Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]3([CH3:14])[CH2:13][CH2:12]3)[N:10]=[C:6]2[CH:5]=[C:4]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])[CH:3]=1.[I:22]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C=O)C>[I:22][C:8]1[N:7]2[C:2]([CH3:1])=[CH:3][C:4]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])=[CH:5][C:6]2=[N:10][C:9]=1[C:11]1([CH3:14])[CH2:12][CH2:13]1
Reactant: CCCCOC(=O)c1cc(C)n2cc(C3(C)CC3)nc2c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1cc(C)n2c(I)c(C3(C)CC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
Butyl 5-methyl-2-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-7-carboxylate (370 mg, 1.29 mmol) obtained in step 1 was dissolved in DMF (3.0 mL), and the solution was stirred at room temperature for 3 hours after adding N-iodosuccinimide (320 mg, 1.42 mmol). Then, a saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the mixture was filtered through a Presep (registered trademark; diatomaceous earth, granular type M, 4.5 g/25 mL). The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=80/20) to give butyl 3-iodo-5-methyl-2-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-7-carboxylate (351 mg, yield 66%).
Reaction SMILES: [OH:1][C:2]1[CH:11]([CH2:12][CH:13]=[CH2:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1C(OC)=O.CS(C)=O.[Cl-].[Li+]>O>[CH2:12]([CH:11]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:1])[CH:13]=[CH2:14]
Reactant: C=CCC1Cc2ccccc2C(C(=O)OC)=C1O
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCC1Cc2ccccc2CC1=O
Temperature: 125 °C
Reaction time: 4.5 h
Yield: 101 %

Procedure:
A mixture of 3,4-dihydro-2-hydroxy-3-(2-propenyl)-naphthalene carboxylic acid, methyl ester (46.1 g, crude), dimethyl sulphoxide (132 ml), water (5 ml) and lithium chloride (9.5 g, 226 mmol) was heated at 125° C., with stirring, under argon for 4.5 h. The mixture was cooled and diluted with water (750 ml) and extracted with ethyl acetate (3×1000 ml). The combined extracts were washed with water (1000 ml) and brine (1000 ml), dried (Na2SO4) and evaporated in vacuo to give a brown oil (35.5 g). This was chromatographed on silica eluting with 10% ether-hexane to give the title compound as a brown oil (25.9 g, 74%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[F:18][C:19]1[O:20][C:21]2[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=2[C:23]=1[Sn](CC)(CC)CC>>[F:18][C:19]1[O:20][C:21]2[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=2[C:23]=1[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: CC[Sn](CC)(CC)c1c(F)oc2ccccc12
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Product: Fc1oc2ccccc2c1-c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2

Procedure:
Prepared by a method analogous to that described for the preparation of Example 4 from (2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] and 2-fluoro-3-triethylstannylbenzofuran. The title compound was obtained as a colourless solid; m/e 351 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([C:18]([OH:20])=O)[CH:14]=[CH:13]2.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Br:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([C:18]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH:14]=[CH:13]2
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2cccc(Br)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc2cccc(Br)c2n1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
At 0° C., oxalyl chloride (2.0 M solution in DCM, 2.73 mL, 5.47 mmol) was added to a suspension of 8-bromoquinoline-2-carboxylic acid (Princeton BioMolecular Research, Monmouth Junction, N.J.; 690 mg, 2.74 mmol) in 5 mL of DCM followed by 3 drops of DMF. The heterogeneous mixture was stirred at RT for 1 h, and it became homogeneous. The volatiles were removed in vacuo, and the residual brown solid was dissolved in 10 mL of DCM and cooled with an ice bath. Morpholine (0.29 mL, 3.28 mmol) and Et3N (0.46 mL, 3.28 mmol) were added. The reaction was stirred at RT for 1 h. The mixture was then diluted with 50 mL of DCM, washed sequentially with 5 mL of 0.5 N HCl, 5 mL of water, 5 mL of 0.5 N NaOH and 5 mL of brine. The DCM solution was dried over Na2SO4 and concentrated to give a brown oil. Re-crystallization from ether/hexanes gave (8-bromoquinolin-2-yl)(morpholino)methanone (855 mg, 97% yield) as a tan crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (1H, d, J=8.6 Hz), 8.22 (1H, m), 8.10 (1H, d, J=8.0 Hz), 7.86 (1H, d, J=8.4 Hz), 7.61 (1H, t, J=7.8 Hz), 3.79 (4H, br.), 3.69 (4H, br). m/z (ESI, +ve) 321/323 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Br:39])=[CH:35][N:34]=4)=[N:12][O:13][C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.C[OH:41]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Br:39])=[CH:35][N:34]=4)=[N:12][O:13][C:14]=3[NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([CH3:28])([CH3:27])[CH2:26][OH:41])=[CH:23][CH:24]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2onc(OCCOc3ncc(Br)cn3)c2-c2ccc3c(c2)OCO3)cc1
Reactant: CO
Product: CC(C)(CO)c1ccc(S(=O)(=O)Nc2onc(OCCOc3ncc(Br)cn3)c2-c2ccc3c(c2)OCO3)cc1
Reaction time: 48 h

