Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[CH:3]1.[CH2:13]1[O:15][CH2:14]1>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[C:3]1[CH2:13][CH2:14][OH:15]
Reactant: C1CO1
Reactant: Cn1cnc(-c2ccccc2)c1
Solvent: C1CCOC1
Product: Cn1cc(-c2ccccc2)nc1CCO
Temperature: -78 °C
Reaction time: 18 h
Yield: 31.3 %

Procedure:
In a 25 ml flask were placed 11-2 (0.500 g, 3.16 mmol), and anhydrous THF (6 mL). The reaction was flushed with N2 gas and cooled to −78° C. Ethylene oxide (27.3 g, 31 mL, 31.6 mmol) was added dropwise via syringe. Upon completion of addition, the reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was then quenched with sat. aq. NH4Cl (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (24 g cartridge), eluting with 0-100% EtOAc/hexanes to give 200 mg (31%) of 11-3. LC/MS: m/z (M+H)=203.2.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:32]
Reactant: COCCCCCCCCCCCC(=O)Cl
Reactant: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCCCCCCCCCCC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 70 %

Procedure:
To a solution of benzylamine (486 mg, 4.5 mmol) in 20 mL of methylene chloride at 0° C. was added dropwise diisopropylethylamine (0.45 ml, 5 mmol) followed by the title product of example 11 (1.0 g, 4 mmol). After stirring at room temperature for 6 days, the reaction mixture was washed successively with 1N HCl, water, saturated NaHCO3, water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in anhydrous methanol and passed through a basic ion exchange resin and eluted with anhydrous methanol. Concentration afforded the title compound (895 mg) as a white solid, m.p. 77.7-79.4° C. (DSC). The structure was supported by NMR, infrared spectroscopy, elemental analysis, and mass spectroscopy.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][CH:3]=[C:2]1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[S:1]1[C:5](/[CH:6]=[CH:21]/[CH:22]=[O:23])=[CH:4][CH:3]=[C:2]1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2cccs2)s1
Product: O=C/C=C/c1ccc(-c2cccs2)s1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting [2,2′-bithiophene]-5-carboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 221 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH:10]12[C:19](=O)[O:18][C:16](=[O:17])[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2>C(O)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:16](=[O:17])[CH:11]3[CH:10]([CH2:15][CH2:14][CH2:13][CH2:12]3)[C:19]2=[O:18])=[C:4]([F:9])[CH:3]=1
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: Nc1ccc(Br)cc1F
Solvent: CC(=O)O
Product: O=C1C2CCCCC2C(=O)N1c1ccc(Br)cc1F
Reaction time: 2 h

Procedure:
11.4 Parts of 4-bromo-2-fluoroaniline were added to a solution of 10 parts of cyclohexane-1,2-dicarboxylic anhydride in 100 parts of glacial acetic acid and the mixture was stirred for 2 hours. The mixture was refluxed for 20 hours and then poured onto 200 parts of ice. The resulting purple crystals were filtered and recrystallized from 70 parts of methanol at -40° to yield 7.6 parts of lavender crystals of 2-(4-bromo-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)-dione melting at 90°-92°.
Reaction SMILES: [C:1]1([Sn:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[Cl-].[Na+].[CH3:24][OH:25]>O1CCCC1>[CH3:24][O-:25].[C:14]1([Sn+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CO
Reactant: Cl[Sn](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: C[O-]
Product: c1ccc([Sn+](c2ccccc2)c2ccccc2)cc1

