Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:33](I)[CH:34]=[CH2:35].[Cl-].[Na+]>C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC.O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:35][CH:34]=[CH2:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCI
Reactant: O=C(Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
Alternately, combine (S)-4-benzyl-3-phenylacetyl-2-oxazolidinone (8.0 g, 27 mmol) and tetrahydrofuran (50 mL). cool in a dry-ice/acetone bath. Add dropwise a solution of sodium hexamethyldisilazide (30 mL, 1.0 M in tetrahydrofuran, 30 mmol). After 30 minutes, add allyl iodide (9.1 g, 54 mmol) and then replace the bath with a dry-ice/carbon tetrachloride bath. After 1.5 hours, quench the reaction by the addition of a saturated aqueous sodium chloride solution, extract with diethyl ether, and separate the layers. Extract the aqueous layer three times with diethyl ether. Combine the organic layers, extract with an aqueous 1 M hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Dissolve in ethyl acetate, extract with a saturated aqueous sodium thiosulfate solution, dry the over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 10% ethyl acetate/hexane. Combine the product containing fractions, evaporate, and recrytallize from chloroform/hexane to give (S)-4-benzyl-3-(2-phenylpent-4-enoyl)-2-oxazolidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH:12]1[CH:17]=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=C[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C=C>C1COCC1>[CH2:17]([O:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[CH:12]=[CH2:13]
Reactant: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=CCO
Solvent: C1CCOC1
Product: C=CCOc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
To a mixture of 5-chloro-3-nitro-pyridin-2-ol (0.600 g, 3.4 mmol), DBAD (1.19 g, 5.16 mmol), triphenylphosphine-polymer supported (3 mmol/g, 1.70 g, 5.16 mmol) in THF (18 mL) was added allyl alcohol (0.42 mL, 6.12 mmol). The reaction mixture was stirred at room temperature overnight, filtered through celite, and concentrated. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (95:5 to 1:1) to give 0.120 g (15%) of the desired product. MS (DCI/NH3) m/z: 214.9 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 5.01 (ddd, J=5.34, 1.40, 1.40 Hz, 2 H) 5.32 (dd, J=10.51, 1.36 Hz, 1 H) 5.49 (dd, J=17.12, 1.53 Hz, 1 H) 6.06 (m, 1 H) 8.28 (d, J=2.37 Hz, 1 H) 8.34 (d, J=2.37 Hz, 1 H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:13]=[C:12]([NH:14]C(=O)C(C)C)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:20]2[CH2:24][C@H:23]([CH2:25][OH:26])[CH:22]=[CH:21]2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)(C)C>[CH:8]1[N:9]([C@H:20]2[CH:21]=[CH:22][C@@H:23]([CH2:25][OH:26])[CH2:24]2)[C:10]2[N:11]=[C:12]([NH2:14])[N:13]=[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)[C:6]=2[N:7]=1
Reactant: CC(C)C(=O)Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 22.5 °C
Yield: 89.8 %

Procedure:
A mixture of N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purin-2-yl}isobutyramide (10 g, 28 mmol), isopropanol (100 ml) and 10% solution of NaOH (16.8 ml, 42 mmol) was refluxed for 1 h. The resulting solution was cooled to 20-25° C. and washed several times with 25% solution of NaOH (10 ml). The wet organic layer was neutralized to pH 7.0-7.5 with 17% hydrochloric acid and it was concentrated to dryness under vacuum. The residue was crystallized in ethyl acetate (150 ml) to afford abacavir (7.2 g, 90%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[N:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:2][C:3]([N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8](=[O:16])[C:7]4[CH:17]=[CH:18][CH:19]=[N:20][C:6]3=4)=[O:4])[CH2:33][CH2:32]2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ncccc21
Reactant: C1CCN(CCCCC2CCNCC2)CC1
Product: O=C1Nc2ccccc2N(C(=O)CN2CCC(CCCCN3CCCCC3)CC2)c2ncccc21
Yield: 37 %

