Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:3]=1[NH2:16].S1C=CC=C1.[O-2].[Ca+2].[H][H]>CO.[Pd]>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:4]1[C:3]([NH2:16])=[CH:2][N:7]=[CH:6][N:5]=1
Reactant: [H][H]
Reactant: Nc1c(Cl)ncnc1NCc1ccccn1
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Solvent: c1ccsc1
Product: Nc1cncnc1NCc1ccccn1
Yield: 100 %

Procedure:
A mixture of 62.2 parts of 6-chloro-N4 -(2-pyridinylmethyl)-4,5-pyrimidinediamine, 3 parts of a solution of thiophene in methanol 4%, 20 parts of calcium oxide and 400 parts of methanol was hydrogenated at normal pressure and at 50° C. with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 63.5 parts (100%) of N4 -(2-pyridinylmethyl)-4,5-pyrimidinediamine as a residue (interim. 15).
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([OH:13])=[O:12].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([CH:6]1[CH2:9][O:10][CH:18]([C:17]2[CH:20]=[CH:21][C:14]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)[O:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCC1COC(c2ccc(C(=O)O)cc2)OC1
Yield: 80.9 %

Procedure:
A mixture of 2-n-pentylpropane-1,3diol (8 g, 0.054 m), 4-carboxybenzaldehyde (8 g, 0.053 m), benzene (200 ml) and a catalytic amount of 4-toluenesulfonic acid was azeotropically refluxed until no more water was collected. The cold reaction mixture was washed with saturated NaHCO3 solution and water and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was crystallized from ethanol to yield 4-(5-n-pentyl-1,3-dioxan-2-yl) benzoic acid (12 g, 80%)
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]O>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[O:23][CH3:22])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: COc1ccccc1CO
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Product: COc1ccccc1CN1C(=O)C(CCO)Oc2ccccc21