Procedure:
115.5 g of triphenyl tin chloride are dissolved in a mixture of 450 g of absolute methanol and 300 g of absolute tetrahydrofuran and mixed with a solution of 7.02 g of sodium in 150 ml of absolute methanol. After stirring for 2 hours at room temperature the resulting precipitate of sodium chloride is filtered off. The solution of triphenyl tin methoxide obtained is combined, accompanied by stirring, with a solution of 600 g of the epoxy resin modified with diketene described in Example 2 dissolved in 300 g of absolute tetrahydrofuran. After stirring for a further 2 hours at room temperature and after distilling off the solvent 696 g of a reddish brown glassy solid product of formula VI above are obtained. Tin content: calculated 5.51%; found 5.45%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([O:13][C:14]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]3[C:15]=2[CH2:16][CH2:17][C@H:18]([CH3:26])[NH:19]3)[CH2:12][CH2:11][CH2:10]1>C(#N)C.ClCCl>[Br:1][C:23]1[C:14]([O:13][CH:9]2[CH2:10][CH2:11][CH2:12]2)=[C:15]2[C:20](=[C:21]([F:25])[C:22]=1[F:24])[NH:19][C@@H:18]([CH3:26])[CH2:17][CH2:16]2
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@H]1CCc2c(OC3CCC3)cc(F)c(F)c2N1
Solvent: CC#N
Solvent: ClCCl
Product: C[C@H]1CCc2c(c(F)c(F)c(Br)c2OC2CCC2)N1
Temperature: -5 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A solution of N-bromosuccinimide (0.703 g, 3.95 mmol) in acetonitrile (10 mL) was added dropwise to a −5° C. solution of (S)-5-cyclobutoxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (1.0 g, 3.95 mmol) in acetonitrile (80 mL) and dichloromethane (15 mL), and the resulting solution stirred for 4 h at −5° C. The reaction mixture was concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 50% ethyl acetate/petroleum ether) to afford (S)-6-bromo-5-cyclobutoxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline (1.05 g, 81%) as a yellow solid. MS (ESI, pos. ion) m/z 332, 334 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:38])[C@H:5]([CH2:14][C:15]1[C:20]([I:21])=[CH:19][C:18]([O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:17]([O:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:16]=1)[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C.[OH-].[Li+].C(O)(=O)C>C1COCC1.O>[C:10]([O:9][C:7]([NH:6][C@H:5]([C:4]([OH:38])=[O:3])[CH2:14][C:15]1[C:20]([I:21])=[CH:19][C:18]([O:22][C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[C:17]([O:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:16]=1)=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: CCOC(=O)[C@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1I)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1I)C(=O)O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
The iodo derivative 17 (3.5 mmol) (prepared as shown in FIG. 6) was dissolved in 40 mL of THF and cooled in an ice bath (0° C.) and a solution of lithium hydroxide (7.0 mmol) in 12 mL of water was added dropwise under argon. The resulting mixture was stirred at 0° C. for 4 h and then 2 h at room temperature. The reaction mixture was then neutralized with acetic acid to pH 5 and extracted with ethyl acetate. The organic phase was dried using Na2SO4, filtered and evaporated to dryness to provide an oil which was purified by silical gel column chromatography resulting in N-(tert-butoxycarbonyl)-3,4-di(tert-butoxycarbonyloxy)-6-iodo-L-phenylalanine (23).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12]([OH:15])(=[O:14])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O.C([O-])(O)=O.[Na+]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][S:12]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:14])=[O:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CCS(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1ccc(CCS(=O)(=O)N2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
A flask was charged with 491 mg (2.12 mmol) of solid 2-(4-nitro-phenyl)-ethanesulfonic acid (as prepared in the previous step), which was treated with 3.10 mL (42.4 mmol) of thionyl chloride and heated to 80° C. for 7 h. The volatile components were removed in vacuo, the residue was taken up in THF (20 mL), and 927 μL (10.6 mmol) of morpholine was added. The mixture was stirred at RT for 16 h, diluted with water (15 mL) and saturated aqueous NaHCO3 (15 mL) and extracted with EtOAc (2×70 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 370 mg (52%) of the title compound as a pale yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 8.20 (d, 2H, J=8.8 Hz), 7.40 (d, 2H, J=8.8 Hz), 3.79-3.73 (m, 4H), 3.31-3.23 (m, 6H), 3.21-3.14 (m, 2H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:19][C:18]2[C@:13]([CH3:22])([C@@H:14]3[CH2:21][C@@H:15]3[C:16](=[O:20])[CH:17]=2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C:7](=[O:23])[CH2:6][CH2:5]1.[CH3:24][C@@H:25]1[C:42]2[C@:37]([CH3:45])([C@@H:38]3[CH2:44][C@@H:39]3[C:40](=[O:43])[CH:41]=2)[C@@H:36]2[C@H:27]([C@H:28]3[C@@:32]([CH2:34][CH2:35]2)([CH3:33])[C:31](=[O:46])[CH2:30][CH2:29]3)[CH2:26]1.C1[C@@H]2C(=O)C=C3[C@](C)([C@H]12)[C@@H]1[C@H]([C@H]2[C@@](CC1)(C)C(=O)CC2)CC3>>[CH3:21][C@H:14]1[C@@:13]2([CH3:22])[C:18]([CH2:19][C@@H:2]([CH3:1])[C@@H:3]3[C@@H:12]2[CH2:11][CH2:10][C@@:8]2([CH3:9])[C@H:4]3[CH2:5][CH2:6][C:7]2=[O:23])=[CH:17][C:16](=[O:20])[CH2:15]1.[CH3:44][C@H:38]1[C@@:37]2([CH3:45])[C:42]([C@@H:25]([CH3:24])[CH2:26][C@@H:27]3[C@@H:36]2[CH2:35][CH2:34][C@@:32]2([CH3:33])[C@H:28]3[CH2:29][CH2:30][C:31]2=[O:46])=[CH:41][C:40](=[O:43])[CH2:39]1
Reactant: C[C@@H]1CC2=CC(=O)[C@H]3C[C@H]3[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@]2(C)C1=CC(=O)[C@H]1C[C@H]12
Agent: C[C@@]12C(=CC(=O)[C@H]3C[C@H]31)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@@H]1CC(=O)C=C2[C@@H](C)C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Product: C[C@@H]1CC2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12