Procedure:
Amycolata autotrophica ATCC35203 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flasks each containing 50 ml of of MY inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. Two mls of this inoculum was then transferred to each of twenty 300 ml Erlenmeyer flask containing 50 ml of MY production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-5-isoxazolyl)-4-(tert-butyl)benzenesulfonamide (Preparation 20) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 144 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:32](=[O:33])[N:6]2[C:7]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:8](OS(C)(=O)=O)[CH2:9][S:10][C@H:5]12)=[O:2].[Na].[SH:35][C:36]1[S:40][N:39]=[N:38][CH:37]=1.C(OCC)(=O)C>CN(C=O)C>[CH:1]([NH:3][C@@H:4]1[C:32](=[O:33])[N:6]2[C:7]([C:16]([O:18][CH:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])=[C:8]([S:35][C:36]3[S:40][N:39]=[N:38][CH:37]=3)[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reactant: Sc1cnns1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=CN[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3cnns3)CS[C@H]12
Temperature: -20 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of diphenylmethyl 7β-formamido-3-methanesulfonyloxy-3-cephem-4-carboxylate (1 g) in DMF (10 ml) was added sodium salt of 5-mercapto-1,2,3-thiadiazole (445 mg) at −30° C. After being stirred at −20° C. for 1 hour, the mixture was poured into a mixture of ice water and ethyl acetate. The organic layer was separated washed with water and brine, dried over magnesium sulfate, and evaporated to give diphenylmethyl 7β-formamido-3-[(1,2,3-thiadiazol-5-yl)thio]-3-cephem-4-carboxylate (961 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([OH:12])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1>CC(N(C)C)=O>[Cl:19][C:20]1[CH:25]=[C:24]([O:12][C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][C:6]=2[C:8]([F:11])([F:9])[F:10])[CH:23]=[CH:22][N:21]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)c(C(F)(F)F)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(C(F)(F)F)n1
Temperature: 95 °C
Reaction time: 0.02 h
Yield: 41.4 %

