Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:24][CH2:23][C:11]2([NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=3)[NH:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27].COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCN(C(OC(C)(C)C)=O)CC1)CC2=O>>[C:30]([O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1([CH2:23][CH2:24][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]1)[NH:20][C:19]2=[O:21])([CH3:33])([CH3:32])[CH3:31]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C1NC2(CCN(Cc3ccccc3)CC2)Nc2ccc(Br)cc21
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: CC(C)(C)OC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(Cc3ccccc3)CC1)N2

Procedure:
(E)-3-{1-Benzyl-3′,4′-dihydro-4′-oxo-spiro[piperidine-4,2′(1′H)-quinazoline]-6′-yl}-acrylic acid tert-butyl ester was synthesized starting from 1-benzyl-6′-bromo-3′,4′-dihydro-spiro[piperidine-4,2′(1′H)-quinazoline]-4′-one (600 mg, 1.55 mmol) and tert-butyl acrylate according to the procedure described for Intermediate 1, Step B, giving 486 mg of the product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH:7]=1.[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([C:28]3(O)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:27][C:22]=2[CH2:21][CH2:20]1>>[CH3:18][O:17][C:15]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:31]1[CH2:32][CH2:33][CH:28]([C:26]2[CH:25]=[CH:24][C:23]3[O:19][CH2:20][CH2:21][C:22]=3[CH:27]=2)[CH2:29][CH2:30]1)=[O:16]
Reactant: COC(=O)c1ccc2[nH]cc(CCCCCl)c2c1
Reactant: OC1(c2ccc3c(c2)CCO3)CCNCC1
Product: COC(=O)c1ccc2[nH]cc(CCCCN3CCC(c4ccc5c(c4)CCO5)CC3)c2c1

Procedure:
of 3-(4-chlorobutyl)-5-methoxycarbonylindole with 4-(2,3-dihydrobenzofuran-5-yl)-4-hydroxypiperidine:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1.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>[N+:18]([C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:1]=1[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=2)=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])([O-:20])=[O:19]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
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: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(-c2ccccc2)ccc1-c1ccc(-c2ccccc2)cc1[N+](=O)[O-]

Procedure:
2.4 g (2.1 mmol) of Pd(PPh3)4 are added to a well-stirred, degassed suspension of 18.8 g (154.5 mmol) of phenylboronic acid, 30 g (74.6 mmol) of 2,5-dibromonitrobenzene and 53 g (212.7 mmol) of potassium carbonate in a mixture of 300 ml of water and 300 ml of THF, and the mixture is heated under reflux for 20 hours. After cooling, the organic phase is separated off, washed three times with 200 ml of water and once with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo in a rotary evaporator. The grey residue is recrystallised from hexane. The deposited crystals are filtered off with suction, washed with a little MeOH and dried in vacuo; yield: 23 g, 80% of theory; purity: 99.2% according to HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([NH:7][O:8][CH3:9])=[O:6].[N:14]([O-])=O.[Na+].[Sn](Cl)Cl>O.Cl>[NH:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([NH:7][O:8][CH3:9])=[O:6])[NH2:14]
Reactant: O=N[O-]
Reactant: CONC(=O)c1ccc(C)c(N)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CONC(=O)c1ccc(C)c(NN)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 3-amino-N-methoxy-4-methyl-benzamide 1 (102 mg, 0.56 mmol, preparation: International Patent Application Publication No. WO 02/40486 A2, pg. 66) in water (5 ml) at 0° C. was added conc. HCl (5 mL) followed by the addition of sodium nitrite (43 mg, 0.62 mmol). The reaction mixture was stirred at 0° C. for 40 min then a solution of tin(II)chloride (241 mg, 1.27 mmol) in conc. HCl (1 mL) was added and the mixture was stirred for 1 hr then allowed to stand at −20° C. for 20 hr before it was warmed to RT and concentrated to a white solid. The solid was triturated with ethanol, the solids were filtered, and the filtrate concentrated to provide 3-hydrazino-N-methoxy-4-methyl-benzamide 2 as white solid (486 mg) as a mixture with tin salts and ethanol which was used without further purification. HPLC (6 minute gradient) tR 0.78 min; MS m/z 195.9 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C(OCC)=O)NN=1)(C)(C)C.[C:34]([O:38][C:39]([N:41]1[CH:50]([C:51]([O:53][CH3:54])=[O:52])[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[C:46](B(O)O)[CH:47]=2)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:13]([O:12][C:10]([C:8]1[N:7]([C:46]2[CH:47]=[C:48]3[C:43](=[CH:44][CH:45]=2)[CH2:42][N:41]([C:39]([O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:40])[CH:50]([C:51]([O:53][CH3:54])=[O:52])[CH2:49]3)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1Cc2cc(B(O)O)ccc2CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1cc(C(=O)OCc2ccccc2)[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1Cc2cc(-n3nc(C(C)(C)C)cc3C(=O)OCc3ccccc3)ccc2CN1C(=O)OC(C)(C)C
Yield: 81 %