Procedure:
Substituting 7α-methyl-1β,2β-methylene-4-androstene-3,17-dione and 6α-methyl-1β,2β-methylene-4-androstene-3,17-dione for the 1β,2β-methylene-4-androstene-3,17-dione above results in the preparation of 1β,7α-dimethyl-4-androstene-3,17-dione and 1β,6α-dimethyl-4-androstene-3,17-dione, respectively.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O(C(CC)(C)C)[K:15].C([Li])CCC>CCCCCC>[C:1]1([CH:7]([K:15])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(C)(C)O[K]
Reactant: c1ccc(Cc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: [K]C(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 18.3 g (109 mmol) of diphenylmethane in 400 mL of hexane were added 11.99 g (109 mmol) of potassium t-amylate. To the resulting pale yellow solution were added 68.75 mL of 1.60M (110 mmol) butyl lithium. The thick, bright orange slurry was stirred overnight. The solids were collected on a filter, washed three times with 100 mL, then twice with 50 mL of hexane, then dried under reduced pressure. The yield of bright orange powder was 18.23 g, 81.2 percent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11]O)=[O:10])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].C(N(CC)CC)C.N[C:25]1[CH:41]=[CH:40][C:28]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=2)=[CH:27][CH:26]=1>CN(C)C=O>[CH3:39][NH:38][C:36]([C:32]1[CH:31]=[C:30]([O:29][C:28]2[CH:27]=[CH:26][C:25]([NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:13]([F:16])([F:15])[F:14])[CH:4]=3)=[O:10])=[CH:41][CH:40]=2)[CH:35]=[CH:34][N:33]=1)=[O:37]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C(NO)Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 125 °C

Procedure:
1-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea (5 g, 0.0196 mol) was suspended in N,N-dimethyl formamide (15 ml) with triethyl amine (8.2 ml, 0.0589 mol) and 4-(4-aminophenoxy)-N-methylpicolinamide (4.7 g, 0.0196 mol). The reaction mass was then heated to 125° C. for 4 days. The reaction mass was concentrated under reduced pressure and the obtained residue was quenched with water (50 ml) at room temperature. The aqueous layer was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was back washed with water. Degassing of the ethyl acetate gave semisolid which upon agitation in acetonitrile (50 ml) at ambient temperature for 2-3 hours gave desired product. The product was filtered and vacuum dried to obtain 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base) (2.5 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21]([OH:23])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[C:43]1([NH:49][CH2:50][CH2:51][O:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:23])[N:49]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:50][CH2:51][O:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=1)([CH3:9])([CH3:10])[CH3:8]
Reactant: c1ccc(NCCOc2ccccn2)cc1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCOc2ccccn2)c2ccccc2)c1)c1ccncc1
Reaction time: 0.17 h
Yield: 40.1 %

Procedure:
2M Oxalyl chloride in dichloromethane (0.16 ml) and dry DMF (0.008 ml) were added to a stirred suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.115 g) in dry dichloromethane (1.5 ml) under nitrogen. After 10 min, DIPEA (0.18 ml) was added followed after a further 40 min by phenyl-2-(pyridin-2-yloxy)-ethylamine (0.059 g) and DMAP (0.008 g). After 7 days the solvent was evaporated and the residue was purified by flash chromatography, eluting with dichloromethane:methanol (98:2 v/v), to give the title compound as a pale yellow oil (0.065 g).
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@H:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:22][OH:23])=[O:19])[NH2:17])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N([CH2:37][CH3:38])CC)C>C(Cl)Cl>[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@H:21]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:22][OH:23])=[O:19])[NH:17][C:22](=[O:23])[CH:21]([C:38]1[CH:37]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: COc1ccc([C@H](CO)NC(=O)[C@@H](N)CCCNC(=O)OCc2ccccc2)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: COc1ccc([C@H](CO)NC(=O)[C@H](CCCNC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 182.2 %