Procedure:
A solution of 6-amino-2-(trifluoromethyl)pyridin-3-ol (0.092 g, 0.517 mmol) in DMA (5 mL) was sparged with Ar, treated with potassium t-butoxide (0.087 g, 0.775 mmol), stirred for 1 minute, treated with 2,4-dichloropyridine (0.092 g, 0.620 mmol), flushed with Ar and heated at 95° C. overnight. The mixture was cooled to RT, treated with EtOAc, washed with satd. NaHCO3 (2×), dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 5-((2-chloropyridin-4-yl)oxy)-6-(trifluoromethyl)pyridin-2-amine (62 mg, 41%). 1H NMR (400 MHz, DMSO-d6): δ 8.27-8.24 (m, 1H), 7.52-7.49 (m, 1H), 7.04 (s, 1H), 6.94-6.91 (m, 1H), 6.76 (d, J=9.1 Hz, 1H), 6.66 (s, 2H); MS (ESI) m/z: 290.1 (M+H+).
Reaction SMILES: [CH3:1]C1C=CC(S([N:11]([N:13]=O)[CH3:12])(=O)=O)=CC=1.[OH-].[K+].[N+:17](=[CH2:19])=[N-:18].[CH3:20][C:21]1[CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]=1C>C(OCCOCCO)C.CCOCC.C(O)(=O)C>[N+:11](=[CH2:12])=[N-:13].[CH3:1][C:19]12[CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:21]1([CH3:23])[CH2:20][N:18]=[N:17]2
Reactant: CCOC(=O)C1C(C)=C1C
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCCOCCO
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)C1C2(C)CN=NC12C
Temperature: 0 °C
Reaction time: 336 h

Procedure:
Diazomethane was prepared from Diazald (21.5 g), KOH (6.6 g) in 2-(2-ethoxyethoxy)ethanol (35 mL). To the diazomethane solution in Et2O was added ethyl 2,3-dimethylcycloprop-2-enecarboxylate as obtained above. The mixture was stirred at 0° C. for 14 days in the dark. A solution of acetic acid in Et2O was added to quench off remaining diazomethane and the volatiles were removed in vacuo. Remaining starting material was removed by Kugelrohr distillation to afford ethyl 1,5-dimethyl-2,3-diaza-bicyclo[3.1.0]hex-2-ene-6-carboxylate (1.25 g, 6.9 mmol) as a yellowish oil in 10% yield over 2 steps.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2([O:23][CH3:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[S:32][C:33]([CH:36]=O)=[CH:34][N:35]=1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2([O:23][CH3:24])[CH2:18][CH2:19][N:20]([CH2:36][C:33]3[S:32][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)=[N:35][CH:34]=3)[CH2:21][CH2:22]2)=[O:14])[CH:3]=1
Reactant: O=Cc1cnc(-c2ccccn2)s1
Reactant: CCOc1nc(C(=O)NCC2(OC)CCNCC2)cc(N)c1C#N
Product: CCOc1nc(C(=O)NCC2(OC)CCN(Cc3cnc(-c4ccccn4)s3)CC2)cc(N)c1C#N

Procedure:
According to the same procedure described in Example 101, starting with the compound prepared in Example 260 instead of the compound prepared in Example 226 and the compound prepared in Example 139 instead of 2-phenylthiazole-5-carbaldehyde, the title compound having the following physical data was obtained.
Reaction SMILES: CS[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][C:6]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=[N:7]2.[CH2:18]([NH2:20])[CH3:19]>O>[CH2:18]([NH:20][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][C:6]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=[N:7]2)[CH3:19]
Reactant: CCN
Reactant: CSc1ncnc2nc(-c3ccncc3)[nH]c12
Solvent: O
Product: CCNc1ncnc2nc(-c3ccncc3)[nH]c12
Temperature: 150 °C
Reaction time: 10 h

Procedure:
A mixture of 6 g of 6-methylthio-8-(4-pyridyl)purine, 30 ml of an aqueous solution of 70% ethylamine and 30 ml of water is stirred at 150° C. for 10 hours in an autoclave. The reaction mixture is concentrated and the residual oil is dissolved into methanol. To the solution is added about 3 g of activated charcoal. The mixture is shaken well, filtered and then concentrated. The resulting crystals are recrystallized from a 1:1 mixture of ethanol and water to give 1.7 g of 6-ethylamino-8-(4-pyridyl)purine, melting at 308°-310° C. The following compounds can also be prepared in a similar manner as the above examples and according to the methods described in the specification:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[F:32][C:33]([F:44])([F:43])[O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:40][CH2:39][C:38]4[CH:41]=[CH:42][C:35]([O:34][C:33]([F:32])([F:43])[F:44])=[CH:36][CH:37]=4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(trifluoromethoxy)benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=620.95 (M+H+); retention time=1.03 minutes.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:6]([CH3:14])[N:5]=[C:4]([NH2:15])[N:3]=1.[CH2:16]([NH2:21])[CH2:17][CH2:18][CH2:19][CH3:20]>>[NH2:15][C:4]1[N:3]=[C:2]([NH:21][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:6]([CH3:14])[N:5]=1
Reactant: CCCCCCc1c(C)nc(N)nc1Cl
Reactant: CCCCCN
Product: CCCCCCc1c(C)nc(N)nc1NCCCCC
Yield: 87 %

