Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:18](=[O:19])[N:5]2[C:6]([C:15]([O-:17])=[O:16])=[C:7]([CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:8][S:9][C@H:4]12>[N+](C)([O-])=O>[NH2:2][C@H:3]1[C:18](=[O:19])[N:5]2[C:6]([C:15]([OH:17])=[O:16])=[C:7]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)[CH2:8][S:9][C@H:4]12
Reactant: N[C@H]1C(=O)N2C(C(=O)[O-])=C(C3CCCC3)CS[C@H]12
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: N[C@H]1C(=O)N2C(C(=O)O)=C(C3CCCC3)CS[C@H]12
Temperature: 0 °C

Procedure:
A current of gaseous hydrogen chloride was passed through a mixture of 585 mg of the product of Step G and 12 ml of nitromethane cooled to 0°C for 15 minutes and the mixture was evaporated to dryness under reduced pressure. The residue was taken up in ether and the crystals were recovered by vacuum filtration. The residue was dissolved in 2 ml of ethanol and 1 ml of water and pyridine was added to a pH of 4. The mixture was agitated until crystallization appeared and the crystals were recovered by vacuum filtration, were rinsed with ethanol and dried to obtain 249 mg of DL cis 7-amino-3-cyclopentyl-3-cepheme-4-carboxylic acid melting at 250°C. The product occurred as colorless crystals slightly soluble in ethanol and insoluble in water and ether.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH2:42])[CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:2]3[N:22]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=5[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)nc12

Procedure:
4-(3-[8-(2-methoxy-5-trifloromethylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl)-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.150 g, 0.5 mmol), and 4-(3-amino-phenyl)piperazine-1-carboxylic acid tert-butyl ester (0.152 g, 0.548 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.19 g, 73%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (d, J=6.1 Hz, 1H), 7.93 (s, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.56 (d, J=6.1 Hz, 1H), 7.46-7.40 (m, 2H), 7.31-7.28 (m, 1H), 7.13 (d, J=8.1 Hz, 1H), 7.00-6.94 (m, 1H), 6.87 (s, 1H), 6.84 (d, J=8.1 Hz, 1H), 3.88 (s, 3H), 2.89-2.75 (m, 2H), 2.73-2.63 (m, 1H), 1.92-1.79 (m, 2H), 1.73-1.63 (m, 4H), 1.52 (s, 9H). MS=568 (MH)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>C1COCC1>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([B:22]([OH:27])[OH:23])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: OCCc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCc1ccc(B(O)O)cc1
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a stirred solution of 4-bromophenethylalcohol (5.00 g, 24.9 mmol) in THF (80 ml) was added a solution of 1.5M n-BuLi in hexane (39.8 ml, 59.7 mmol) at −78° C. over 30 min. After 1 hour, a solution of B(OiPr)3 (8.61 ml, 37.3 mmol) in THF (20 ml) was added slowly to the mixture at −78° C. The resultant mixture was warmed to room temperature, and treated with 2M HCl (100 ml) for 1 hour. This was extracted with CH2Cl2 and dried over MgSO4, then filtered. After evaporation in vacuo, the residue was purified by silica-gel column chromatography eluting with CH2Cl2/MeOH=20/1 to afford 2.61 g (63%) of the title compound.
Reaction SMILES: Cl.[CH:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[NH:9])([CH3:4])[CH3:3].[Na].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.Cl>C(O)C.C(O)(=O)C>[O:18]=[C:19]1[NH:10][C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH:2]([CH3:4])[CH3:3])=[N:9][CH:26]=[C:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)Oc1ccccc1C(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2OC(C)C)[nH]c1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2-Isopropoxybenzamidine hydrochloride (10.0 g., 0.0465 mole) was added to a stirred, cooled (ice-water) solution of sodium (2.14 g., 0.093 g-atom) in ethanol (100 ml.). To this cooled, stirred solution was added dropwise a solution of diethyl ethoxymethylenemalonate (10.1 g., 0.0465 mole) in ethanol (30 ml.) over a 10 minute period. The mixture was refluxed for 2 hours and stored at 22° for 18 hours. The mixture was then poured onto ice-water containing acetic acid (10 ml.) and concentrated HCl (10 ml.) to precipitate the desired product. The precipitate was washed and dried to give 15.5 g. of the title product, m.p. 123°-124°. Recrystallizations from ethyl acetate and then cyclohexane gave colorless crystals of the ester, m.p. 128°-130°.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:6]=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:16])[CH3:5].I[C:18]1[CH:19]=[C:20]([O:24][CH3:25])[CH:21]=[CH:22][CH:23]=1.CCOCC>CCCCCC.CN(C)C=O>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7](=[CH:6][N:4]([CH3:3])[CH3:5])[C:8]2=[O:16])[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(I)c1
Reactant: CN(C)C=C1C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cccc(N2C(=O)C(=CN(C)C)c3ccccc32)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried flask under nitrogen, sodium hydride (50% dispersion in oil, 0.96 g, 20 mmoles) was washed free of oil with hexane. Dry dimethylformamide (DMF, 50 ml) and 3-(dimethylaminomethylene)-2(1H,3H)-indolone [Chem. Ber. 85: 774 (1952); 3.77 g, 20 mmoles] were added, and the mixture stirred for 30 minutes (until gas evolution ceased). m-Iodoanisole (9.36 g, 40 mmoles) in 20 ml DMF was added, followed by Cu2Br2 (5.74 g, 20 mmoles). The reaction mixture was heated at 120°-130° for 40 hours, poured over 300 g of ice, stirred with 300 ml ether, filtered and the ether layer separated, dried over MgSO4, filtered and concentrated to an oil. The oil was chromatographed on silica gel, using ethyl acetate as eluant and title product initially isolated as an oil, crystallized from ether, 2.46 g (42%), m.p. 106°-108.5° (dec.).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:18])[CH2:15][O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC.[CH3:43][C:44]1[O:48][C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[N:46][C:45]=1[CH2:55][CH2:56][O:57][C:58]1[C:66]2[CH:65]=[CH:64][S:63][C:62]=2[C:61]([CH:67]=[O:68])=[CH:60][CH:59]=1>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:18])[C@@H:15]([O:16][CH3:17])[C@H:67]([OH:68])[C:61]1[C:62]2[S:63][CH:64]=[CH:65][C:66]=2[C:58]([O:57][CH2:56][CH2:55][C:45]2[N:46]=[C:47]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[O:48][C:44]=2[CH3:43])=[CH:59][CH:60]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c2sccc12
Reactant: COCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12

