Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])[CH3:20].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([N:37]2[CH2:42][CH2:41][CH:40]([C:43](O)=[O:44])[CH2:39][CH2:38]2)=[O:36])[CH:29]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl>C1COCC1.C(OCC)(=O)C.O>[O:21]=[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][C:43]([CH:40]1[CH2:41][CH2:42][N:37]([C:35]([O:34][C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[O:36])[CH2:38][CH2:39]1)=[O:44]
Reactant: CC(=O)c1ccccc1
Reactant: O=C(O)C1CCN(C(=O)Oc2cccnc2)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=C(CC(=O)C1CCN(C(=O)Oc2cccnc2)CC1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A mixture of diisopropylamine (3.23 g) and THF (20 mL) was cooled to 0° C., and 1.57 M n-butyllithium/hexane (20.4 mL) was slowly added thereto, followed by stirring at the same temperature for 1 hour. Then, the mixture was cooled to −70° C., and acetophenone (3.84 g) was added dropwise thereto, followed by stirring at the same temperature for 1 hour (reaction liquid 1). Meanwhile, to a suspension of 1-[(pyridin-3-yloxy)carbonyl]piperidine-4-carboxylic acid (2.0 g) in THF (30 mL) was added CDI (1.56 g), followed by stirring at room temperature for 1 hour (reaction liquid 2). The reaction liquid 2 was cooled to −70° C., and the reaction liquid 1 was added dropwise thereto, followed by stirring at the same temperature for 1 hour. Then, the mixture was warmed to 0° C. and then warmed to room temperature. To the reaction liquid was added 0.1 M hydrochloric acid (50 mL), then water and ethyl acetate were added thereto, and the organic phase was separated. The organic phase was washed with water and saturated brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10) to obtain pyridin-3-yl 4-(3-oxo-3-phenylpropanoyl)piperidine-1-carboxylate (0.93 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[C:24]4[CH2:25][C:26]5([O:31][C:23]=4[C:22]([O:32][CH3:33])=[CH:21][CH:20]=3)[CH2:30][CH2:29][CH2:28][CH2:27]5)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[C:34]1(=[O:40])[NH:38][C:37](=[O:39])[CH2:36][CH2:35]1>>[CH3:33][O:32][C:22]1[C:23]2[O:31][C:26]3([CH2:27][CH2:28][CH2:29][CH2:30]3)[CH2:25][C:24]=2[C:19]([C:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:38]4[C:34](=[O:40])[CH2:35][CH2:36][C:37]4=[O:39])[CH2:6][CH2:7]3)[N:12]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2
Reactant: O=C1CCC(=O)N1
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2

Procedure:
Prepared analogously as described for example 1 using 2-[1-(chloroacetyl)piperidin-4-yl]-5-(7-methoxy-3H-spiro[1-benzofuran-2,1′-cyclopentan]-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A6) and succinimide as starting compounds.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][CH2:27][CH2:28][CH3:29])[N:14]([CH2:15][CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[NH2:31][OH:32]>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][CH2:27][CH2:28][CH3:29])[N:14]([CH2:15][CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:31][OH:32])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCC(=O)c1ccccc1
Reactant: NO
Agent: Cl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCC(=NO)c1ccccc1

Procedure:
By the general method described in Part F of Example 30, 4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one was reacted with hydroxylamine hydrochloride to provide 4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one oxime in about a 10 to 1 mixture of E and Z isomers as white crystals after recrystallization from methanol, mp 242-244° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1(C(OCC)=O)[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][NH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl.[C:24](=O)(O)[O-:25].[Na+]>C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([CH2:24][OH:25])[N:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1(NC(=O)OC(C)(C)C)C=C(Cl)C=CN1
Reactant: O=C([O-])O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cc(Cl)cc(CO)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
To a mixture of 1.00 g (3.3 mmol) of ethyl 2-(t-butoxycarbonyl)amino-4-chloropicolinate and 20 mL of anhydrous ethanol, 0.38 g (10.0 mmol) of sodium borohydride was added, followed by stirring at room temperature for 17 hours. To the reaction solution, dilute hydrochloric acid was added thereby adjusting the pH to 2 and the solution was neutralized by adding saturated sodium bicarbonate aqueous solution. After ethanol was removed under reduced pressure, the resultant was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1 (v/v)) to obtain 0.75 g (2.9 mmol, yield of 87%) of 2-(t-butoxycarbonyl)amino-4-chloro-6-hydroxymethylpyridine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([NH2:16])=[C:11]([CH3:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>Cl>[NH2:16][C:12]1[C:11]([CH3:17])=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:19]([CH3:18])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:7]=2)=[C:14]([CH3:15])[CH:13]=1
Reactant: CNc1ccccc1
Reactant: Cc1cc(Oc2ccnc(Cl)n2)c(C)cc1N
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccnc(N(C)c3ccccc3)n2)c(C)cc1N