Procedure:
Prepared analogously to Example 1 from 11-(chloroacetyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 4-[4-(1-piperidinyl)butyl]piperidine in a yield of 37% of theory.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:19]([CH2:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([OH:25])=O)=[O:20])=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:44][C@@H:45]([CH2:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:46]([N:48]([CH3:64])[CH2:49][CH2:50][NH:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=1)=[O:53])=[O:47]>C(Cl)Cl>[C:40]([O:39][C:37]([NH:36][CH2:35][CH2:34][N:18]([CH2:17][CH2:16][NH:15][C:13]([O:12][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:14])[C:19]([CH2:21][C@H:22]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:23](=[O:25])[NH:44][C@H:45]([C:46](=[O:47])[N:48]([CH3:64])[CH2:49][CH2:50][NH:51][C:52]([C:54]1[CH:55]=[CH:56][C:57]([C:60]([F:62])([F:63])[F:61])=[CH:58][CH:59]=1)=[O:53])[CH2:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:20])=[O:38])([CH3:41])([CH3:43])[CH3:42]
Reactant: CN(CCNC(=O)c1ccc(C(F)(F)F)cc1)C(=O)[C@@H](N)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(CCNC(=O)c1ccc(C(F)(F)F)cc1)C(=O)[C@H](CCc1ccccc1)NC(=O)[C@H](CC(=O)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
A solution of CDMT (0.22 g, 1.26 mmol) in DCM (30 mL) was cooled to 0° C. before adding N-methylmorpholine (0.3 mL, 2.62 mmol). After 15 min, (2S)-3-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}propanoic acid CXXIV (0.62 g, 1.20 mmol) was added and the solution was stirred for additional 40 min. After that time, (2S)-2-amino-N-methyl-4-phenyl-N-(2-{[4-(trifluoromethyl)phenyl]formamido}ethyl)butanamide CXXIII (0.56 g, 1.26 mmol) was added and the mixture stirred at r.t. overnight. The mixture was washed with 1 M HCl (5×), 1 M K2CO3 (5×), brine and dried over MgSO4. The solvent was evaporated under vacuum and the residue was purified on a silica gel column (50:1 DCM/methanol) to give tert-butyl N-[(1S)-2-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-1-{[(1S)-1-[methyl(2-{[4-(trifluoromethyl)phenyl]formamido}ethyl)carbamoyl]-3-phenylpropyl]carbamoyl}ethyl]carbamate as yellow solid (0.78 g, 0.86 mmol, 68% yield). ESIMS found for C44H64F3N7O10 m/z 908 (M+H).
Reaction SMILES: C(N(CC)CC)C.C([SiH](CC)CC)C.[N:15]1([S:19]([C:22]2[CH:23]=[C:24](Br)[C:25]([O:28][C:29]3[CH:30]=[C:31]([CH:41]=[C:42]([O:44][C@@H:45]([CH3:49])[CH2:46][O:47][CH3:48])[CH:43]=3)[C:32]([NH:34][C:35]3[CH:39]=[CH:38][N:37]([CH3:40])[N:36]=3)=[O:33])=[N:26][CH:27]=2)(=[O:21])=[O:20])[CH2:18][CH2:17][CH2:16]1.CO>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:15]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]3[CH:30]=[C:31]([CH:41]=[C:42]([O:44][C@@H:45]([CH3:49])[CH2:46][O:47][CH3:48])[CH:43]=3)[C:32]([NH:34][C:35]3[CH:39]=[CH:38][N:37]([CH3:40])[N:36]=3)=[O:33])=[N:26][CH:27]=2)(=[O:21])=[O:20])[CH2:16][CH2:17][CH2:18]1
Reactant: COC[C@H](C)Oc1cc(Oc2ncc(S(=O)(=O)N3CCC3)cc2Br)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N3CCC3)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Reaction time: 0.25 h
Yield: 45.9 %