Procedure:
0.249 g of (S)-4-Benzyl-3-methoxyacetyl-oxazolidin-2-one (1.00 mmol) was dissolved under an argon atmosphere in 2.5 ml of abs. CH2Cl2 and treated with 0.167 ml of triethylamine (1.2 eq.). After cooling to −78°, nBu2BOTf was added slowly (1.1 ml of 1M solution in CH2Cl2) and enolborinate formation allowed to proceed for 50 Min. at −78° and for 50 Min. at 0°. After recooling, a solution of 0.363 g of 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophene-7-carbaldehyde (1.0 mmol) in 3.5 ml of abs. CH2Cl2 was added via dropping funnel and the mixture kept for 30 Min. at −78° and for 60 Min. at 0°. Pouring onto crashed ice, twofold extraction with AcOEt, washing with brine and water, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=7/3) left finally 0.259 g of the title compound as light yellow foam. According to NMR, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]3[C:13]([F:23])=[C:14]([CH:19]=[CH:20][C:21]=3[F:22])[O:15][CH2:16][CH2:17][OH:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.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>[F:23][C:13]1[C:12]([CH2:11][C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:3]=3)[NH:8][CH:9]=2)=[C:21]([F:22])[CH:20]=[CH:19][C:14]=1[O:15][CH2:16][CH2:17][OH:18]
Reactant: OCCOc1ccc(F)c(Cc2c[nH]c3ncc(Br)cc23)c1F
Reactant: OB(O)c1cccnc1
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: CC#N
Solvent: O
Product: OCCOc1ccc(F)c(Cc2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Yield: 31.7 %

Procedure:
To 2-[3-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-2,4-difluoro-phenoxy]-ethanol (P-1392, 35.0 mg, 0.091 mmol) in acetonitrile (4.0 mL) were added 3-pyridylboronic acid (14.6 mg, 0.12 mmol), tetrakis(triphenylphosphine)palladium(0) (3.0 mg, 0.0026 mmol) and 1 M potassium carbonate solution (1.5 mL). The reaction was microwaved (300 watts) at 160° C. for 7 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting 4% methanol in methylene chloride to give the compound as white solid (P-1394, 11.0 mg, 32%). MS (ESI) [M+H+]+=382.2.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH2:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][NH:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH3:21]>>[CH2:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][NH:28][CH2:29][CH2:30][CH2:31][NH:32][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17])[CH3:21]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: CCN1CCCC1CNCCCN
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCCNCC3CCCN3CC)s2)c(C)[nH]c1=O
Yield: 19 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 3-[(1-ethyl-pyrrolidin-2-ylmethyl)-amino]-propyl amine as described in Step 5, Example 24 to give the title compound (19% yield). LC/MS: RT 2.19 min; m/e 467 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:21][CH:22]=2)O1>>[Br:8][C:4]1[N:3]=[C:2]([C:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:19][CH:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)OB(C2=CCN(C(=O)OCc3ccccc3)CC2)OC1(C)C
Reactant: Brc1cccc(Br)n1
Product: O=C(OCc1ccccc1)N1CC=C(c2cccc(Br)n2)CC1