Procedure:
A solution of 2.50 g (10 mmol) 4-(2-chloro-pyrimidin-4-yloxy)-2,5-dimethyl-phenylamine and 2.14 g N-methylaniline (20 mmol) in 50 ml hydrochloric acid were stirred for 20 h at 80° C. After cooling down to ambient temperature 50 ml ethyl acetate was added and the organic layer was separated. The water layer was brought to pH 8 with sodium carbonate and the formed precipitate was filtered by suction and washed with hexane. After separation the organic layer was concentrated in vacuo and column chromatography (dichloromethane) yielded 380 mg (11%) with a purity of 89% log P (pH=2.3)=1.72.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:38][C:39]([C:42](OCC)=[O:43])([CH3:41])[CH3:40])=[C:12]([CH:14]2[C:19]3([C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH:18]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[CH2:17][C:16](=[O:37])[NH:15]2)[CH:13]=1>C(OCC)C>[Cl:28][C:24]1[CH:23]=[C:22]2[NH:21][C:20](=[O:29])[C:19]3([CH:18]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=4)[CH2:17][C:16](=[O:37])[NH:15][CH:14]3[C:12]3[CH:13]=[C:8]([Br:7])[CH:9]=[CH:10][C:11]=3[O:38][C:39]([CH3:40])([CH3:41])[CH2:42][OH:43])[C:27]2=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(CO)Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.3 %

Procedure:
To a mixture of LiAlH4 (2.5 mg, 0.066 mmol) in diethyl ether (1 mL) was added racemic (2′R,3R,4′S)-2′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (10 mg, 0.016 mmol). The mixture was stirred at room temperature for 10 min, quenched with MeOH, purified by Prep-HPLC to give product (3.7 mg, 38%). (M+H)+: 603
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu]I.CCCCCC.C(OCC)(=O)C>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2ccc3ccccc32)cc1

