Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](N)[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18].[ClH:19].N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:19])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18]
Reactant: CC1(C)CC(=O)C(c2ccc(N)cc2Cl)C(=O)C1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(=O)C(c2ccc(Cl)cc2Cl)C(=O)C1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
A suspension of 5.00 g (0.0188 mol) of 2-(2'-chloro-4'-aminophenyl)-5,5-dimethyl-1, 3-cyclohexanedione in 75 ml of water containing 4.0 ml of concentrated HCl was stirred and heated almost to boiling for 10 min., then cooled to 10° C. and an additional 7 ml of conc. HCl added and the solution cooled to 0°-5° C. A solution of 2.00 g (0.0282 mol) of sodium nitrite in 6.0 ml of water was added dropwise to the amine hydrochloride solution while maintaining the temperature at 0°-5° C. When all the NaNO2 solution had been added, the diazonium salt solution was stirred for 30 min. at 0° C.
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[CH:7]=O.[CH2:9]([O:11][C:12](=[O:22])[CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:10].O>C1(C)C=CC=CC=1>[CH2:15]([N:14]1[C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:22])=[CH:7][C:3]2[CH2:4][CH2:5][CH2:6][C:2]1=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CC1=C(Cl)CCC1
Reactant: CCOC(=O)CNCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(n1Cc1ccccc1)CCC2

Procedure:
46.7 g (0.358 mol) of 2-chloro-1-formylcyclopent-1-ene are dissolved in 400 ml of toluene. 138 g (0.716 mol) of N-benzylglycine ethyl ester are added. The mixture is refluxed for one hour, the water of reaction being separated off via a water separator. After cooling, any precipitate formed is filtered off with suction and the toluene solution is washed with water, dried and concentrated. The residue is taken up in 300 ml of ethanol, 600 ml of 2N hydrochloric acid are added and the mixture is extracted 3× with petroleum ether. The petroleum ether phase is washed with 2×175 ml of ethanol/2N hydrochloric acid 1:2 and then with 100 ml of saturated NaHCO3 solution, the organic phase is dried over MgSO4, stirred with active charcoal and filtered with suction, and the filtrate is evaporated in vacuo. Yield: 53.1 g of oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>C(Cl)(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:2][CH:3]2[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=S(=O)(NC1CCC(O)CC1)c1ccc(Cl)cc1
Yield: 95 %

Procedure:
To 100 g of trans-4-aminocyclohexanol hydrochloride suspended in 11 of chloroform are added, at 5° C., 184 ml of triethylamine, followed by a solution containing 143 g of 4-chlorophenylsulfonyl chloride in 150 ml of chloroform. After reaction for 2 hours, the reaction mixture is poured onto 500 ml of water. The expected product is obtained by filtration of the precipitate.
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46].C(=O)([O-])[O-].[Na+].[Na+].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.O>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:34]2[CH:33]=[C:32]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:46])[N:31]([CH3:30])[CH:35]=2)[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1-c1cc(C(=O)OCc2ccccc2)n(C)c1
Temperature: 95 °C

Procedure:
A mixture of N-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.032 g, 0.066 mmol, from Example 113, Step 2, Chiral intermediate), benzyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (0.027 g, 0.080 mmol), sodium carbonate (0.16 mL, 0.17 mmol), 1,4-dioxane (0.6 mL)/water (0.2 mL) and tetrakis(triphenylphosphine)palladium(0) (4.6 mg, 0.0040 mmol) was degassed with N2 for 5 minutes, then heated at 95° C. overnight. The mixture was diluted with EtOAc, washed with sat. NaHCO3, water, brine, and dried over Na2SO4 and concentrated. The crude product (20 mg, 50%) was purified by chromatography eluting with 0 to 40% EtOAc in CH2Cl2. LCMS calculated for C33H36ClN6O4 (M+H)+: m/z=615.2. found: 615.2.
Reaction SMILES: ClC1C(C)=C(Cl)C2C(=CC=CC=2F)N=1.Cl[C:16]1[C:25]([CH3:26])=[C:24]([Cl:27])[C:23]2[C:18](=[CH:19][C:20]([F:28])=[CH:21][CH:22]=2)[N:17]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1>>[Cl:27][C:24]1[C:23]2[C:18](=[CH:19][C:20]([F:28])=[CH:21][CH:22]=2)[N:17]=[C:16]([C:31]2[CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[CH:34]=[CH:35][C:30]=2[F:29])[C:25]=1[CH3:26]
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Agent: Cc1c(Cl)nc2cccc(F)c2c1Cl
Product: Cc1c(-c2cc([N+](=O)[O-])ccc2F)nc2cc(F)ccc2c1Cl

