Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[CH2:21][CH2:20]2)=[O:16])[C:5]1=[O:39])([CH3:3])[CH3:2].[ClH:40]>>[ClH:40].[ClH:40].[CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)[CH2:21][CH2:20]2)=[O:16])[C:5]1=[O:39])([CH3:3])[CH3:2]
Reactant: Cc1cccc2c1cc(C(=O)NCC1CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC1)c(=O)n2C(C)C
Agent: Cl
Product: Cc1cccc2c1cc(C(=O)NCC1CCN(CC3CCNCC3)CC1)c(=O)n2C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
tert-Butyl 4-{[4-({[(1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinolin-3-yl)carbonyl]amino}methyl)piperidine-1-yl]methyl}piperidine-1 carboxylate (150 mg, 0.28 mmol, step 1) was dissolved in 10% methanolic hydrogen chloride (20 mL) and the mixture was stirred for 16 h at room temperature. The mixture was concentrated to give yellow oil, which was crystallized from diethyl ether and n-hexane. The solid was collected by filtration to give 110 mg (96%) of the title compound as a pale yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH3:8][CH:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:37][CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][O:11][CH3:12]
Reactant: CS(=O)(=O)OCC1CCOCC1
Reactant: COCC(C)Oc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC(C)Oc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 54.3 %

Procedure:
To a solution of 2-{[1-methyl-2-(methoxy)ethyl]oxy}-8-(methoxy)-9H-purin-6-amine trifluoroacetic acid salt (500 mg) in dry N,N-dimethylformamide (4.5 ml) at room temperature and under nitrogen was added potassium carbonate (0.75 g) in one go. The reaction was stirred at 60° C. for 1.5 hours. Tetrahydro-2H-pyran-4-ylmethyl methanesulfonate (0.29 g) was added in one go and the reaction heated at 90° C. for 3 hours. The reaction was cooled to room temperature and then diluted with ethyl acetate (20 ml) and washed with water (15 ml). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (10-45%) to afford the title compound as a viscous clear oil (260 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])[CH2:3]1.C(N(CC)CC)C.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>CN(C)C1C=CN=CC=1.ClCCl>[C:26]1([C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([S:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]([N:4]4[CH2:5][CH:2]([O:1][C:41](=[O:42])[N:40]([CH3:44])[CH3:39])[CH2:3]4)=[O:7])=[CH:13][CH:12]=3)(=[O:16])=[O:15])[CH:18]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CC(O)C1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)OC1CN(C(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)C1
Reaction time: 15 h
Yield: 74 %

Procedure:
Combine (3-Hydroxy-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone (95 mg, 0.219 mmol), triethylamine (0.200 mL, 1.43 mmol, excess) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in dichloromethane (1.0 mL) and treat with N,N-dimethylcarbamoyl chloride (0.050 mL) at room temperature. Stir for 15 h, load directly onto pre-packed silica gel column and purify by flash column chromatography (EtOAc/Hexanes) to yield 82 mg of Dimethyl-carbamic acid 1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-yl ester as a white foam (74%). LRMS: MH+ 503.97.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C@@H:8]([NH2:10])[CH3:9])[N:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.[F:21][C@H:22]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30]1[CH:35]=[CH:34][N:33]=[C:32](F)[N:31]=1)[CH3:23].CCN(C(C)C)C(C)C>CS(C)=O>[F:21][C@H:22]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH:10][C@H:8]([C:6]2[N:5]=[CH:4][C:3]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=3)=[C:2]([CH3:1])[CH:7]=2)[CH3:9])[N:31]=1)[CH3:23]
Reactant: Cc1cc([C@H](C)N)ncc1-c1ccnc(C(F)(F)F)c1
Reactant: C[C@H](F)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@H](C)Nc2nccc(N3C(=O)OC[C@@H]3[C@H](C)F)n2)ncc1-c1ccnc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A solution of (S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine (28.1 mg, 0.1 mmol), (R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (22.9 mg, 0.100 mmol) and DIPEA (52.4 μl, 0.300 mmol) in DMSO (Volume: 500 μl) was heated at 110° C. for 1 hr. The solution was then cooled to rt, and RP-HPLC (acetonitrile:water) purification provided a white solid. This material was purified again with flash column chromatography (0-10% MeOH/EtOAc) to give 14 mg (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a white solid. 1H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.0 Hz, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.69 (dd, J=5.0, 1.6 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J=5.8 Hz, 1H), 5.08 (br s, 1H), 4.73 (br d, J=26.0 Hz, 1H), 4.56-4.27 (m, 3H), 2.32 (s, 3H), 1.58 (d, J=7.1 Hz, 3H), 1.12 (br s, 3H); HRMS (B) m/z 491.1782 (M+H)+. Anal. RP-HPLC tR=3.42 min. Purity 100%/100%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:15])([F:14])[C:9](OCC)=[O:10])[CH:5]=[CH:6][CH:7]=1.FC(F)(CCC1C=CC=CC=1)CO>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:14])([F:15])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)c1cccc(Br)c1
Agent: OCC(F)(F)CCc1ccccc1
Product: OCC(F)(F)c1cccc(Br)c1