Procedure:
Prepared according to the method described in Example 1(d) above from (R)-N5 -(Cbz)-(S)-N-[2-hydroxy-1-(4-methoxyphenyl)ethyl]ornithine amide hydrochloride (2.32 g, 5.13 mmol; from step (b) above), 2-nitrophenyl diphenyl acetate (1.81 g; 5.65 mmol; see Example 1(c) above), triethylamine (0.78 g, 7.70 mmol) and CH2Cl2 (150 mL), 60 hours reaction time. The reaction mixture was submitted to aqueous work up, dried, filtered and concentrated to give the crude product as an off-white solid (3.39 g). The crude product was chromatographed on silica gel eluting with CH2C2 :MeOH (98:2). Concentration of the appropriate fractions gave pure sub-title compound as a white solid (2.85 g).
Reaction SMILES: [O:1]1[CH:7]2[C:2]1([CH3:11])[CH2:3][CH:4]1[C:8]([CH3:10])([CH3:9])[CH:5]1[CH2:6]2.C([OH:14])C>>[C:4]12[C:8]([CH3:10])([CH3:9])[CH:5]1[CH2:6][CH:7]([OH:1])[C:2]([OH:14])([CH3:11])[CH:3]=2
Reactant: CC12CC3C(CC1O2)C3(C)C
Reactant: CCO
Product: CC1(O)C=C2C(CC1O)C2(C)C

Procedure:
(b)subjecting 3,4-epoxycarane to a hydration reaction in the presence of a base catalyst in aqueous ethanol under pressure to obtain 3,4-carenediol of the formula [I].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH:9]1([C:13](O)=O)[CH2:12][CH2:11][CH2:10]1.N>>[CH:9]1([C:13]2[NH:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccncc1N
Reactant: O=C(O)C1CCC1
Agent: N
Product: c1cc2[nH]c(C3CCC3)nc2cn1
Temperature: 110 °C
Yield: 72.2 %

Procedure:
[step 1] 3,4-Diaminopyridine (2.0 g, 18.4 mmol) was mixed with polyphosphoric acid (20g), cyclobutanecarboxylic acid (2.63 mL, 27.5 mmol) was added, and the mixture was stirred with heating at 110° C. for 3 hr. The mixture was added dropwise to 5% aqueous ammonia solution under ice-cooling, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the obtained residue was added ethyl acetate (7 mL), and the precipitated crystals were collected by suction filtration to give 2-cyclobutyl-1H-imidazo[4,5-c]pyridine (2.3 g, 73%).
Reaction SMILES: [O:1]1[CH2:5]C[CH2:3][CH2:2]1.[CH3:6][C:7]1[NH:8][C:9]([CH3:38])=[C:10]([C:30]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH3:37])=[O:31])[CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:12]=1[C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH3:20])=[O:14].[H-].[Na+].ClCOCC>O.C(O)(=O)C>[CH2:2]([O:1][CH2:5][N:8]1[C:7]([CH3:6])=[C:12]([C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH3:20])=[O:14])[CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:10]([C:30]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH3:37])=[O:31])=[C:9]1[CH3:38])[CH3:3]
Reactant: CCOCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCC)C1c1cccc([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOCCOC(=O)C1=C(C)N(COCC)C(C)=C(C(=O)OCCOCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 20 ml. of anhydrous tetrahydrofuran was dissolved 10 g. of bis(2-ethoxyethyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4 -dihydropyridine-3,5-dicarboxylate and then the solution was added dropwise to 10 ml. of an anhydrous tetrahydrofuran suspension of 1.2 g. of a 50% oil dispersion of sodium hydride under stirring. After stirring the mixture further for 30 minutes at room temperature, the mixture was cooled to -10° C., 5 ml. of anhydrous tetrahydrofuran solution of 2.5 g. of chloromethoxyethane was added thereto over a period of 15 minutes, the temperature of the system was elevated gradually up to 0° C. over a period of about 15 minutes, and then the mixture was maintained at 0° C. for 15 minutes. The reaction product was cooled again to -10° C. and 2 ml. of acetic acid was added to the product. After stopping the cooling, 100 ml. of water was added to the product and then the product was extracted three times each time with 30 ml. of ether. The ether extracts were combined, dried over anhydrous sodium sulfate and then ether was distilled away. By recrystallizing the residue from 20:1 hexane-ethanol mixed solvent, 8.6 g. of colorless plate crystals of bis(2-ethoxyethyl) N-ethoxymethyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate melting at 63°-63.5° C. were obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH2:21][N+:22]([O-:24])=O)[CH2:16][C:17](OC)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Al].C1(C)C=CC=CC=1.Cl>O1CCCC1.O>[OH:24][N:22]1[CH2:21][CH:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)[CH2:16][C:17]1=[O:18]
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(OC)c(OC2CCCC2)c1
Agent: Cl
Agent: [Al]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2CC(=O)N(O)C2)cc1OC1CCCC1