Procedure:
Essentially prepared according to Procedure F using a mixture of 2,4-dichloro-5-fluoro-3-methylquinoline and 2,4-dichloro-7-fluoro-3-methylquinoline (˜1:4 mixture) (690 mg, 3.00 mmol) and 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to give 4-chloro-7-fluoro-2-(2-fluoro-5-nitrophenyl)-3-methylquinoline. Mass Spectrum (ESI) m/e=335.0 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[NH2:14])[CH2:3][CH2:2]1.[C:15](Cl)(=[O:17])[CH3:16]>>[CH:1]1([C:4]2[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[NH:14][C:15](=[O:17])[CH3:16])[CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1C1CC1
Product: CC(=O)Nc1cc([N+](=O)[O-])c(F)cc1C1CC1
Yield: 84 %

Procedure:
The general procedure described in Example 51 was followed. N-(2-cyclopropyl-4-fluoro-5-nitrophenyl)acetamide (2.04 g, 84%) was obtained from 2-cyclopropyl-4-fluoro-5-nitrobenzenamine (described in WO2011068898) and acetyl chloride.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Product: CCS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (92 mg, 87%), MS (ISP) m/z=423.3 [(M+H)+], mp 224° C., was prepared in accordance with the general method of example 48 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and ethanesulfonyl chloride.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C4CCCCO4)[CH:19]=3)=[C:16]([CH3:31])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:32]C4CCCCO4)[CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.[CH3:39][NH:40][CH2:41][CH2:42][OH:43].[F:44][CH2:45][CH2:46][CH2:47]I>>[F:44][CH2:45][CH2:46][CH2:47][N:40]([CH3:39])[CH2:41][CH2:42][O:43][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)=[C:16]([CH3:31])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:32])[CH:14]=3)[O:9]2)=[CH:6][CH:7]=1
Reactant: CC1=C(c2cccc(OC3CCCCO3)c2)C(c2ccc(I)cc2)Oc2ccc(OC3CCCCO3)cc21
Reactant: CNCCO
Reactant: FCCCI
Product: CC1=C(c2cccc(O)c2)C(c2ccc(OCCN(C)CCCF)cc2)Oc2ccc(O)cc21