Procedure:
Obtained from Intermediate 48 (21.1 g, 75.6 mmol) by the procedure described in Intermediate 2. The title compound was obtained (17.2 g, 96%) as oil.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[OH:19])[CH2:13][CH:14]=3)[N:5]=2)[CH2:3][CH2:2]1.[Cr](O)(O)(=O)=O.O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.CO>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[O:19])[CH2:13][CH:14]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: OC(CCCN1CC=C(c2noc(C3CC3)n2)CC1)c1ccc(F)cc1
Agent: O=[Cr](=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCCN1CC=C(c2noc(C3CC3)n2)CC1)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
A 0.36 g. portion of 4-(5-cyclopropyl-1,2,4-oxadiazol- 3-yl)-3,6-dihydro-α-(p-fluorophenyl)-1(2H)-pyridinebutanol, prepared as described in Example 11, in 10 ml. of acetic acid is stirred at room temperature. A 6 ml. portion of chromic acid in acetic acid solution is added dropwise. The mixture is stirred for 2 hours and then allowed to stand overnight. A few drops of methanol and some water is added and the solution is neutralized with solid sodium bicarbonate. The mixture is extracted 3 times with ether. The extracts are dried over magnesium sulfate, filtered and evaporated, yielding a white solid which is recrystallized from aqueous methanol, m.p. 67°-68° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:29]=[CH:28][C:15]2[CH2:16][NH:17][CH2:18][CH2:19][C@@:20]34[C@@H:25]([O:26][C:13]=1[C:14]=23)[CH2:24][C@@H:23]([OH:27])[CH:22]=[CH:21]4.[OH-].[Na+]>CC(C)=O>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:17]2[CH2:18][CH2:19][C:20]34[CH:21]=[CH:22][C@H:23]([OH:27])[CH2:24][CH:25]3[O:26][C:13]3=[C:12]([O:11][CH3:10])[CH:29]=[CH:28][C:15](=[C:14]43)[CH2:16]2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCNC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc2c3c1OC1C[C@@H](O)C=CC31CCN(c1nc(Cl)nc(Cl)n1)C2
Yield: 57.7 %