Procedure:
Triethylamine (0.025 mL, 0.18 mmol) then triethylsilane (0.96 mL, 6.03 mmol) were added to palladium (II)acetate (12 mg) in DCM (2 mL) and stirred under argon for 15 mins. 3-{[5-(Azetidin-1-ylsulfonyl)-3-bromopyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.175 g, 0.3 mmol) in DCM (2 mL) was added dropwise and the reaction stirred at RT for 24 hours. Methanol was added, the reaction filtered through celite and the solvent removed in vacuo. Ethyl acetate (30 mL) was added and the mixture washed with water (30 mL), citric acid (30 mL), brine (30 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a white solid. This was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in isohexane, to give the desired compound (69 mg).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([CH2:30][S:31](Cl)(=[O:33])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][S:31]([CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:33])=[O:32])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NS(=O)(=O)Cc3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Sulfonylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with α-toluenesulfonyl chloride (12 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (25 ml) was performed according to the acylation method described in example 6.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.[C:18]([O:21][C@@H:22]1[C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:43]([O:49][C:50](=[O:52])[CH3:51])[C@@H:42]([CH2:53][O:54][C:55](=[O:57])[CH3:56])[O:41][C@H:23]1OC1C=CC=CC=1C(C)C1C=CC(C#N)=CC=1)(=[O:20])[CH3:19]>>[C:18]([O:21][C@@H:22]1[C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:43]([O:49][C:50](=[O:52])[CH3:51])[C@@H:42]([CH2:53][O:54][C:55](=[O:57])[CH3:56])[O:41][C@H:23]1[O:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)(=[O:20])[CH3:19].[O:1]([C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)[C@@H:23]1[O:41][C@H:42]([CH2:53][OH:54])[C@@H:43]([OH:49])[C@H:44]([OH:45])[C@H:22]1[OH:21]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2ccccc2C(C)c2ccc(C#N)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#CCc1ccc(Cc2ccccc2O)cc1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(CC#N)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: N#CCc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1

Procedure:
2-(4-Cyanomethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside was prepared in a similar manner to that described in Reference Example 8 using 4-(2-hydroxybenzyl)-phenylacetonitrile instead of methyl 4-(2-hydroxybenzyl)-benzoate. Then the title compound was prepared in a similar manner to that described in Example 2 using 2-(4-cyano-methylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside instead of 2-(4-methoxycarbonylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C1(C)C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:19]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Temperature: 80 °C

Procedure:
A mixture of 10 g. (0.065 mol) of 2-amino-4-nitrophenol, 125 ml. of dry toluene and 25 ml. of glacial acetic acid is heated to affect solution. Acetic anhydride (7.57 g., 0.074 mol) is added dropwise over a period of twenty minutes and the resulting mixture is heated at about 80° C. for two hours. The reaction mixture is filtered and the solid is washed with toluene, then recrystallized from methanol to give 2-acetamido-4-nitrophenol, m.p. 283°-284° C.
Reaction SMILES: [H-].[Na+].CN(C)P(=O)(N(C)C)N(C)C.[O:14]=[C:15]1[C@@H:21]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[CH2:20][S:19][CH2:18][C@@H:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:16]1.Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C)C=O.C(OCC)(=O)C>[O:14]=[C:15]1[C@@H:21]([N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[CH2:20][S:19][CH2:18][C@@H:17]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:16]1[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1N[C@H](c2ccccc2)CSC[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N2C(=O)c3ccccc3C2=O)CSC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.6 %

Procedure:
270 mg of a 50% w/w suspension of sodium hydride in mineral oil were added to a solution containing 5 ml of hexamethylphosphoric triamide and 1.9 g of 5-oxo-3(R)-phenyl-6(R)-phthalimidoperhydro-1,4-thiazepine [prepared as described in step (e) above] dissolved in 20 ml of dimethylformamide, and the mixture was stirred for 5 minutes at room temperature, 1.8 g of t-butyl bromoacetate was then added to the mixture. The resulting mixture was stirred for 1 hour at room temperature, after which a further 0.2 g of a 55% w/w suspension of sodium hydride in oil and 1 g of t-butyl bromoacetate were added. The mixture was stirred for a further 1 hour at room temperature. Ethyl acetate was then added to the mixture, and the mixture was washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate, after which the solvent was distilled off. The residue was subjected to silica gel column chromatography, using a 1:40 by volume mixture of ethyl acetate and methylene chloride as eluent, to give 1.65 g of the title compound as an amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:17])[C:14](O)=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:17])[C:14]([Cl:21])=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)C(=O)O)cc(OC)c1OC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)C(=O)Cl)cc(OC)c1OC