Procedure:
Using the general procedure outlined in Example 63, indole (0.117 g, 1.00 mmol) was coupled with 4-chlorotoluene (1 mL, 8.45 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol) and trans-1,2-cyclohexanediamine (24 μL, 0.20 mmol, 20 mol %) to give the crude product. Column chromatography (2×15 cm, hexane:ethyl acetate 50:1) provided 0.066 g (32% GC yield) of the product as a white solid. This product was pure by 1H NMR when compared to the known spectra.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)/[C:27]([O-])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].CS(Cl)(=O)=O.[NH2:57][C@@H:58]1[C:89](=[O:90])[N:60]2[C:61]([C:73]([O:75][CH:76]([C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=3)[C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=3)=[O:74])=[C:62]([CH2:65][S:66][C:67]3[CH2:71][O:70][C:69](=[O:72])[CH:68]=3)[CH2:63][S:64][C@H:59]12.N1C=CC=CC=1>CN(C)C=O>[O:72]=[C:69]1[CH:68]=[C:67]([S:66][CH2:65][C:62]2[CH2:63][S:64][C@@H:59]3[C@H:58]([NH:57][C:27](=[O:28])/[C:26](/[C:24]4[N:25]=[C:21]([NH:20][C:1]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[S:22][CH:23]=4)=[N:30]\[O:31][C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:89](=[O:90])[N:60]3[C:61]=2[C:73]([O:75][CH:76]([C:83]2[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=2)[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[O:74])[CH2:71][O:70]1
Reactant: O=C([O-])/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSC3=CC(=O)OC3)CS[C@H]12
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C1C=C(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)CO1
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A stirred solution of sodium 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetate (762 mg) in dimethylformamide (4 ml) was cooled to -55° C. to -60° C. and methanesulphonyl chloride (0.085 ml) was added. The mixture was stirred at the same temperature for 30 mins and then a solution of diphenylmethyl 7β-amino-3-(2,5-dihydro-2-oxofuran-4-ylthiomethyl)ceph-3-em-4-carboxylate (494 mg) in dimethylformamide (4 ml) was added followed by pyridine (0.08 ml). The mixture was then stirred at 0° C. for 90 mins and then partitioned between ethyl acetate and aqueous citric acid solution. The organic phase was washed successively with water, sodium bicarbonate solution, water, and brine. The solution was dried over magnesium sulphate and evaporated. The title compound (744 mg) was isolated by column chromatography of the residue using gradient elution (Kieselgel 2:1 going to 1:1 hexane:ethyl acetate). υmax (CHCl3) 3400, 1785, 1745 and 1685cm-1 . δH(CDCl3) 3.23 (1H, d, J 18.2Hz), 3.52 (1H, d, J 18.2Hz), 3.93 (1H, d, J 12.6Hz), 3.99 (1H, d, J 12.5Hz), 4.70 (2H, s), 5.08 (1H, d, J 5.0Hz),5.65 (1H, s), 6.11 (1H, dd, J 5.0 and 8.9Hz), 6.43 (1H, s), 6.75 (1H, s), 6.98 (1H, s), 7.15-7.5 (41H, m). [mass spectrum: +ve ion (thioglycerol) MH+ 1148].
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[N:8]=[CH:7]2)[O:4][C@H:3]([CH2:16][OH:17])[C@H:2]1[OH:18]>O>[CH2:1]1[C@@H:5]([N:6]2[C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[N:8]=[CH:7]2)[O:4][C@@H:3]([CH2:16][OH:17])[C@@H:2]1[OH:18]
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@@H](O)[C@H](CO)O1

Procedure:
1H NMR (200 MHz, DMSO-D6): δ 8.35 and 8.14 (2s, 2H, H2 and H8), 7.34 (sl, 2H, NH2), 6.35 (dd, 1H, H1′, J 6.1 Hz, J 7.85 Hz), 5.33 (d, 1H, OH2′, J 4.0 Hz), 5.28 (dd, 1H, H3′, J 4.95 Hz; J 6.6 Hz), 4.42 (m, 1H, OH5′), 3.88 (m, 1H, H4′), 3.63-3.52 (m, 2H, H5′a and H5′b), 2.71 (m, 1H, H2′a), 2.28 (m, 1H, H2′b). (identical to commercial 2′-deoxy-D-adenosine) αD+26° (c 0.5 water) (commercial 2′-deoxy-D-adenosine-25° (c 0.5 water)).
Reaction SMILES: CC([Si](C)(C)[O:6][C@@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][C@@H:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18]([O:28][CH:29]([O:31][CH2:32][CH3:33])[CH3:30])[C:17]4([CH3:35])[CH3:34])=[CH:11][CH2:10]1)[CH3:8])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:32]([O:31][CH:29]([O:28][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C:13]3[C:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@H:7]([OH:6])[CH3:8])[CH2:10][CH:11]=4)[C:17]1([CH3:35])[CH3:34])[CH3:30])[CH3:33]
Reactant: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@@]1(C)CC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)O[C@H]1CC[C@]2(C)C3=C(CC[C@H]2C1(C)C)C1=CC[C@H]([C@@H](C)O)[C@@]1(C)CC3
Reaction time: 24 h
Yield: 82.4 %