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by methods F and G, alkylating with the methanesulfonate ester of 2-methoxybenzyl alcohol, in 47% overall yield as a light yellow gum after flash chromatography, eluting with EtOAc/hexanes, IR (Neat) 3436, 2941, 1583, 1683, 1501, 1466, 1403, 1281, 1246, 1113, 1052, 751 cm-1 ; 1H NMR (CDCl3) δ 2.18-2.36 (m, 2H), 2.39 (br t, J=6.0 Hz, 1H), 3.90 (s, 3H), 3.92 (br q, J=5.5 Hz, 2H), 4.85 (dd, J=7.4, 5.7 Hz, 1H), 5.15 (s, 2H), 6.81-7.03 (m, 7H), 7.23 (td, J=8.3, 1.7 Hz, 1H); MH+ at m/z=314; Anal. Calc'd for C18H19NO4.0.2 H2O: C, 68.21; H, 6.17; N, 4.42. Found: C, 68.36; H, 6.18; N, 4.36.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37]>>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([N:23]1[CH2:24][CH2:25][CH:20]([N:18]2[C:17](=[O:26])[C:16]([CH3:28])([CH3:27])[C:15]([C:7]3[C:8]4[CH2:9][C:10]([CH3:14])([CH3:13])[O:11][C:12]=4[C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)=[N:19]2)[CH2:21][CH2:22]1)(=[O:38])=[O:37]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4F)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5*HCl) and 2-fluorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([C:3]([O:2][CH3:1])([CH3:4])[CH3:5])=[CH:14][CH:13]=2)=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: COC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(C)(C)c1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
To a solution of 4-(2-methoxypropan-2-yl)benzoic acid (0.09 g, 0.46 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.23 g, 0.61 mmol) in dichloromethane (10 mL) was added triethylamine (0.15 g, 1.5 mmol). The reaction mixture was stirred for 15 minutes at room temperature, then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.08 g, 0.53 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water (20 mL), concentrated and purified by column chromatography (silica gel:dichloromethane:methanol=30:1) to give the pure product N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(2-methoxypropan-2-yl)benzamide (0.09 g, 61%) as a white solid. LRMS (M+H+) m/z: calcd for 328.18. found 328. HPLC Purity (214 nm) 99.8%. 1H NMR (300 MHz, DMSO-d6) δ: 11.47 (s, 1H), 8.32 (d, J=1.5 Hz, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 5.86 (s, 1H), 4.30 (d, J=4.8 Hz, 2H), 2.97 (s, 3H), 2.17 (s, 3H), 2.11 (s, 3H), 1.44 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:22][O:23]/[N:24]=[C:25](/[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1)\[CH2:26]Br.Cl>CS(C)=O>[CH2:34]([C:31]1[CH:32]=[CH:33][C:28]([C:25](=[N:24][O:23][CH3:22])[CH2:26][O:1][C:2]2[CH:15]=[CH:14][C:5]([CH2:6][CH:7]3[S:11][C:10](=[O:12])[NH:9][C:8]3=[O:13])=[CH:4][CH:3]=2)=[N:29][CH:30]=1)[CH3:35]
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: CCc1ccc(/C(CBr)=N/OC)nc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1ccc(C(COc2ccc(CC3SC(=O)NC3=O)cc2)=NOC)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (210 mg, 0.941 mmol) in DMSO was added potassium tert-Butoxide (227 mg, 2.02 mmol) in a single portion. Stirred at RT for 15 minutes. Added a solution of (1Z)-2-bromo-1-(5-ethylpyridin-2-yl)ethanone O-methyloxime (242 mg, 0.941 mmol; Supplier=Kalexsyn; Lot=1003-TTP-186) in DMSO (2 ml). Added 1M HCl until pH of mixture was about 3. Extracted with EtOAc. The extract was washed with water, dried (Na2SO4), filtered and evaporated in vacuo to give an off-white foam. 278 mg. 1H-NMR (DMSO-d6): δ12.05 (brs, 1H), 8.47 (d, J=1.7 Hz, 1H), 7.77 (m, 1H), 7.70 m, 1H), 7.14 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 5.17 (s, 2H), 4.87 (dd, J=8.9, 4.4 Hz, 1H), 4.01 (s, 3H), 3.30 (dd, J=14.2, 4.5 Hz, 1H), 3.06 (dd, J=14.1, 9.1 Hz, 1H), 2.64 (q, J=7.7 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H). HPLC: 3.103 min., 82 area % and 3.379 min., 18 area % @254 nm; 3.109 min., 91 area % and 3.379 min., 9 area % @ 254 nm. MS (ESI—) for C20H21N3O4S m/z 400.3 (M+H)+: m/z 398.3 (M−H)−
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:13][C:12]=1[CH3:34])([CH3:6])([CH3:5])[CH3:4].CI.[CH3:38]COC(C)=O>CN(C=O)C>[C:3]([O:7][C:8](=[O:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[N:22]([CH3:38])[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:13][C:12]=1[CH3:34])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3N(C)c3ccccc32)ccc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
Sodium hydride (14 mg, 0.34 mmol) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid tert-butyl ester from Example E45 (125 mg, 0.28 mmol) in DMF (2 ml) at 0° C. The mixture was stirred for 20 min at room temperature then cooled down to 0° C. Methyl iodide (0.09 ml, 1.4 mmol) was added and the mixture was stirred for 20 h at room temperature. EtOAc was added and the mixture was washed with 0.3M KHSO4 then brine, dried, concentrated in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (46 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH:19]=[C:13]2[CH:14]=[N+:15]([O-])[CH:16]=[CH:17][C:12]2=[N:11]1.P(Cl)(Cl)([Cl:22])=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:22][C:14]1[C:13]2=[CH:19][N:10]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=3[Cl:9])[N:11]=[C:12]2[CH:17]=[CH:16][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc2nn(-c3c(Cl)cc(F)cc3Cl)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Fc1cc(Cl)c(-n2cc3c(Cl)nccc3n2)c(Cl)c1
Temperature: 85 °C
Yield: 47 %