Procedure:
To a solution of benzyl 3-t-butyl-1H-pyrazole-5-carboxylate (0.100 g, 0.387 mmol, synthesized by trans-esterification of commercially available ethyl 3-t-butyl-1H-pyrazole-5-carboxylate), 2-(t-butoxycarbonyl)-3-(methoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-ylboronic acid (0.195 g, 0.581 mmol, made analogously to Example A56) and pyridine (0.092 g, 1.16 mmol) in methylene chloride (4 mL) was added copper(II)-acetate (0.105 g, 0.581 mmol) and the resulting mixture was stirred at Rt for 1d. The mixture was directly loaded on a silica gel column, chromatographed and concentrated to yield 2-t-butyl 3-methyl 6-(5-(benzyloxycarbonyl)-3-t-butyl-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2,3 (1H)-dicarboxylate (171 mg, 81% yield) as a colorless foam. MS expected 548.3 found 548.3. To this material (0.136 g, 0.248 mmol) in EtOAc (5 mL) was added palladium on charcoal (10%, 0.013 g, 0.012 mmol) and the mixture was stirred under an atmosphere of H2 overnight. The mixture was filtered and the filtrate was concentrated to yield 1-(2-(t-butoxycarbonyl)-3-(methoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-t-butyl-1H-pyrazole-5-carboxylic acid (114 mg, 100%) as a colorless foam. MS expected 458.2 found 458.3.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:3]1.[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C(=O)C.ClCCl.O.C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:3]2)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1cccc([C@H]2CC[C@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cccc([C@H]2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl trans-3-(4-aminocyclohexyl)benzoate obtained in Example (193a) (50 mg, 0.202 mmol) was dissolved in a mixed solution of N,N-dimethylacetamide/dichloromethane=1/1 (8 mL). 4-Chloro-5-ethyl-1H-imidazole-2-carboxylic acid (described in Example 1d, 71 mg, 0.404 mmol), 1-hydroxybenzotriazole (109 mg, 0.808 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (155 mg, 0.808 mmol) and triethylamine (112 μL, 0.808 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1) to obtain 43 mg of the title compound as a white solid (53%).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]2=[O:18])=[CH:5][CH:4]=1>O1CCCC1>[OH:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])([CH3:17])[CH2:11][C:10]2=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2C(=O)CC(C)(C)CC2=O)cn1
Solvent: C1CCOC1
Product: CC1(C)CC(=O)N(c2ccc(O)nc2)C(=O)C1
Temperature: 190 °C
Yield: 89.5 %