Procedure:
iv)—A solution of (3β,5α,20R)-20-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[(1-ethoxyethyl)oxy]-4,4-dimethylpregna-8,14-diene (18b; 16.4 g) in a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (42 ml) was stirred at 50° C. for 6 h and then at room temperature for 24 h. The reaction mixture was poured into water and the product was extracted into ethyl acetate. The combined organic phases were washed with brine and concentrated under reduced pressure. Column chromatography afforded (3β,5α,20R)-3-[(1-ethoxyethyl)oxy]-4,4-dimethylpregna-8,14-dien-20-ol (compound 19b; 10.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1F.[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[Cl:17]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Reactant: Nc1ccccc1Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1Cl
Temperature: 140 °C
Reaction time: 144 h
Yield: 12 %

Procedure:
4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4 (2.00 g, 8.62 mmol) is suspended in xylenes (15 mL) and 2-chloro aniline (9.06 mL, 86.15 mmol) is added. The reaction mixture is heated to 140° C. under a nitrogen atmosphere. After 6 days, the reaction mixture is cooled to room temperature, and diluted with ethyl acetate. The reaction mixture is washed with water, 10% HCl solution and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure. The crude product is triturated with diethyl ether, twice, to give 0.35 g (12%) pure desired product as a brownish solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1.Cl.Cl.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC>[C:12]1([N:8]2[CH2:7][CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:29]3[CH2:30][CH2:31][N:26]([C:21]4[N:20]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:27][CH2:28]3)[O:10][C:9]2=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C1OC(CCCCCl)CN1c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: O=C1OC(CCCCN2CCN(c3ncccn3)CC2)CN1c1ccccc1
Yield: 90.6 %

Procedure:
Following the procedure of Example 5, a mixture of 5-(4-chlorobutyl)-3-phenyl-2-oxazolidinone (3.0 g, 0.01186 mol), 1-(2-pyrimidinyl)piperazine dihydrochloride (2.81 g, 0.01186 mol), potassium carbonate (9.85 g, 0.0713 mol), and potassium iodide (1.0 g) in n-butanol (75 mL) gave a solid (4.1 g, 91% yield). The solid was recrystallized from isopropanol/isopropyl ether and dried under high vacuum to give 2.58 g, mp 94°-96° C.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.[C:11]([O-:14])(=[O:13])[CH3:12].[Na+]>C(O)(=O)C.[I-].[Na+]>[C:11]([O:14][CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1)(=[O:13])[CH3:12]
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1cc(=O)[nH]c(=O)[nH]1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture of 16.05 g (0.10 mol) of 6-chloromethyl-uracil, 9.85 g (0.12 mol) of sodium acetate and 0.3 g of sodium iodide in 50 ml of glacial acetic acid is heated at reflux for 20 minutes. The mixture is subsequently cooled to room temperature and filtered. The filtrate is treated with 250 ml of diethyl ether and the resulting crystals are filtered off. The combined crystallizate is added to 200 ml of water and thus liberated from the residual salts. 11.3 g of 6-acetoxymethyl-uracil are isolated by filtration.
Reaction SMILES: [CH:1]12[O:8][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:9]>O1CCCC1>[OH:9][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:8])[CH2:1]1
Reactant: O=C1CCCCC2OC12
Solvent: C1CCOC1
Product: O=C1CCCCC(O)C1
Reaction time: 2 h
Yield: 97 %

Procedure:
To a 25° C. solution of 45.9 g. (0.364 mole) of 8-oxabicyclo[5.1.0]octan-2-one in 950 ml. of 10% aqueous tetrahydrofuran was added 39.7 g. (1.47 mmoles) of aluminum amalgam. (The aluminum amalgam was prepared by 15-30 second successive washing of small pieces of aluminum foil with 2 N sodium hydroxide, distilled water, 0.5% mercuric chloride, distilled water, 2 N sodium hydroxide, distilled water, 0.5% mercuric chloride, distilled water, ethanol and ether). The mixture was stirred for 2 hours, then filtered through diatomaceous earth. The filtrate was evaporated on a rotovapor, the residue saturated with solid sodium chloride and extracted with three 500 ml. portions of ether. The ether extract was dried over magnesium sulfate and evaporated to yield 45 g. (97%) of the title compound as an oil.
Reaction SMILES: C(OC([NH:11][C:12]1([C:25](=[O:27])[NH2:26])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[NH2:11][C:12]1([C:25](=[O:27])[NH2:26])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(N)=O)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Yield: 90 %