Procedure:
2-(2,6-Dichloro-4-fluorophenyl)-2H-pyrazolo[4,3-c]pyridine-5-oxide (1.4 g, 4.7 mmol) was slowly added to phosphorous oxychloride (10 mL). Tetrabutylammonium chloride (1.31 g, 4.7 mmol) was then added and the reaction mixture was heated at 85° C. for 45 minutes. The mixture was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and sodium hydrogen carbonate. The organic layer was washed with sodium hydrogen carbonate (sat. aq.) and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (10-20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (706 mg, 47% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.28 (s, 1H), 8.11 (d, J=6.3 Hz, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.72 (d, J=6.3 Hz, 1H).
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([O:52][Si](C(C)(C)C)(C)C)[CH:47]=2)=[O:43])[CH:39]=[C:38]([CH3:60])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([OH:37])=[O:36])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])=[O:23]>O1CCCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([OH:52])[CH:47]=2)=[O:43])[CH:39]=[C:38]([CH3:60])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([O:37][CH3:2])=[O:36])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])=[O:23]
Reactant: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(Cl)c1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
Tetra-n-butylammonium fluoride (1 M in tetrahydrofuran; 3.4 mL, 3.4 mmol) was added to a solution of N-[2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine (2.0 g, 3.1 mmol) in tetrahydrofuran (10 mL). The solution was stirred at room temperature for 20 min, then diluted with ethyl acetate and washed with water and then brine. The solution was dried (MgSO4), filtered, evaporated, concentrated, evaporated, dried overnight under high vacuum and then crystallized from methanol to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (1.06 g) as a solid. The mother liquors were concentrated and chromatographed (70% ethyl acetate/hexanes then methanol/ethyl acetate/hexanes 10:133:57) to give a further portion of the product (0.16 g). The overall yield was 1.22 g (74%).
Reaction SMILES: [O-]CC.[Na+].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1.[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22]>C(O)C.O1CCCC1>[CH2:22]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: C=CCCCCCCBr
Reactant: OCCc1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCCCCCCOc1ccc(CCO)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Sodium ethoxide (4.98 g) was added to a solution (240 ml) of 2-(4-hydroxyphenyl)ethyl alcohol (8.68 g) in absolute ethanol and the mixture was stirred at 50° C. for 30 minutes. A solution of 7-octenyl bromide (10 g) in anhydrous tetrahydrofuran was dropwise added thereto and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was concentrated, poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel chromatography (eluent; ethyl acetate:hexane=1:5) to give the subject compound (10.76 g) as an oily substance.
Reaction SMILES: [C:1]1([S:7](NC2SC3CCCCC=3C=2C(OCC)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:25][C:26]1[S:30][C:29]2[CH2:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH2:34][C:28]=2[C:27]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38].C1(S(Cl)(=O)=O)C=CC=CC=1>>[CH3:36][C:33]1([CH3:35])[CH2:32][CH2:31][C:29]2[S:30][C:26]([NH:25][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[C:27]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:28]=2[CH2:34]1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: CCOC(=O)c1c(N)sc2c1CC(C)(C)CC2
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CC(C)(C)CC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-5,5-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (prepared according to Pinkerton et al., Bioorg. Med. Chem. Lett., 2007, 17, 3562-3569) and benzenesulphonyl chloride.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[S:22](N)([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:24])=[O:23].CN([N+]1C=CC=CC=1)C.C(N(CC)CC)C>C(#N)C>[C:29]([O:28][C:26](=[O:27])[NH:25][S:22]([NH:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)[CH:20]=[CH:19]2)(=[O:24])=[O:23])([CH3:32])([CH3:30])[CH3:31]
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CC(C)(C)OC(=O)NS(N)(=O)=O
Agent: CN(C)[n+]1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NS(=O)(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
(R)—N2-Indan-1-yl-quinoline-2,6-diamine (0.09 g, 0.33 mmol) and dimethylamino pyridinium N-tert butoxycarbonyl sulfamide (0.12 g, 0.36 mmol) were dissolved in acetonitrile (2.0 mL). After addition of triethylamine (0.05 mL, 0.36 mmol) the reaction mixture was heated to reflux for 16 h. The solvent was removed and the residue subjected to column chromatography (silica gel, heptane/ethyl acetate=9:1/4:1/1:1). The title compound was obtained as a yellow solid (15 mg; 10%); MS: m/e=455.7 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=O)[CH2:7][CH2:6][O:5][CH2:4]1.C([O-])=O.[NH4+:13]>[Pd].O.CO>[CH3:1][O:2][C@H:3]1[C@@H:8]([NH2:13])[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: [NH4+]
Reactant: COC1COCCC1=O
Agent: [Pd]
Agent: O=C[O-]
Solvent: O
Solvent: CO
Product: CO[C@@H]1COCC[C@@H]1N
Yield: 50.8 %

Procedure:
A slurry of 3-methoxy-tetrahydro-pyran-4-one (0.4 g, 3 mmol—described in WO03/093266(A1)), ammonium formate (1.9 g, 30 mmol), 10% palladium on charcoal (1 g) in water:MeOH (1:5, 6 ml) was stirred overnight after which time it was filtered through Hyflo, the mixture concentrated to remove the MeOH, the residue taken up in Et2O, dried (Na2SO4) and concentrated to afford the title product (0.2 g, 49%) as a yellow oil (contaminated by 10-20% of the trans isomer). 1H NMR (300 MHz, CDCl3) (cis isomer) δ 1.60-1.80 (2H, m), 2.95-3.00 (1H, m), 3.22-3.43 (5H, m). 3.82-3.95 (1H, m), 4.01-4.13 (1H, m).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([OH:22])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[C:39](Cl)=[O:40]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([O:22][C:39](=[O:40])[C:38]2[CH:37]=[C:36]([O:35][CH3:34])[C:44]([O:45][CH3:46])=[C:43]([O:47][CH3:48])[CH:42]=2)[CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C(C)(C)C)c(O)c1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: COc1cc(C(=O)Oc2cc(C(=O)CNC(C)(C)C)ccc2OC(=O)C(C)(C)C)cc(OC)c1OC

