno[2,3-f]1,4-oxazepin-5 (4H)-one in 55% yield, mp 244°-245° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[C-:20]#[N:21].[Na+].[Na+].[I-]>C(#N)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][C:20]#[N:21])=[CH:14][CH:15]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: [C-]#N
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: N#CCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
30.0 g of molecular sieves were activated under vacuum, at 100° C., for 1 h. 5.00 g of 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride (15.94 mmol, 1 eq), 9.38 g of NaCN (191.3 mmol, 12 eq), 428 mg of Bu4NCN (1.59 mmol, 0.1 eq), 9.56 g of NaI (63.77 mmol, 4 eq) and 150 mL of ACN were added. The mixture were stirred at RT, O/N. Sieves were filtered and washed with EtOAc. The filtrate was washed twice with NaHCO3, dried on MgSO4, filtered and concentrated to give 4.95 g of crude. It was purified by silica gel chromatography (MeOH/CH2Cl2, 0 to 5%) and gave two batches: batch #01 (very pure)=3.90 g, batch #02 (some impurities) was purified on activated carbon to give 0.90 g. Total yield=82%. m/e+=268 (M+H+).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-:15].[Na+]>>[NH2:6][C:7]1([C:13]([NH2:14])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: N#CC1(N)CCCCC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C1(N)CCCCC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 20 g concentrated sulfuric acid at 5° C is added with stirring 10 g of 1-aminocyclohexanecarbonitrile. After the addition, the mixture is heated with stirring at 100° C for 1 hour. The hot solution is then poured onto ice, the solution made strongly basic with 50% aqueous sodium hydroxide solution, and extracted three times with chloroform. The extract is washed with water, saturated NaHCO3 solution, dried, and the solvent removed in vacuo to leave the product, 1-aminocyclohexanecarboxamide, as a crystalline residue, melting point 99°-102° C. This can be recrystallized from either benzene or ether to give a pure product, melting point 101°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:35][CH2:36][O:37][CH3:38])(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:35][CH2:36][O:37][CH3:38])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Reactant: COCCOS(=O)(=O)C(F)(F)F
Product: COCCC(C(=O)OC(C)(C)C)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O

Procedure:
312 mg (0.75 mmol) of tert-butyl {4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate in the presence of 0.90 ml (0.90 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 312 mg (1.50 mmol, 1.5 eq.) of 2-methoxyethyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 201 mg (purity 91%, 51% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:34])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[N:17]=[CH:18][N:19]=[C:20]3[C:27]=2[C:26]2[C@@H:25]([CH2:28][O:29][CH2:30][C:31](O)=[O:32])[CH2:24][CH2:23][C:22]=2[S:21]3)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:41]C=2C=1.CCN=C=NCCCN(C)C.[NH4+].[Cl-]>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:31]([CH2:30][O:29][CH2:28][C@H:25]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[C:27](=[C:16]([O:15][CH:12]4[CH2:11][CH2:10][CH:9]([N:8]([CH3:34])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:14][CH2:13]4)[N:17]=[CH:18][N:19]=3)[C:26]1=2)(=[O:32])[NH2:41]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCC(=O)O)CC4)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 63.7 %

Procedure:
To a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of 2-[[(3S)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]methoxy]acetic acid (120 mg, 0.24 mmol, 1.00 equiv), HOBT (49 mg, 0.36 mmol, 1.49 equiv), EDCI (70 mg, 0.37 mmol, 1.50 equiv), 4-dimethylaminopyridine (44 mg, 0.36 mmol, 1.48 equiv) and NH4Cl (76 mg, 1.42 mmol, 5.82 equiv) in distilled DMF (5 mL) at room temperature under nitrogen. The resulting solution was stirred for 14 hrs at ambient temperature, quenched with water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to afford the desired tert-butyl N-(4-[[(3S)-3-[(carbamoylmethoxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (75 mg, 63%) as a colorless oil. MS: m/z 491 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11]C)=[C:5]([CH3:13])[C:4]=1[CH:14]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].[N+]([O-])([O-])=O.[NH4+].[Ce].C(=O)([O-])O.[Na+]>C(#N)C.O>[CH3:13][C:5]1[C:6](=[O:11])[C:7]([CH3:10])=[C:8]([CH3:9])[C:3](=[O:2])[C:4]=1[CH:14]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: COc1c(C)c(C)c(OC)c(C(CCCC(=O)O)c2cccnc2)c1C
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Solvent: CC#N
Solvent: O
Product: CC1=C(C)C(=O)C(C(CCCC(=O)O)c2cccnc2)=C(C)C1=O
Yield: 54.5 %