Procedure:
A solution containing 13.0 g (0.039 mol) methyl 3-(3-cyclopentyloxy-4-methoxyphenyl)-4-nitrobutanoate prepared above in 400 ml tetrahydrofuran containing 4 ml water was gradually added to 3.8 g aluminium foil treated before with a solution of mercuric chloride (1 g) in water. The temperature was held at 15°-20° C. by cooling. The mixture was stirred overnight at ambient temperature after which toluene and 200 ml 6N hydrochloric acid were added. The organic phase was separated and washed with 0.8M sodium hydrogen carbonate solution and evaporated to dryness in vacuo. The residue was crystallized from a mixture of dichloromethane-ether. Yield 1.7 g (15 mp 126°-130° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.N1[CH:16]=[CH:15]N=C1.C(Cl)(=O)C.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C>[F:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:15]([CH3:16])[N:22]([CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30])[C:4]2=[O:6]
Reactant: NC1CCC(=O)NC1=O
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: c1c[nH]cn1
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Cc1nc2ccc(F)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a stirred mixture of 2-amino-5-fluorobenzoic acid (1.2 g, 7.8 mmol) and imidazole (0.63 g, 9.3 mmol) in acetonitrile (15 mL), was added acetyl chloride (0.66 mL, 9.3 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (1.3 g, 7.7 mmol), imidazole (1.2 g, 17 mmol) and triphenyl phosphite (2.2 mL, 8.5 mmol) and heated to reflux for 22 hours. The suspension was filtered and washed with water (2×50 mL), ethyl acetate (2×50 mL), and water (50 mL) to give 3-(6-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (1.2 g, 53% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min. 240 nm, 20/80 CH3CN/0.1% H3PO4, 5.99 min (99.3%); mp: 273-275° C.; 1H NMR (DMSO-d6) δ 2.13-2.23 (m, 1H, CHH), 2.57-2.71 (m, 5H, CH3, 2CHH), 2.75-2.95 (m, 1H, CHH), 5.30 (dd, J=6, 11 Hz, 1H, NCH), 7.70-7.73 (m, 3H, Ar), 11.06 (s, 1H. NH); 13C NMR (DMSO-d6) δ 20.82, 23.31, 30.58, 56.63, 110.54 (d, JC-F=23 Hz), 121.40 (d, JC-F=8 Hz), 123.24 (d, JC-F=24 Hz), 129.47 (d, JC-F=8 Hz), 143.75, 154.45, 159.83 (d. JC-F=245 Hz), 159.86 (d, JC-F=3 Hz), 169.37, 172.58; LCMS: MH=290; Anal Calcd for C14H12N3O3F 1.3H2O: C, 53.78; H, 4.71; N, 13.44. Found: C, 53.75; H, 4.61; N, 13.50.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[NH3:18]>O1CCOCC1>[CH:12]1([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:18])[C:3]=3[C:10]([I:11])=[CH:9]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: N
Reactant: Clc1ncnc2c1c(I)cn2C1CCCC1
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(I)cn2C1CCCC1
Yield: 92 %

Procedure:
To a pressure tube with dioxane (5 mL) was added 4-Chloro-7-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine, then ammonia hydroxide (5 mL). The pressure tube was sealed and heated at 120 C overnight. All solvents were removed via reduced pressure, and the residue were purified through flash column (methylene chloride/methanol:97/3). The product was obtained as a white solid (300 mg, 92%). MS: 329.1 (MH+); HPLC Rf: 5.018 min.; HPLC