Procedure:
The title compound was synthesized as described in general procedures F, I and J (z=1) using Intermediate 3 and 2-(methylamino)ethanol in general procedure F, and 1-fluoro-3-iodopropane in general procedure I. 1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H), 8.95 (s, 1H), 7.19 (d, 2H), 7.13 (t, 1H), 6.79 (d, 2H), 6.75-6.72 (m, 1H), 6.68 (d, 1H), 6.67-6.62 (m, 1H), 6.62-6.60 (m, 1H), 6.48 (s, 2H), 5.84 (s, 1H), 4.50 (t, 1H), 4.38 (t, 1H), 3.95 (t, 2H), 2.65 (t, 2H), 2.44 (t, 2H), 2.19 (s, 3H), 2.03 (s, 3H), 1.81-1.72 (m, 1H), 1.72-1.69 (m, 1H). LCMS: 464.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH3:2].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:1]([N:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:4]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCNc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CCOC(=O)N(CC)c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
Subsequently, a mixture of 5.2 g of 2-ethylamino-5-chlorobenzophenone thus obtained and 20 ml of ethyl chloroformate was heated at 110° C for 5 hours. Then, the reaction mixture was concentrated to dryness under reduced pressure to give 2-(N-ethyl-ethoxycarbonylamino)-5-chlorobenzophenone as brown oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([F:20])[CH:13]=2)[CH2:7]1)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>O1CCOCC1>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([F:20])[CH:13]=2)[CH2:7]1)(=[S:30])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Solvent: C1COCCO1
Product: CNc1ccc(N2C[C@H](CNC(C)=S)OC2=O)cc1F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(S)-acetamidomethyl-3-[4′-methylamino-3′-fluorophenyl]oxazolidine-2-one (0.100 g, 0.356 mmol) and Lawesson reagent (0.144 g, 0.356 mmol) in dioxane (3 mL) was stirred at 65° C. for 2 h. Solvent was removed under vacuum and the residue purified by PTLC (10% methanol/dichloromethane) to give a product as foam. Yield 0.097 g (92%). MS (m/z): [M+H]+=298.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[O:7]1[C:12]2[CH:13]=[CH:14][C:15](O)=[CH:16][C:11]=2[O:10][CH2:9][CH2:8]1.I[CH3:19]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C>[CH3:19][CH:9]1[O:10][C:11]2[CH:16]=[CH:15][C:14]([O:4][CH3:1])=[CH:13][C:12]=2[O:7][CH2:8]1
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: O=C([O-])[O-]
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OCC(C)O2
Yield: 78.2 %

Procedure:
To a mixture of K2CO3 (47.54 g, 344 mmol) and Bu4NI (1.256 g, 3.4 mmol) in DMF was added 2,3-dihydro-benzo[1,4]dioxin-6-ol (26.2 g, 172 mmol) followed by iodomethane (16.1 ml, 258 mmol). After 16 hours the mixture was filtered. The solution was mixed with H2O and extracted with ethyl acetate. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification via flash chromatography (95:5 hexane/ethyl acetate) afforded methyl 6-methoxy-2,3-dihydro-benzo[1,4]dioxine (24.23 g, 85%) as a clear oil.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C@@H:2]([CH3:4])[OH:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](O)=[CH:14][CH:13]=1.C1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.CCOCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](Oc1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of known tert-butyl D-(-)-lactate (292 mg), 4-chlorophenol (197 μl) and triphenylphosphite (343 μl) in dry tetrahydrofuran (16 ml) on an ice bath, diethylazodicarboxylate (315 μl) was added dropwise over about 5 minutes. After the addition, the ice bath was removed and the mixture was further stirred at room temperature for 3 hours. The reaction mixture was evaporated with a rotary evaporator (water bath temperature 25° C.). The residue thus obtained was dissolved in ether (20 ml) and the ethereal solution was washed with water. Ether was evaporated. The residue obtained was then purified by silica gel chromatography [silica gel 55 g, eluant:ethyl acetate-hexane (1:10)] to give tert-butyl (2S)-(-)-2-(4'-chlorophenoxy)propionate (330 mg).
Reaction SMILES: C(O[CH:4](OCC)[N:5]([CH3:7])[CH3:6])C.[Cl-:11].[CH3:12][N:13]([CH3:39])[C:14]1[CH:38]=[CH:37][C:17]([CH:18]=[N:19][N+:20]2[CH:24]=[CH:23][N:22]([N:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[C:21]=2[CH3:36])=[CH:16][CH:15]=1.CCOCC>CN(C)C=O>[Cl-:11].[CH3:35][N:33]([CH3:34])[C:30]1[CH:31]=[CH:32][C:27]([CH:26]=[N:25][N+:22]2[CH:23]=[CH:24][N:20]([N:19]=[CH:18][C:17]3[CH:16]=[CH:15][C:14]([N:13]([CH3:12])[CH3:39])=[CH:38][CH:37]=3)[C:21]=2[CH:36]=[CH:4][N:5]([CH3:7])[CH3:6])=[CH:28][CH:29]=1
Reactant: CCOC(OCC)N(C)C
Reactant: Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Agent: [Cl-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)C=Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 96 h