Procedure:
The title compound was prepared by using the procedure listed in Example 177 Step 3 with 2,6-dibromopyridine (0.77 g, 3.21 mmol) and benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.05 g, 3.06 mmol) as the starting materials.
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH:5](OC)OC.[C:12]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(=O)[CH3:13].C(O)(=O)C.C([O-])(=O)C.[NH4+:29].[OH-].[Na+]>CC(O)C>[N:29]1[CH:5]=[CH:4][CH:3]=[CH:13][C:12]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccncc1
Reactant: [NH4+]
Reactant: COC(CC(OC)OC)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: c1ccc(-c2ccncc2)nc1
Temperature: 25 °C
Yield: 24.7 %

Procedure:
14.2 g (87 mmol) of 1,1,3,3-tetramethoxypropane, 10 g (83 mmol) of 4-acetylpyridine, 30 ml (500 mmol) of acetic acid and 39 g (500 mmol) of ammonium acetate were dissolved in 160 ml of 2-propanol, and the reaction solution was allowed to undergo the reaction at 80° C. for 9 hours. After completion of the reaction, this was cooled to room temperature, neutralized with 200 g (1.2 mol) of 25% sodium hydroxide aqueous solution and then extracted three times with 200 ml of toluene. The organic layer was concentrated and then purified by distillation under a reduced pressure to obtain 3.2 g (yield 27.6%) of the title compound (purity 98.2%).
Reaction SMILES: [CH:1]([S:4]([CH3:7])(=[O:6])=[O:5])([CH3:3])[CH3:2].CO.C[O-].[Na+].[C:13]([O:18][CH3:19])(=[O:17])[C:14]([O-])=[O:15].Cl>C1COCC1>[CH:1]([S:4]([CH2:7][C:14](=[O:15])[C:13]([O:18][CH3:19])=[O:17])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)S(C)(=O)=O
Reactant: COC(=O)C(=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(=O)CS(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To a mixture of i-propylmethylsulfone (5.17 g, 42.3 mmol) and THF (20 mL) was added 28% sodium methoxide methanol solution (8.58 g, 44.5 mmol) at room temperature, and then methyl oxalate (5.0 g, 42.3 mmol) was gradually added to the mixture at room temperature. The resulting mixture was stirred at room temperature overnight. To the reaction mixture was added ice-water (200 mL), and the pH of the resulting mixture was adjusted pH3 or less than pH3 with 2 mol/L hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL). The extract was washed with brine (200 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified on a silica gel column chromatography (ethyl acetate/n-hexane) to give methyl 3-(i-propylsulfonyl)-2-oxopropanoate (2.7 g, yield: 28%) as colorless oil.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.S(=O)(=O)(O)O.[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=O)c1ccccc1C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
A solution of 83 g of diethyl oxalate in toluene (170 g) was cooled to −40° C. or lower. The Grignard reagent prepared as described above was added dropwise at −40° C. or lower, and this was retained at −40° C. for 2 hours. To the reaction mixture was added 234 g of 10% sulfuric acid, and an organic layer was recovered. The resulting organic layer was washed with 134 g of water, and dried with magnesium sulfate. After concentration with an evaporator, distillation under high vacuum, and silica gel column purification afforded 33.1 g of ethyl 2-(methyl-phenyl)-2-oxoacetate.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:29][CH2:28][C@H:27]([CH2:30][O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1.O>CN(C=O)C>[CH:39]([Si:32]([CH:33]([CH3:35])[CH3:34])([CH:36]([CH3:38])[CH3:37])[O:31][CH2:30][C@H:27]1[CH2:28][CH2:29][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1)([CH3:40])[CH3:41]
Reactant: CC(C)[Si](OC[C@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@H]1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 36.6 %

Procedure:
To a solution of Intermediate A (179 mg, 1.10 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 120 mg, 3.00 mmol) and the mixture stirred at RT for 25 min. A solution of Intermediate 92b (958 mg, 1.10 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.5 h. The solution was cooled, water added, and the mixture extracted with DCM (4×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-16% MeOH in DCM, to give the title compound as a brown gum (216 mg, 37%). LCMS (Method 3): Rt 3.08 min, m/z 536 [MH+].
Reaction SMILES: [N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][CH2:5][C:4]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][S:7]2)[CH2:3][CH2:2]1.[OH:22]OS([O-])=O.[K+].O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(Cl)Cl.CC(C)=O>[N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][CH2:3][C:4]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][S:7]2=[O:22])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)SCc1ccccc12
Reactant: O=S([O-])OO
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2=O
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 133.9 %