Procedure:
6′-Methoxy-4,4-dimethyl-4,5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione (2.56 g, 10.3 mmol) was dissolved in a mixture of tetrahydrofuran and diethyl ether. HCl-gas was bubbled into the solution for 5 minutes. More diethyl ether was added and the white precipitate was collected by suction, washed twice with diethyl ether and heated in a kugelrohr apparatus at 190° C. for 15 minutes yielding the title compound (2.16 g, 89% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]1[CH:16]=[C:15]([O:17]C)[C:14]([CH:19]([CH3:21])[CH3:20])=[C:13]([O:22]C)[CH:12]=1.Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]1[CH:12]=[C:13]([OH:22])[C:14]([CH:19]([CH3:20])[CH3:21])=[C:15]([OH:17])[CH:16]=1
Reactant: COc1cc(C=Cc2c(F)cccc2F)cc(OC)c1C(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1c(O)cc(C=Cc2c(F)cccc2F)cc1O
Yield: 29 %

Procedure:
This material was prepared from 1-(2,6-difluorophenyl)-2-(3,5-dimethoxy-4-i-propylphenyl)ethene and pyridine hydrochloride in 29% yield in the same way as described in example 34. 1HNMR (CDCl3, ppm): δ 1.42 (d, J=7.1 Hz, 6H), 3.50 (qint, J=7.1 Hz, 1H), 4.77 (br, 2H), 6.57 (s, 2H), 6.8-7.4 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C[Al](C)C.C[O:14][C:15]([C:17]1[N:18]=[C:19]([CH3:23])[S:20][C:21]=1[Br:22])=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([C:17]2[N:18]=[C:19]([CH3:23])[S:20][C:21]=2[Br:22])=[O:14])=[N:3][CH:4]=1
Reactant: Nc1ccc(F)cn1
Reactant: COC(=O)c1nc(C)sc1Br
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2ccc(F)cn2)c(Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
A solution of 2-amino-5-fluoropyridine (6.0 g, 53 mmol) in 40 ml dry dioxane was treated at 0° C. with trimethylaluminium (2M in hexane, 26.8 ml, 53 mmol). The mixture was stirred at room temperature for 1 h. A solution of 5-bromo-2-methyl-thiazole-4-carboxylic acid methyl ester (4.2 g, 18 mmol) in 40 mL dry dioxane was added and the reaction mixture was refluxed for 4 h. 10 ml water and 10 g sodium sulfate were sequentially added and filtered. The filtrate was evaporated and the residue purified by flash chromatography (hetane, ethyl acetate) to yield 5-bromo-2-methyl-thiazole-4-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (3.0 g, 53%) as a white solid, MS (ISP): m/e=318.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[H-].[Na+].[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>CN(C)C=O>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[C:3]1=[O:12]
Reactant: Cc1cccc2c1NC(=O)C2(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1N(COCC[Si](C)(C)C)C(=O)C2(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The stirred solution of 2.00 g of 3,3,7-trimethyl-1,3-dihydroindol-2-one and 10 ml of N,N-dimethylformamide is cooled to 0° C. and admixed with 0.479 g of sodium hydride dispersion (60%). The mixture is stirred at 0° C. over 1 hour and subsequently admixed with 2.33 ml of 2-(trimethylsilyl)ethoxymethyl chloride. The ice bath is removed and the reaction mixture is stirred further at room temperature over 14 hours. The reaction mixture is poured onto ice-water (100 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed successively with water (2×100 ml) and brine (1×100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.51 (1:3 EtOAc-heptane); Rt=5.93.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)C(C)(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(=O)C(C)(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(2,2-dimethyl-propionylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:16]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N+:6]([O-:16])[CH:7]=1
Reactant: Fc1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Product: [O-][n+]1cc(F)cc2cc[nH]c21
Temperature: 5 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a stirred solution of 5-fluoro-1H-pyrrolo[2,3-b]pyridine (5.00 g, 36.73 mmol) in Et2O (120 mL), under a nitrogen atmosphere, is added 3-chloroperoxybenzoic acid (11.09 g, 64.28 mmol) portionwise over 5 minutes and the reaction stirred for 3 h. The reaction is then cooled to 5° C., filtered and the solid washed with Et2O (ca. 100 mL). This is dried in vacuo to give the title compound as a pale green crystalline solid (4.317 g, 28.38 mmol). MS (m/z): 153 (M+1).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:12]([O:13][C:14](=[O:16])[CH3:15])[CH:11]([O:17][C:18](=[O:20])[CH3:19])[C:10]2([CH2:22]Br)[CH2:21][CH:6]1[NH:7][C:8](=[O:24])[O:9]2)(=[O:3])[CH3:2].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]1[CH:12]([O:13][C:14](=[O:16])[CH3:15])[CH:11]([O:17][C:18](=[O:20])[CH3:19])[C:10]2([CH3:22])[CH2:21][CH:6]1[NH:7][C:8](=[O:24])[O:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C2CC(CBr)(OC(=O)N2)C(OC(C)=O)C1OC(C)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)OC1C2CC(C)(OC(=O)N2)C(OC(C)=O)C1OC(C)=O
Reaction time: 1 h