Procedure:
A solution of 2,4,6-trichloro-1,3,5-triazine (0.66 g, 3.7 mmol) in acetone (16 ml) was poured onto ice water (35 ml) and added in small portions at 0° C. to (+/−)-norgalanthamine (1.0 g, 3.7 mmol). After the addition of 2N-sodium hydroxide (2 ml), the reaction mixture was refluxed for 40 hours. The aqueous phase was extracted with EtOAc (3×30 ml). The combined, organic phases were washed with common salt solution (30 ml), dried (Na2SO4) and concentrated by evaporation, to produce 0.90 g (59.5%) of compound 4e: 1H-NMR (CDCl3) δ 6.82 (d, J=10.0 Hz, 1H), 6.63 (d, J=10.0 Hz, 1H), 6.02 (b, 2H), 5.30 (d, J=11.0 Hz, 1H), 4.75 (d, J=16.0, 1H), 4.50 (b, 1H), 4.22 (d, J=11.0 Hz, 1H), 4.11 (b, 1H), 3.78 (s, 3H), 3.59 (m, 1H), 3.06 (m, 1H), 2.61 (d, J=16.0 Hz, 1H), 1.90 (m, 3H); 13C-NMR (CDCl3) δ 207.0 (s) 171.2 (s), 163.7 (s), 146.2 (s), 143.9 (s), 132.3 (d), 129.5 (s), 127.6 (s), 126.7 (d), 121.5 (d), 110.8 (d), 88.0 (d), 61.7 (d), 55.7 (q), 51.8 (t), 48.2 (5), 43.4 (t), 35.9 (t), 29.7 (t).
Reaction SMILES: [N+](C)([O-])=O.C[C:6]([O:8][CH2:9][C:10]1[CH2:19][S:18][C@@H:13]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:12]2[C:11]=1[C:20]([OH:22])=[O:21])=O.B(F)(F)F.N>[Cl-].[Zn+2].[Cl-].CO.O>[NH2:17][CH:14]1[C:15](=[O:16])[N:12]2[C:11]([C:20]([OH:22])=[O:21])=[C:10]([CH2:9][O:8][CH3:6])[CH2:19][S:18][C@H:13]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Agent: N
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 60 °C

Procedure:
To 10 ml of nitromethane were added 3.0 g of 7-ACA, 10.0 g of zinc chloride and 3.9 g of a complex of boron trifluoride with methanol (boron trifluoride content: 51%). The mixture was heated at 60° C. for 20 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. To the reaction mixture were added 30 ml of water and 5 ml of methanol. Then, the mixture was adjusted to pH 8.0 with 28% aqueous ammonia at a temperature of -5° C. The resulting precipitate was filtered off, and then washed with water. The filtrate was combined with the washings. The resulting mixture was adjusted to pH 3.5 with 36% hydrochloric acid to thereby form a precipitate. The precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 20 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 1.4 g. The yield of the desired product was 52%.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[CH3:19][O:20][C:21](=[O:50])[N:22]=[C:23]([S:48][CH3:49])[C:24]([C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([OH:46])[C:39]=1[F:47])=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:19][O:20][C:21](=[O:50])[N:22]=[C:23]([S:48][CH3:49])[C:24]([C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:39]=1[F:47])=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O)c1F
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCCO[Si](C)(C)C(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
After adding 313 mg of cesium carbonate and 0.257 ml of (3-bromopropoxy)-t-butyldimethylsilane to a solution of 339 mg of [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (3d)) in 8 ml of DMF, the mixture was stirred at room temperature for 15 hours. Next, 100 ml of water was added to the reaction mixture and extraction was performed with 300 ml of ethyl acetate. The organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (413 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:18]=1)[C:14](OC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:13]([CH2:14][OH:15])[CH:12]=[N:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cncc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cncc(OCc2ccccc2)c1
Reaction time: 0.92 h
Yield: 77.9 %