Procedure:
Following a procedure similar to that described in Example 30A above, when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with 3,4,5-trimethoxybenzoyl chloride there is obtained 3-(3,4,5-trimethoxybenzoyloxy)-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3-(3,4,5-trimethoxybenzoyloxy)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9](C(O)=O)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.[Br:19]NC(=O)CCC(N)=O>CN(C)C=O.C(OCC)(=O)C>[Br:19][C:9]1[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:12][N:11]2[CH2:13][CH2:14][CH2:15][C:10]=12
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1cccc(-c2nn3c(c2C(=O)O)CCC3)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nn3c(c2Br)CCC3)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (1.4 g, 5.8 mmol) in N,N-dimethylformamide (20 mL) is treated with N-bromosuccinamide (1 g, 5.6 mmol) and stirred at room temperature for 16 h. The mixture is diluted with ethyl acetate and washed three times with water, once with brine, dried (sodium sulfate), filtered, and concentrated in vacuo to yield the title compound, 1.5 g (94%), as light yellow solid.
Reaction SMILES: B(O)(O)O.[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:16].O>C1(C)C(C)=CC=CC=1>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([C:15](/[CH:14]=[CH:5]/[C:6]2[CH:13]=[CH:12][CH:11]=[C:8]([CH3:9])[CH:7]=2)=[O:16])=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cccc(C=O)c1
Agent: OB(O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1cccc(/C=C/C(=O)c2ccc([N+](=O)[O-])cc2)c1
Reaction time: 8 h

Procedure:
10 g of boric acid are added to a solution of 76 g (0.63 mole) of 3-methylbenzaldehyde and 104.5 g (0.63 mole) of 4-nitroacetophenone in 1 l of xylene, and the mixture is refluxed for 8 hours under a water separator. A further 5 g of boric acid are added, after which the mixture is boiled for a further 8 hours. This process is repeated until the theoretical amount of water has been separated off (2-3 times). The cooled reaction mixture is filtered under suction and the residue is washed with toluene and dried under reduced pressure to give 131 g (77% of theory) of a yellowish brown powder of melting point 130°-132° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:7][N:8]=[C:9]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=1)[C:10]([NH:12][CH:13]1[C:31](=[O:32])[N:15]2[C:16]([C:28]([O-:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]3[N:26]([CH3:27])[N:25]=[N:24][N:23]=3)[CH2:18][S:19][C@H:14]12)=[O:11].[Na+]>O.N1C=CC=CC=1>[CH2:5]([O:4][C:2]([O:7][N:8]=[C:9]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=1)[C:10]([NH:12][CH:13]1[C:31](=[O:32])[N:15]2[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]3[N:26]([CH3:27])[N:25]=[N:24][N:23]=3)[CH2:18][S:19][C@H:14]12)=[O:11])=[O:3])[CH3:6]
Reactant: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3cccc(O)c3)[C@H]2SC1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1cccc(O)c1
Yield: 52.5 %

Procedure:
Ethyl chloroformate (10.9 g.) was dropwise added by small portions with stirring and ice-cooling to a solution of sodium 7-[2-hydroxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (16.3 g.) in a mixture of water (80 ml.) and pyridine (80 ml.), and the mixture was stirred for 1 hour at the same temperature. Water (200 ml.) was added thereto and the mixture was washed with ether. The aqueous layer was adjusted to pH 2 with hydrochloric acid and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and with a sodium chloride aqueous solution and dried over magnesium sulfate. After treating with activated charcoal, the solvent was distilled off and the residual oil was pulverized with a mixture of diisopropyl ether and ether. The powder was collected by filtration, dried and suspended in water (150 ml.). To the suspension was added sodium bicarbonate (1.7 g.). The solution was adjusted to pH 6 with dilute hydrochloric acid and treated with activated charcoal. Dilute hydrochloric acid was added thereto with cooling and stirring and precipitates were collected by filtration, washed with water and dried to give 7-[2-ethoxycarbonyloxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (9.4 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[F:9]
Reactant: Fc1ccc(F)c(Cl)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a stirred solution of 1-chloro-2,5-difluorobenzene (0.770 g, 5.18 mmol) in concd H2SO4 (8.0 mL) at 0° C., KNO3 (0.525 g, 5.19 mmol) was added in one lot. The resulting yellow solution was allowed to warm to room temperature and stirred overnight at room temperature. It was then poured into ice (80 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous Na2SO4, removed under vacuum and the residue was dried further under vacuum to afford 0.845 g (85%) of title compound as a yellow liquid; 1H NMR (CDCl3) δ 7.43 (dd, 1 H, J1 =9.6 Hz, J2 =6.0 Hz), 7.93 (t, 1 H, J=7.2 Hz).