Procedure:
A mixture of 4-chloro-5-hexyl-6-methylpyrimidine-2-ylamine (1.00 mg, 0.44 mmol) and amylamine (2 ml) was refluxed for 11 hours. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (MeOH:CHCl3=1:20) to give the object compound (107 mg, 87%) as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Si:5]([CH3:35])([CH3:34])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12.C(=O)([O-])[O-].[K+].[K+].CC(O)(C)C.[CH3:47][NH:48][CH3:49]>O.O1CCCC1>[CH3:47][N:48]([CH3:49])[CH2:2][CH2:3][CH2:4][Si:5]([CH3:35])([CH3:34])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12
Reactant: CNC
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCN(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A mixture of Compound 11 (50 mg) and potassium carbonate (37 mg) in deionized water (1 mL) was stirred at room temperature for 30 min. To the resulting mixture, t-BuOH (1 mL) and 2 molar dimethylamine in tetrahydrofuran (0.14 mL) were added and stirred at room temperature for 24 hours. Finally, the reaction mixture was concentrated under vacuum and the resulting residue was dissolved in a mixture of acetic acid (10 mL) and trifluoroacetic acid (1 mL) and stirred at room temperature for 8 hours. The crude material was obtained by concentrating the acetic acid solution under vacuum and the residue was partitioned between 7% aqueous NaHCO3 solution (5 mL) and chloroform (2×10 mL). The combined organic layer was dried and concentrated and the residue was eluted on a silica gel column using 10% ethanol in dichloromethane to obtain the required product in 56% yield (26 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([CH3:70])=[CH:66][CH:65]=1>>[C:67]1([CH3:70])[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Cc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)C2NC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.2 g, 0.36 mmol), was reacted with diisopropylethylamine (0.18 g, 1.4 mmol), diphenylphosphinic chloride (0.25 g, 1.1 mmol), then reacted with p-toluidine (Aldrich) (0.057 g, 0.53 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid p-tolylamide as a white solid (Yield, 30 mg, 15%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:18]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH4+].[Cl-].O>[Fe].CO>[S:11]1[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=[C:10]1[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3cnccc3s2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1cccc(-c2nc3cnccc3s2)c1
Yield: 62.7 %

Procedure:
A mixture of 2-(3-nitrophenyl)thiazolo[4,5-c]pyridine (1.53 g, 5.9 mmol), NH4Cl (2.76 g, 51.6 mmol), iron powder (1.80 g, 32.2 mmol), H2O (30 mL) and methanol (120 mL) was heated to reflux for 5.5 h under N2. The mixture was filtered and the filtrate was diluted with H2O (400 mL). The precipitate was collected by filtration and dried in vacuo to afford 3-(thiazolo[4,5-c]pyridin-2-yl)benzenamine as a brown solid (841 mg, 63%). 1HNMR (400 MHz, DMSO-d6) δ: 9.28 (1H, s); 8.52 (1H, s); 8.21(1H, s); 7.23-7.38 (3H, d), 6.79 (1H, s), 5.51 (2H, s); MS (ESI) calcd. for C12H9N3S (m/z): 227, found: 228 [M+H]P
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:25]2[C:16](=[N:17][C:18]3[C:23]([C:24]=2[S:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[N:14]=1>C(Cl)(Cl)Cl>[CH3:12][C:13]1[C:25]2[C:16](=[N:17][C:18]3[C:23]([C:24]=2[S:26]([CH2:27][CH2:28][CH3:29])=[O:9])=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[N:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCSc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Solvent: ClC(Cl)Cl
Product: CCCS(=O)c1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Reaction time: 2.5 h
Yield: 52.1 %