Procedure:
6,7,8-Triacetoxy-1-bromomethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane (as described in Example 1 of the Japanese Patent Application No. 144309/1981, pp. 37) (800 mg) is dissolved in toluene (50 ml), and tri-n-butyltin hydride (1 ml) and α,α'-azo-bis-isobutyronitrile (100 mg) are added to the solution, followed by reflux with stirring for 1 hour. The reaction mixture is concentrated under reduced pressure, and petroleum ether is added to the residue, which is allowed to stand overnight in a refrigerator. The resulting precipitates are recovered by filtration, dried and chromatographed on a column of silica gel (180 ml), followed by elution with ethyl acetate. The eluate is concentrated under reduced pressure, and ethyl ether-petroleum ether (1:1) is added to the residue, which is allowed to stand overnight in a refrigerator to produce crystalline 6,7,8-triacetoxy-1-methyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane (510 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][CH:20]([F:29])[O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>O1CCOCC1.C(OCC)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([O:21][CH:20]([F:19])[F:29])=[CH:23][CH:24]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Solvent: CCOCC
Solvent: C1COCCO1
Product: FC(F)Oc1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine prepared as described in Example 1.B. (1.09 g, 4.21 mmol) and 4-(difluoromethoxy)benzenamine (1.34 g, 8.42 mmol) in 1,4-dioxane (15 mL) was heated in a sealed tube at 100° C. for 16 h. The dark slurry was cooled to r.t. and diluted with diethyl ether. The solid was collected by flitration and triturated with ethyl acetate:hexane (1:9) and dried to give a tan solid (1.3 g, 81%) which was used directly.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:13]([N:21]=[C:22]=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[C:13]([NH:21][C:22]([NH:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)=[S:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cnc2c(c1)CCCC2N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: Cc1cnc2c(c1)CCCC2NC(=S)NC(=O)c1ccccc1
Yield: 60.2 %

Procedure:
A solution of 8-amino-3-methyl-5,6,7,8-tetrahydroquinoline (6 g.) in acetone (48 ml.) was treated with benzoylisothiocyanate (6 g.) and the mixture heated at reflux for 45 minutes. The solvent was removed in vacuo and the residual solid recrystallised from ethanol-ether to give the title compound as colourless needles (7.2 g.) m.p. 168° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:4][O:3]1.CC1(C)O[O:14]1>C(Cl)Cl>[C:6]1([CH:5]2[C:2]3([CH2:1][O:14]3)[O:3][CH2:4]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC1(C)OO1
Reactant: C=C1OCC1c1ccccc1
Solvent: ClCCl
Product: c1ccc(C2COC23CO3)cc1
Yield: 99 %