Procedure:
73.5 g of N,N-dimethylformamide diethyl acetal are added to 20.5 g of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-methylimidazolium chloride in 400 ml of dry dimethylformamide. After stirring at 50° for 4 days, the mixture is left to cool. Then, 250 ml of ether are added thereto and the product is removed by filtration and is recrystallized from dry ethanol. There is obtained 1,3-bis[[p-(dimethylamino) benzylidene]amino]-2-[2-(dimethylamino)vinyl]imidazolium chloride of melting point 265° (decomposition).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][C:12]1[C:13]([CH2:19][CH3:20])=[N:14][NH:15][C:16]=1[CH2:17][CH3:18])C.O>O1CCCC1>[CH2:17]([C:16]1[C:12]([CH2:11][CH2:10][OH:9])=[C:13]([CH2:19][CH3:20])[NH:14][N:15]=1)[CH3:18]
Reactant: CCOC(=O)Cc1c(CC)n[nH]c1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1n[nH]c(CC)c1CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
Lithium aluminum hydride (190 mg, 4.8 mmol) was added slowly to tetrahydrofuran (10 mL) under 0° C. (3,5-Diethyl-1H-pyrazol-4-yl)-acetic acid ethyl ester (1.0 g, 4.8 mmol) in tetrahydrofuran (5 mL) was slowly added under nitrogen atmosphere. The reaction was allowed to slowly warm to room temperature and stirred for 16 h. After the reaction was cooled at 0° C., water (0.3 mL) was added slowly and the reaction was stirred for 30 minutes, filtered through a short silica gel column, which was rinsed with ethyl acetate followed by 20% methanol/methylene chloride. The solution was concentrated in vacuo to provide 2-(3,5-diethyl-1H-pyrazol-4-yl)-ethanol (0.8 g, 100% yield).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)=[N:4][CH:3]=1.[CH2:18]([C:20]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[O:23])[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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:17][C:9]1[CH:8]=[C:7]([C:5]2[S:6][C:2]([C:27]3[C:20]([CH2:18][CH3:19])=[C:21]([CH:24]=[CH:25][CH:26]=3)[CH:22]=[O:23])=[CH:3][N:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1Cl
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 120 °C
Yield: 86.2 %

Procedure:
To a solution of 5-bromo-2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazole (D71) (500 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (430 mg) and tripotassium phosphate (638 mg) in N,N-dimethylformamide (DMF) (12 mL) and water (2 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (174 mg) in one charge. The reaction vessel was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (250 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylbenzaldehyde (D74) (500 mg) as a brown oil. MS (ES): C21H20ClNO2S requires 385. found 386.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][CH2:11][OH:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25](O)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1>>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:12][CH2:11][CH2:10][CH2:9][N:2]([CH3:1])[C:3]4[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CN(CCCO)c1ccncc1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCN(C)c1ccncc1
Product: Cl
Yield: 119 %

Procedure:
Using a procedure analogous to that described in Example 47, 3-(N-methyl-N-(4-pyridyl)amino)propanol (116 mg, 0.7 mmol) was treated with 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol), (prepared as described for the starting material in Example 24), to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(N-methyl-N-(4-pyridyl)amino)propoxy)quinazoline hydrochloride (150 mg, 55%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1)[CH3:2].C[O:24][C:25](=[O:48])[C@H:26]([C@@H:45]([CH3:47])O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2([O:22][C@H:45]([CH3:47])[C@@H:26]([C:25]([OH:48])=[O:24])[NH2:27])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][CH:8]=1)[CH3:2]
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: CCc1ccc(C2(O)c3ccccc3-c3ccccc32)cc1
Product: CCc1ccc(C2(O[C@H](C)[C@H](N)C(=O)O)c3ccccc3-c3ccccc32)cc1