Procedure:
A stirred suspension of 3,4,5-trimethoxyphenyl-2-oxoacetic acid (1.60 g, 6.66 mmoles) in dry methylene chloride (26 mL) at room temperature was treated with 2M oxalyl chloride in methylene chloride (14 mL, 4 equiv.) and dry dimethylformamide (1 drop). After 3 h the solvents were evaporated. The residue was flushed with dry methylene chloride (3×50 mL) and dried in vacuo for 2 h during which time a solid formed. The crude acid chloride was carried on without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24](I)[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:38](=[N:41][OH:42])([NH2:40])[CH3:39].[CH3:43]N(C)C=O>C(N(CC)CC)C.C(OCC)(=O)C.Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([C:43]3[O:42][N:41]=[C:38]([CH3:39])[N:40]=3)[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(I)c(Cl)cc3[nH]c2=O)c1
Reactant: CC(N)=NO
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(-c4nc(C)no4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-iodo-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (EXAMPLE 4.2 Step B, 200 mg in a mixture of 3 mL dry N,N-dimethylformamide and 0.9 mL triethylamine) was added 118 mg of acetamide oxime followed by 11 mg of dichlorobis(triphenylphosphine) palladium (II) and the mixture heated to reflux on an oil bath under an atmosphere of carbon monoxide. After 12 hours, the mixture was cooled to room temperature and diluted with ethyl acetate and 0.5N hydrochloric acid. This was extracted with ethyl acetate and the organic portion washed with brine then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 1:4; then 3:7) gave the title compound (88 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18]C3C=NC=CC=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].Br[C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Fc1cc(F)cc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)c(C)n2)n1
Product: Cc1ccc(Nc2cc(F)cc(F)c2)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide (example 11) in accordance with the general method of example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=373.1 (M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([CH2:30][OH:31])[CH2:29][CH2:28]1>>[CH:27]1([CH2:30][O:31][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:29][CH2:28]1
Reactant: OCC1CC1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCC3CC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.193 mmol), intermediate 42.1, and cyclopropylmethanol (58 mg; 0.773 mmol), example 55 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](CC(N3CCOCC3)=S)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:19]([OH:22])(=[O:21])[CH3:20].S(=O)(=O)(O)O>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:20][C:19]([OH:22])=[O:21])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: S=C(Cc1ccc2c(c1)CCO2)N1CCOCC1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)CCO2

Procedure:
2,3-dihydrobenzofuran-5-ylthioacetic acid morpholide (5.0 g) was heated at reflux in a solution of acetic acid (20 ml), concentrated sulfuric acid (3.0 ml) and water (4.5 ml). After 3 hours the reaction mixture was cooled and added to water. The product was extracted with ethyl acetate and the combined extracts washed five times with water. The organic solution was then extracted with aqueous saturated sodium bicarbonate solution. The aqueous solution was then acidified and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated to give a residue which was recrystallized from acetone/hexane to give 2,3-dihydrobenzofuran-5-ylacetic acid, m.p. --96°-98° C.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=[O:15])=[CH:12][NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH:18](Br)([CH3:20])[CH3:19].C(O)(=O)C>CN(C)C=O.O>[CH:18]([N:11]1[CH:12]=[C:13]([CH:14]=[O:15])[C:9]([C:7]2[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:10]1)([CH3:20])[CH3:19]
Reactant: CC(C)Br
Reactant: O=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)n1cc(C=O)c(-c2ccc([N+](=O)[O-])o2)n1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Add 10 g of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde to a suspension of 1.6 g of 80% sodium hydride in 100 ml of dimethylformamide under nitrogen at 10° to 20° C. Add 7.1 g of isopropyl bromide to the resulting admixture and then stir it for 4 hours at 40° C and 7 hours at 50° C. Mix 0.8 ml of glacial acetic acid therein to obtain (after addition to 190 g of ice and water) 8.9 g of product. Recrystallize three times from dimethylformamide and water to obtain 1-isopropyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde [m.p. 168.5° to 170.5° C]. Evaporate the mother liquor and chromatograph the residue to obtain 1-isopropyl-5-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:6]=1[O:13][CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:3])[CH3:2].P([O-])(O)(O)=[O:19].[Na+].OO.Cl([O-])=O.[Na+]>C(#N)C.O.C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[O:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:19])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C=O)ccc1OCC(C)C
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(C(=O)O)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
In 38 ml of acetonitrile is dissolved 4.1 g of 5-formyl-2-isobutoxyphenyl acetate. To the solution thus obtained, 6.8 g of sodium dihydrogenphosphate dissolved in 20 ml of water and 3.6 ml of 30% aqueous hydrogen peroxide are successively added at ambient temperature, and then 3.6 g of sodium chlorite dissolved in 18 ml of water is dropwise added at 5-10° C. The mixture thus obtained is stirred at ambient temperature for 2 hours. Chloroform and water are added to the reaction mixture, the organic layer is separated, the organic layer thus obtained is washed successively with 5% aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 4.0 g of 3-(acetyloxy)-4-isobutoxybenzoic acid is obtained as a light yellow solid product.