Procedure:
The solution of 400 mg (1.12 mmol) of 5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-(3-pyridyl)pentanoic acid in 8 ml of acetonitrile-water (1:1) was cooled to 0° C., to which the solutioin of 1.55 g (2.82 mmol) of cerium ammonium nitrate in 6 ml of acetonitrile-water (1:1) was added with stirring. The reaction mixture was stirred for 30 minutes, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was evaporated off. The residue was purified with silica gel column (ethyl acetate), and recrystallized from ethanol, to give 200 mg (54.3%) of 5-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-5-(3-pyridyl)pentanoic acid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20](OS(C(F)(F)F)(=O)=O)[CH:19]=[CH:18]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CN.Cl.C[CH2:37][N:38](CC)CC.CN(C=O)C>[Cl-].[Na+].O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([NH:38][CH3:37])[CH:19]=[CH:18]3)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2nc(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: CN
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2nc(NC)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
Ethyl 3-t-butyl-1-(2-(trifluoromethylsulfonyloxy)quinolin-6-yl)-1H-pyrazole-5-carboxylate (see WO 2006/071940A2, 0.380 g, 0.806 mmol), MeNH2.HCl (0.109 g, 1.61 mmol) and Et3N (0.449 ml, 3.22 mmol) were combined DMF (8 mL) and stirred at RT overnight. Additional portions of MeNH2.HCl (0.109 g, 1.61 mmol) and Et3N (0.449 ml, 3.22 mmol) were added and the reaction was stirred an additional 4 h at RT and 3 h at 60° C. The completed reaction was diluted with brine and extracted with EtOAc. The extracts were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to provide ethyl 3-tert-butyl-1-(2-(methylamino)quinolin-6-yl)-1H-pyrazole-5-carboxylate (240 mg, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J=9.2 Hz, 1H), 7.68 (d, J=2.8 Hz, 1H), 7.53 (d, J=9.2 Hz, 1H), 7.46 (dd, J=8.8, 2.0 Hz, 1H), 7.17 (q, J=4.8 Hz, 1H), 6.98 (s, 1H), 6.80 (d, J=8.8 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 2.92 (d, J=4.8 Hz, 3H), 1.32 (s, 9H), 1.13 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 353.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([CH:23]=O)[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:25])[O:4][N:3]=1.Cl.[NH2:27][OH:28].N1C=CC=CC=1.CCOC(C)=O>CO>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([CH:23]=[N:27][OH:28])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: NO
Reactant: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C=NO
Temperature: 25 °C

Procedure:
2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbaldehyde (18 mg, 0.05 mmol) was dissolved in 5 ml MeOH. 5 eq hydroxylamine hydrochloride and 6 eq pyridine were added. The mixture was heated at reflux for 1.5 h and then allowed to cool to rt. 50 ml EtOAc were added, the resulting mixture was washed with brine 3× and then dried over Na2SO4. The solvent was concentrated and the crude product was purified using preparative HPLC. 3.5 mg 2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbaldehyde oxime was obtained. The title compound was identified by 1H-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 348.01 (M+H), 346.18 (M−H); 1H NMR (MeOD, 500 MHz): 8.38 (s, 1H), 8.26 (m, 1H), 7.66 (m, 1H), 7.35 (m, 1H), 7.25 (m, 1H), 7.11 (m, 2H), 6.80 (m, 2H), 2.13 (s, 3H) and 1.99 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12]
Reactant: COCCOCOc1cccc(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOCOc1cccc(CN)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled (0° C.) solution of 3-[(2-methoxyethoxy)-methoxy]-benzonitrile (3.9 g, 18.8 mmol, example 8) in THF (40 mL) is added LAH (40 mL, 1M in THF). The resulting solution is stirred for 10 min. then the cold bath removed and stirring continued for 2 h. The resulting mixture is cooled to 0° C. then water (1.5 mL) added dropwise followed by NaOH solution (1.5 mL, SM) and water (1.5 mL). The resulting suspension is diluted with ether then filtered through celite. The filtrate is concentrated to give the title compound which is used without further purification. MS (ESI) 211 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:27])[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1)=O.[ClH:28].[NH:29]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>O1CCCC1.C(N(CC)CC)C>[ClH:28].[ClH:28].[CH3:27][N:17]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][CH:3]([CH2:1][N:29]3[CH2:33][CH2:32][C:31](=[O:34])[CH2:30]3)[CH2:4][N:5]=1)=[CH:16]2)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)(=[O:20])=[O:19]
Reactant: O=C1CCNC1
Reactant: CN(c1cccc2cc(C3=NCC(C=O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(CN4CCC(=O)C4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
To a mixture of N-[2-(5-formyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylpyridine-2-sulfonamide (200 mg), pyrrolidin-3-one hydrochloride (120 mg), triethylamine (150 μL) and tetrahydrofuran (5 mL) was added sodium triacetoxyborohydride (210 mg), and the mixture was stirred at room temperature for 10 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give a colorless oil from a fraction eluted with ethyl acetate. The colorless oil was dissolved in ethyl acetate (3 mL), and 4N hydrogen chloride-ethyl acetate solution (1 mL) was added. The precipitated solid was collected by filtration, washed with diethyl ether, and dried to give the title compound (110 mg, yield 40%) as a yellow amorphous solid. MS: 470 (MH+).