Procedure:
from 9-(4-ethylphenyl)-9H-fluoren-9-ol (Example 3o) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: [ClH:1].[SH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.CS[C:9]1[S:10][CH2:11][CH2:12][N:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[ClH:1].[SH:2][CH:3]1[CH2:6][N:5]([C:9]2[S:10][CH2:11][CH2:12][N:13]=2)[CH2:4]1
Reactant: CSC1=NCCS1
Reactant: SC1CNC1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: SC1CN(C2=NCCS2)C1
Yield: 76.4 %

Procedure:
To a solution of 22.7 mg of 3-mercaptoazetidine hydrochloride (12) obtained in the above Example 11 dissolved in 95% methanol (including 1 ml of water), there were added 26.6 mg of 2-(methylthio)-1,3-thiazoline and 5.2 mg of triphenylphosphine, and the resulting solution was subjected to heating and reflux for six hours. After the reaction was over, the solvent was evaporated in a vacuum, and the obtained residue was dissolved in a 0.1N hydrochloric acid, and the resulting mixture was washed with ethylacetate. The solvent in the obtained aqueous layer was evaporated in a vacuum, and the obtained residue was separated and purified by high performance liquid chromatography, and, thus, there was produced 29.1 mg (yield: 73.4%) of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine hydrochloride (8) in the form of colorless needle crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH:14]=[C:13]2[O:32]CC2C=CC=CC=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](C1C=CC(COC(C2N3C(=O)[C@@H](NC(=O)COC4C=CC=CC=4)[C@H]3SCC=2OCC2C=CC=CC=2)=O)=CC=1)([O-])=O>FC(F)(F)C(O)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:17]3[C:18](=[O:31])[C@@H:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[OH:32])=[O:11])=[CH:40][CH:41]=1)([O-:3])=[O:2]
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(OCc3ccccc3)=CS[C@H]12
Agent: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OCc3ccccc3)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The isomer mixture obtained, consisting of 7β-phenoxyacetamido-3-benzoxy-ceph-2-em-4α-carboxylic acid p-nitrobenzyl ester and 7β-phenoxyacetamido-3-benzoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in the ratio of about 3:1, is dissolved in 8 ml of trifluoroacetic acid and the solution is stirred for 90 minutes at room temperature. The reaction mixture is then concentrated by evaporation in vacuo and residual trifluoroacetic acid is repeatedly driven off with toluene. The residue is chromatographed on 20 g of acid-washed silica gel, using toluene/ethyl acetate (3:1), giving 7β-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in the form of a colourless foam. IR spectrum (methylene chloride): characteristic bands at 2.95, 3.3, 5.6, 5.75 sh, 5.9, 5.95 sh, 6.55, 7.45, 8.15 and 8.3μ; NMR spectrum (deuterochloroform): characteristic bands at 3.4 (2H, AB q, J=17 Hz), 4.57 (2H, s), 5.06 (1H, d, J=5 Hz), 5.35 (2H, AB q, J=14 Hz), 5.7 (1H, dd, J=5, 10 Hz), 6.8-8.4 (10H, c), 11.4 (1H, br.s.) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:11][OH:12])[NH2:7])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=NO)c1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
To a solution of 4-bromobenzonitrile (5.0 g, 27.5 mmol) in ethanol (42 ml) at room temperature, hydroxylamine hydrochloride (1.91 g, 27.5 mmol) and DIPEA (4.8 ml, 27.5 mmol) were added. The reaction mixture was stirred at 90° C. for 5 hours. After cooled to room temperature, the resulting mixture was concentrated to yield a colorless viscous liquid. The liquid was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate, filtered and then concentrated to give a crude compound, which was washed with n-hexane to yield product 15 as a white solid (5.0 g).