Procedure:
To a stirring solution of 363 mg (1.49 mmol) of methyl 5-(benzyloxy)nicotinate in 10 mL of THF at 0° C. was added 141 mg (3.71 mmol) of LiAlH4. The ice bath was removed, and after 55 min., 20.5 mg of LiAlH4 was added. After 40 min., the reaction was quenched by adding successively 160 μL of H2O, 160 μL of 15% aqueous NaOH, and 480 μL of brine. Purification by flash silica gel chromatography (2 mL MeOH/100 mL CHCl3) provided 250 mg of (5-(benzyloxy)pyridin-3-yl)methanol (yellow oil) in 78% yield.
Reaction SMILES: [Li]CCCC.[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH2:33][C:34]3[CH:42]=[CH:41][C:37]4[O:38][CH2:39][O:40][C:36]=4[CH:35]=3)[CH2:17][C:18]3[N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH:21]=[N:20][C:19]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:14][C:9]=2[O:8][CH2:7]1.[CH3:43][C:44](OC(C)=O)=[O:45]>C1COCC1>[O:38]1[C:37]2[CH:41]=[CH:42][C:34]([CH2:33][N:16]([CH2:17][C:18]3[N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[C:21]([C:44](=[O:45])[CH3:43])=[N:20][C:19]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:15][C:13]3[CH:12]=[CH:11][C:10]4[O:6][CH2:7][O:8][C:9]=4[CH:14]=3)=[CH:35][C:36]=2[O:40][CH2:39]1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCn1cnc(-c2ccccc2)c1CN(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCn1c(C(C)=O)nc(-c2ccccc2)c1CN(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-BuLi (1.2 equivalents in 175 μl hexane) is added to a solution of 1-(1,3-benzodioxol-5-yl)-N-(1,3-benzodioxol-5-ylmethyl)-N-[(1-butyl-4-phenyl-1H-imidazol-5-yl)methyl]methanamine (118 mg), obtained as a minor product in Example 2, step 4, in 10 mL anhydrous THF under N2 at −78° C. The resulting mixture is stirred at −78° C. for 1 hour. Ac2O (118.4 mg, 1.2 equivalents) is added. The reaction mixture is stirred at −78° C. for 2 more hours, warned to room temperature, and stirred overnight. The reaction is quenched with 5 mL of H2O and diluted with 20 mL ethyl acetate. The organic phase is collected, washed with brine, dried and concentrated. Purification via silica gel chromatography provides the title compound (Compound 8).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][C:11]([C:15]2[N:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]2[N:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1C=C(c2cnc(N)cn2)CCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@@H](c2cnc(N)cn2)C1
Reaction time: 3 h

Procedure:
A mixture of 5-(3-((tert-butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)pyrazin-2-amine (238 mg, 0.779 mmol) and Pd/C (10%) (50 mg, 0.779 mmol) in MeOH (7.79 mL) was stirred under H2 atmosphere for 3 h. LCMS indicated about 60% conversion. More Pd/C (20 mg) was added, and stirred about another 4 h. LCMS indicated still little amount of starting material left. More Pd/C (20 mg) was added and stirred overnight. Catalyst was filtered out and solvent was evaporated. The residue was purified with flash chromatography eluting with 0-100% of EtOAc/heptane to provide 110 mg of desired cis racemate compound. LCMS (m/z): 308.4 (MH+), 1.01 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[NH:11][NH:10][C:9]2=[O:19])=[CH:4][CH:3]=1>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:19])[NH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C1NNC(c2ccncc2)C1c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCO
Product: O=c1[nH][nH]c(-c2ccncc2)c1-c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
To solution of 4-(4-Chloro-phenyl)-5-pyridin-4-yl-pyrazolidin-3-one 20 mg in ethyl alcohol 5 mL was added Pd/C 1 mg. The reaction was heated to 50° C. for 48 hours, cooled to room temperature, filtered and concentrated to a solid. Purification by TLC plate followed by crystallization from chloroform and methanol give the title compound as an off-white solid. MS (ES+): 272 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:18]1[C:23]([I:24])=[C:22]([CH:25]([OH:27])[CH3:26])[N:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1>[OH:27][CH:25]([C:22]1[N:21]=[CH:20][N:19]=[C:18]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:23]=1[I:24])[CH3:26]
Reactant: CC(O)c1ncnc(Cl)c1I
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(O)c1ncnc(NCCc2ccccc2)c1I
Temperature: 60 °C