Procedure:
A solution of m-chloroperbenzoic acid (0.96 g, 5.6 mmol) in chloroform (55 mL) was added dropwise to a solution of 3-methyl-4-propylsulfanyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.54 g, 4.6 mmol) in chloroform (55 mL) at a temperature of lower than 0° C., and the mixture was stirred at the same temperature for another 2.5 hours. The reaction solution was washed with an aqueous saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:chloroform:ethyl acetate=2:1:1 to 1:1:1) to give the title compound (0.84 g, 52% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([OH:15])[CH2:10]2)[CH:5]=[CH:4][N:3]=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[C:31](O)=[O:32]>>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[C:31]([O:15][C@H:11]1[CH2:12][CH2:13][CH2:14][N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)[CH2:10]1)=[O:32]
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: O[C@@H]1CCCN(Cc2ccnc(F)c2)C1
Product: O=C(O[C@H]1CCCN(Cc2ccnc(F)c2)C1)[C@@H]1CCCCN1c1nc2ccccc2o1

Procedure:
The title compound was prepared by a similar method to Example 36 from (3R)-1-[(2-fluoro-4-pyridinyl)methyl]-3-piperidinol [see Preparation 39] and (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3]. The crude product was partly purified by column chromatography on silica gel eluting with a solvent gradient of 3:1 changing to 1:1, by volume, ethyl acetate:hexane, the product was further purified by trituration with 95:5, by volume, hot hexane:ethyl acetate, followed by trituration with hot petroleum ether:diethyl ether, 95:5 to afford (3S)-1-[(2-fluoro-4-pyridinyl)methyl]-3-piperidinyl (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylate. The hydrochloride salt was prepared by addition of saturated hydrogen chloride gas in diethyl ether to a solution of product in ethyl acetate, and isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]1[CH:12]=[C:13]([N:20]2[C:24]3[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[CH:28][C:23]=3[N:22]=[CH:21]2)[S:14][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:9].C(N(C(C)C)CC)(C)C.[C:41]([NH:44][NH2:45])(=[O:43])[CH3:42].CN(C=O)C>C(Cl)Cl.O>[C:41]([NH:44][NH:45][C:29]([C:27]1[CH:26]=[CH:25][C:24]2[N:20]([C:13]3[S:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:11]([O:10][C@@H:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH3:9])[CH:12]=3)[CH:21]=[N:22][C:23]=2[CH:28]=1)=[O:30])(=[O:43])[CH3:42]
Reactant: COC(=O)c1sc(-n2cnc3cc(C(=O)O)ccc32)cc1O[C@H](C)c1ccccc1Cl
Reactant: CC(=O)NN
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cc(C(=O)NNC(C)=O)ccc32)cc1O[C@H](C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
A 20.0 mL flask was charged with 150 mg (0.329 mmol) of 1-{4-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-[(methyloxy)carbonyl]-2-thienyl}-1H-benzimidazole-5-carboxylic acid (Intermediate 34, 0.120 mL, 0.658 mmol) of diisopropyl ethylamine, 24.4 mg (0.329 mmol) of acethydrazide and 2.00 ml of DMF. Next, 125 mg (0.329 mmol) of O-(7-Aza benzotriazole-1-yl)-N,N,N′,N′ tetramethyluranium hexafluoro phosphate was added and the reaction mixture stirred at rt for 30 min. 10 mL of water and 30 mL of DCM was added and the organic layer separated. The organic layer was adsorbed onto silica gel and chromatographed to give 154 mg (91% yield) of a tan solid. MS (APCI): 513 [M+H]+.