Procedure:
10.0 g of the crude tert-butyl spiro[benzo[c]thiophene-1(3H),4′-piperidine]-1′-carboxylate, obtained in Example 1, were added to 50 ml of methylene chloride and 150 ml of acetone followed by cooling to 0 to 5° C. A solution of 15.0 g (24.4 mmol) of Oxone™ in 75 ml of water was dropped in at 5° C. or lower followed by stirring for 3 hours at 0 to 5° C. A solution of 1.72 g (9.8 mmol) of sodium thiosulfate-hydrate in 50 ml of water was added followed by stirring for 30 minutes at 20 to 25° C. 100 ml of methylene chloride and 100 ml of water were then added followed by separation of the aqueous layer. After washing the organic layer with 100 ml of water, it was dried with anhydrous magnesium sulfate followed by distilling off the solvent to obtain 10.5 g of tert-butyl spiro[benzo[c]thiophene-1-(3H),4′-piperidine]-1′-carboxylate 2-oxide as a white foamy substance (crude yield: 100%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:46])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[C:41]4[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=4)[N:35]=[CH:34][N:33]=3)=[CH:27][CH:26]=2)=[CH:18][C:17]=1[CH:47]=O.[CH:49]([NH2:52])([CH3:51])[CH3:50].C(OC)(OC)OC>C(Cl)Cl.CO>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:46])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[C:41]4[C:36](=[CH:37][C:38]([O:44][CH3:45])=[C:39]([O:42][CH3:43])[CH:40]=4)[N:35]=[CH:34][N:33]=3)=[CH:27][CH:26]=2)=[CH:18][C:17]=1[CH2:47][NH:52][CH:49]([CH3:51])[CH3:50]
Reactant: COc1cc2ncnc(Oc3ccc(CC(=O)Nc4ccc(Cl)c(C=O)c4)cc3)c2cc1OC
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCl
Solvent: CO
Product: COc1cc2ncnc(Oc3ccc(CC(=O)Nc4ccc(Cl)c(CNC(C)C)c4)cc3)c2cc1OC
Yield: 35.5 %

Procedure:
Sodium triacetoxyborohydride (0.072 g) was added portionwise to a stirred mixture of N-(4-chloro-3-formylphenyl)-2-[4-(6,7-dimethoxyquinazolin-4-oxy)phenyl]acetamide (0.08 g), isopropylamine (0.021 g), trimethyl orthoformate (0.2 ml), methanol (0.2 ml) and methylene chloride (0.6 ml) and the resultant mixture was stirred at ambient temperature for 12 hours. The mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘β Basic Hypersil’ reversed-phase column (5 microns silica, 20 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound as a solid (0.031 g); 1H NMR: (DMSOd6) 1.03 (d, 6H), 1.88 (br s, 1H), 2.71-2.8 (m, 1H), 3.7 (s, 2H), 3.72 (br s, 2H), 3.97 (s, 3H), 3.99 (s, 3H), 7.26 (d, 2H), 7.32 (d, 1H), 7.39 (s, 1H), 7.44 (d, 2H), 7.55 (s, 1H), 7.64 (m, 1H), 7.73 (d, 1H), 8.53 (s, 1H), 10.34 (s, 1H); Mass Spectrum: M+H+ 521 and 523.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[N:42]1([CH2:47][CH2:48][NH2:49])[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:49][CH2:48][CH2:47][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:40])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCCN1CCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCCN4CCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in chloroform (5 ml), and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (77 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-tetrahydro-1H-1-pyrrolyl-1-ethanamine (30 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (40 mg, yield 46%).
Reaction SMILES: CN(C)C.CN(C=O)C.Cl/[CH:11]=[C:12]1/[C:13](=[N:22]/[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)/[S:14][CH:15]2[CH:20]([CH2:21]/1)[CH2:19][CH2:18][CH:17]=[CH:16]2.[C:30]1([SH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23](/[N:22]=[C:13]2\[S:14][CH:15]3[CH:20]([CH2:21]\[C:12]\2=[CH:11]/[S:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:19][CH2:18][CH:17]=[CH:16]3)=[CH:24][CH:25]=1
Reactant: Sc1ccccc1
Reactant: Cl/C=C1\CC2CCC=CC2S\C1=N/c1ccc(Cl)cc1
Agent: CN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(/N=C2\SC3C=CCCC3C\C2=C/Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
65 mg of trimethylamine and 1 ml of DMF solution including {3-[1-chloro-(E)-methylidene]-3,4,4a,5,6,8a-hexahydro-thiochromene-(2Z)-ylidene}-(4-chloro-phenyl)-amine were added to 2 ml of DMF solution including 47 mg of thiophenol at 0° C. The resulting solution was stirred at room temperature for an additional 30 minutes, and added with water, and then extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.17 g of the title compound.