Procedure:
A solution of 2-methylene-3-phenyloxetane (0.10 g, 0.69 mmol) in dry CH2Cl2 (˜0.5 M) was cooled to −78° C. A solution of DMDO (˜0.35 M in CH2Cl2, 1.0-1.2 equiv) was added dropwise with stirring. The reaction mixture was stirred at −78° C. for 1 hour after which the solvent was removed in vacuo to give 3-phenyl-1,5-dioxaspiro[3.2]hexane as a colorless oil (0.11 g, 99%) and as a mixture of diastereomers (93:7). Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.33 (m, 5H), 4.85 (m, 1H), 4.49 (m, 2H), 2.93 (d, J=3.4 Hz, 1H), 2.54 (d, J=3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 136.6, 128.9, 127.8, 127.5, 95.0, 70.1, 50.5, 47.9. Minor diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.33 (m, 5H), 4.85 (m, 1H), 4.65 (app t, J=6.6 Hz, 1H), 4.58 (dd, J=6.3, 5.0 Hz, 1H), 3.06 (d, J=3.4 Hz, 1H), 2.76 (d, J=3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 135.5, 129.3, 128.6, 128.2, 92.7, 72.0, 51.4, 46.7; HRMS (FAB) calculated for C10H11O2 (M++1) m/z: 163.0759. Found: 163.0762.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[CH:25](N(CC)C(C)C)(C)C>C(#N)C.C(OCC)(=O)C>[CH3:25][O:15][C:14]([C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CI
Product: COC(=O)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Yield: 97.6 %

Procedure:
1-tert-Butyloxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (0.9162 g, 3 mmol) was allowed to react with methyl iodide (1.87 mL, 30 mmol, 10 eq.) in the presence of N,N-diisopropylethylamine (2.61 mL, 15 mmol, 5 eq.) in acetonitrile (30 mL) at 20° C. for 16 hours. The solution was diluted with ethyl acetate and washed with 1N HCl, saturated sodium bicarbonate and saturated sodium chloride. The organic phase was dried over magnesium sulfate and the solvent was concentrated in vacuo to give 0.935 g (98%) of the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](=[O:11])([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[OH:7][CH:1]([CH3:6])[CH2:2][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:3][CH:4]([CH3:5])[CH2:8][OH:11]
Reactant: Oc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)COc1ccccc1CC(C)CO
Temperature: 25 °C

Procedure:
To the phenol T81-6(S) (1.4 g, 8.42 mmol, 1.0 eq) in DMF (16 mL) was added potassium carbonate (1.6 g, 8.42 mmol, 1 eq), and (R)-methylcarbonate (T81-A, 0.73 mL, 8.42 mmol, 1.0 eq). The resulting mixture was stirred at 85° C. for 72 h with monitoring of the reaction by TLC [(ethyl acetate/hexanes:2/8); Rf=0.30, UV, CMA]. The mixture was cooled to room temperature and brine was added. The aqueous phase was extracted with ethyl acetate and the combined organic phases were extracted with brine. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/hexanes, 2/8, Rf=0.30) to give T81-7(1R,8S) (1.45 g, 76%). Use of (S)-methylcarbonate in this reaction led to T81(1S,8S) containing a (1S)-stereocenter through the same transformations as described below for the corresponding (1R)-isomer.
Reaction SMILES: O.NN.[CH3:4][N:5]([CH3:39])[C:6](=S)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([C:24]4[C:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)=[N:27][N:26]5[CH2:35][CH2:36][CH2:37][C:25]=45)=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH:8]=1>CO.[Ni]>[CH3:4][N:5]([CH3:39])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([C:24]4[C:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)=[N:27][N:26]5[CH2:35][CH2:36][CH2:37][C:25]=45)=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH:8]=1
Reactant: CN(C)C(=S)c1cccc(Oc2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN(C)Cc1cccc(Oc2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a refluxing mixture of Raney-nickel and hydrazine-monohydrate (0.5 mL, 10.17 mmol) in methanol (5 mL) is added N,N-dimethyl-3-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-thiobenzamide (311.0 mg, 0.63 mmol) in methanol (20 mL). The mixture is stirred 10 min and cooled to room temperature, filtered, and concentrated in vacuo. The residue is chromatographed by HPLC (C18 column) to yield the title compound, 60.2 mg (20%).