Procedure:
1B (1.0 equivalent) and a catalytic amount of acetic acid in MeOH (0.05M) was passed through H-cube hydrogenator equipped with Pd/C cartridge at 50° C. The methanol in the reaction mixture was then removed under reduced pressure, and the product was washed with cold ether twice to afford the tert-butyl 4-amino-4-carbamoylpiperidine-1-carboxylate (1C, 90%).
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=3)[O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.C1COCC1.[OH-].[Li+].Cl>CO>[F:37][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=3)[O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH:26]([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]3)=[N:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CCN(CCOc2cccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCN(CCOc2cccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To ethyl 1-(2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylate 41 (78 umol) is added THF (3 mL), MeOH (2 mL) and 3M lithium hydroxide (0.5 mmol). The reaction mixture is stirred at rt for 6 h until complete as detected by LCMS. Subsequently the organic solvents are evaporated and the reaction mixture is diluted with water (5 mL) and neutralized with 3M HCl (0.5 mmol). The resulting precipitate is filtered, washed with water and air dried to yield 1-(2-(3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylic acid E1 as white solid. 1H NMR (400 MHz, d6-DMSO) δ 12.12 (s, 1H), 9.79 (s, 1H), 8.85 (s, 2H), 7.78 (d, J=8.0 Hz, 2H), 7.52 (bs, 1H), 7.34 (bd, J=8.0 Hz, 1H), 7.31 (t, J=74.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H), 6.56 (bd, J=8.0 Hz, 1H) 4.05 (m, 2H), 2.88 (m, 2H), 2.67 (m, 2H), 2.20 (m, 1H), 2.09 (m, 2H), 1.78 (m, 2H), 1.57 (m, 2H). MS (m/z) (M+1)+: 484.2.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][OH:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[F:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][O:27][C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Over the course of 30 minutes, 10.5 ml of diethyl azodicarboxylate are poured onto a mixture of 13.5 g of N-tert-butyloxycarbonyl-4-hydroxymethylpiperidine, 7.45 g of p-fluorophenol, 17.4 g of triphenylphosphine and 140 ml of tetrahydrofuran. After stirring for 12 hours at ambient temperature, the reaction mixture is concentrated, taken up in ether, washed with water and then 1N sodium hydroxide solution, and then washed with water. After drying, filtration and evaporation under reduced pressure, chromatography over silica gel (cyclohexane/ethyl acetate: 90/10) allows the expected product to be isolated.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH:6]1[CH2:12][C:11]([CH3:14])([CH3:13])[C:10]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:9]=2[NH:8][CH2:7]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:19][C:17]2[CH:16]=[CH:15][C:10]3[C:11]([CH3:14])([CH3:13])[CH2:12][CH:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:7][NH:8][C:9]=3[CH:18]=2)=[N:22][CH:23]=1
Reactant: COCCNC1CNc2cc(N)ccc2C(C)(C)C1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NCC(NCCOC)CC3(C)C)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethylamino)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide was prepared from N(3)-(2-Methoxy-ethyl)-5,5-dimethyl-2,3,4,5-tetrahydro-1H-1-benzazepine-3,8-diamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1d. Title compound was isolated as a white solid (29 mg, 27%), HPLC purity=90%, LCMS 544 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.22 (s, 1H), 9.12 (s, 1H), 8.51-8.47 (m, 3H), 8.13 (s, 1H), 7.52-7.50 (m, 2H), 7.45-7.38 (m, 1H), 6.97 (s, 2H), 6.91 (s, 1H), 4.95-4.88 (m, 1H), 3.62-3.58 (m, 2H), 3.55-3.42 (m, 2H), 3.33 (s, 3H), 3.22-3.18 (m, 2H), 2.73-2.67 (d, 3H), 1.96-1.92 (m, 1H), 1.73-1.70 (m, 1H), 1.36 (s, 3H), 1.23 (s, 3H).