Procedure:
In 20 ml of toluene were dissolved 2-phenylethylamine (0.6 g) and triethylamine (0.6 g), then, 4-chloro-6-(1-hydroxy-ethyl)-5-iodopyrimidine (1.4 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][C:18]=2[C:28]([O:30]CC)=[O:29])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:19][C:18]=2[C:28]([OH:30])=[O:29])[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2sc(-c3ccccc3)nc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
1 N NaOH (5.4 mL) was added to a solution of ethyl 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-phenylthiazole-4-carboxylate (1.50 g, 3.6 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo. H2O was added and the mixture was washed with EtOAC. The pH of the aqueous layer was adjusted to 5 by the addition of 1N HCl and the resulting ppt was collected by filtration, washed with H2O, and dried to give 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-phenylthiazole-4-carboxylic acid as a white solid (0.9 g, 64% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>N1C=CC=CC=1>[S:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])=[CH:17][CH:18]=1)([CH3:22])(=[O:21])=[O:20]
Reactant: Nc1ccc(C=C2C(=O)Nc3ncccc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C=C2C(=O)Nc3ncccc32)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a stirred solution of 3-(4-aminobenzylidene)-7-azaoxindol (2.373 g, 10 mmol) in pyridine (10 ml) was added gradually mesylchloride (1.146 g, 10 mmol) at 0°-5° C. under cooling. The reaction mixture was stirred for about 5 h at 0°-5° C. and then for 15 h at room temperature. The mixture was poured onto an ice-water mixture, the precipitate filtered off, the residue washed thoroughly with water and then chromatographed on silica gel using CHC3 -MeOH mixtures as eluant. Thus pure title compound was obtained in about 70% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:38])=[C:21]([NH:26][S:27]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=2[F:25])[CH:5]=[CH:4][N:3]=1.[NH4+:39].[OH-]>>[NH2:39][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:38])=[C:21]([NH:26][S:27]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=2[F:25])[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Agent: [OH-]
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2c(F)ccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 21 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,6-difluorobenzenesulfonamide (150 mg, 0.256 mmol) and NH4OH (2.5 mL, 17.97 mmol) heated in the microwave at 130° C. for 15 min the title compound was obtained as a light yellow solid (124 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (br. s., 1H), 7.90 (d, J=5.3 Hz, 1H), 7.60-7.74 (m, 1H), 7.49 (td, J=8.7, 6.1 Hz, 1H), 7.16-7.34 (m, 3H), 6.62 (s, 2H), 5.63 (d, J=5.3 Hz, 1H), 3.67-3.74 (m, 4H), 3.40-3.48 (m, 4H). MS (ESI): 566 [M+H]+.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][C@H:4]1[O:14][CH2:15][CH3:16])#[N:2].N.[H][H]>CO.[Ni]>[NH2:2][CH2:1][C@@H:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][C@H:4]1[O:14][CH2:15][CH3:16]
Reactant: CCOC(=O)N1CC[C@@H](C#N)[C@H](OCC)C1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOC(=O)N1CC[C@@H](CN)[C@H](OCC)C1
Yield: 27.4 %

Procedure:
A mixture of intermediate (13) (0.19 mol) in methanol saturated with NH3 (500 ml) was hydrogenated at 14° C. with Raney nickel as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The desired fractions were collected and the solvent was evaporated, yielding 12 g of ethyl (trans)-4-(aminomethyl)-3-ethoxy-1-piperidinecarboxylate (intermediate 14).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][O:3]1>Cl>[CH2:9]([O:8][CH2:7][CH:5]([CH2:4][OH:3])[OH:6])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCOCC1COC(C)(C)O1
Agent: Cl
Product: CCCCCCCCCCCCCCCCOCC(O)CO
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To compound 1a (3.363 g) was added 10% HCl solution (40 mL) and refluxed at 120° C. for 30 min. The reaction mixture was then kept at RT for 24 hours. The white lumps formed were filtered. The filtrate was extracted with hexane (50 mL, 2×) and the extracts added to the white lumps after removal of solvent. It was dried in a vacuum dessicator for 24 hours to obtain 2a which was quantitative. 1H NMR (in CDCl3): δ in ppm 0.83-0.87 (3H, m), 1.23 (26H, m), 1.52-1.55 (2H, m), 2.67 (1H, D2O exchangeable), 3.42-3.51 (4H, m), 3.60-3.70 (2H, m), 3.84-3.85 (1H, m), 6.63-6.70 (1H, D2O exchangeable); 13C NMR (in CDCl3): δ in ppm 14.6, 23.1, 26.5, 29.8, 29.9, 30.0, 30.1, 30.2, 32.4, 64.5, 71.0, 72.3, 72.9.