Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[C:18]([F:22])=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH:30](=O)[CH2:31][CH2:32][CH2:33]C.OO>O.S(=O)(=O)(O)O>[CH2:30]([C:21]1[C:20]2[CH:19]=[C:18]([F:22])[C:17]([F:23])=[CH:16][C:15]=2[N:14]=[C:13]2[C:24]3[N:10]([CH2:11][C:12]=12)[C:9](=[O:27])[C:8]1[CH2:7][O:6][C:5](=[O:28])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:29])[C:26]=1[CH:25]=3)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCC=O
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(F)c(F)cc3nc2-1
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: CCCCc1c2c(nc3cc(F)c(F)cc13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product of Stage 95d (100 mg; 0.25 mmol) is dissolved in a mixture of water (1.33 ml) and sulphuric acid at 95% (1 ml). Heptahydrated iron (III) sulphate (28 mg; 0.10 mmol); valeraldehyde (0.17 ml; 1.60 mmol) are added to this solution and the resulting solution is cooled down with an ice bath. The reaction medium is then treated dropwise with hydrogen peroxide at 30% (0.38 ml; 1 mmol); agitated for 5 hours at ambient temperature, then diluted with water (50 ml) and extracted with dichloromethane (4×50 ml). The combined extracts are washed with water and with a saturated aqueous solution of sodium chloride, then dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography at medium pressure (SiO2, MeOH/CH2Cl2, 5/95) in order to produce the expected solid (m.p.>275° C.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH2:23][CH3:24])[CH:4]=1.[OH:25][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:23]([O:22][C:5]1[CH:4]=[C:3]([CH:21]=[CH:20][C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[O:12][C:13]=1[CH3:14])[CH2:2][O:25][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1)[CH3:24]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: CCOc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a mixture of 4-(4-chloromethyl-2-ethoxyphenoxy)methyl-5-methyl-2-(2-furyl)-1,3-oxazole (0.56 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.25 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.06 g) at room temperature. After stirring the reaction mixture at room temperature for 30 min, the mixture was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (0.56 g, yield 86%) from a fraction eluted with tetrahydrofuran-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 149-150° C.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[S:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].C(O)C>O>[OH:12][CH2:11][C:9]1[S:10][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CO)s1
Reaction time: 0.67 h
Yield: 49.4 %

Procedure:
Sodium borohydride (0.24 g) was added to a mixture of 5-nitro-2-thiophenecarboxaldehyde (1.0 g) and ethanol (30 ml) at 0° C. and then this mixture was stirred at the same temperature for 40 minutes. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was washed with water and dried (MgSO4), after which the solvent was evaporated off, to yield 2-hydroxymethyl-5-nitrothiophene (0.5 g, 49%).
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[OH:14])[CH2:9][CH2:8]1)=O)C>FC(F)(F)C(O)=O>[NH:7]1[CH2:12][CH2:11][CH:10]([CH:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[OH:14])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2cccnc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: OC(c1cccnc1)C1CCNCC1
Temperature: 0 °C

Procedure:
Trifluoroacetic acid (100 mL) was cooled to 0° C. and added to a flask containing 1-(1,1-dimethylethyl-oxycarbonyl)piperidin-4-yl-pyridin-3-ylmethanol (20.4 g, 69.77 mmol). Vigorous gas evolution was observed. The mixture was stirred at 0° C. until judged complete by TLC. The excess trifluoroacetic acid was removed in vacuo, and the resulting residue was dissolved in water (50 mL). The aqueous solution was cooled to 0° C. and basified to pH~ 12 by addition of sodium hydroxide pellets. The product was isolated by extraction of the aqueous solution with dichloromethane (10×100 mL). The dichloromethane was evaporated to leave the title compound as an off white solid (12.06 g, 62.73 mmol, 90%). 1H NMR(d6 -DMSO): δ8.45 (m, 2H, H--C(2'), H--C(6')), 7.66 (brd, J=7.8 Hz, 1H, H--C(4')), 7.34 (dd, J=4.8, 7.8 Hz, 1H, H--C(3')), 4.29 (d, J=6.7 Hz, 1H, CHOH), 2.67 (m, 2H, eq-H--C(2)), 2.27 (m, 2H, ax-H--C(2)), 1.70 (br, 1H, NH), 1.52 (m, 1H, H--C(4)), 1.10-1.00 (m, 4H, H--C(3)).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[O:6][C@H:5]([CH2:7][O:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([C:19](O)=[O:20])[CH:17]=3)[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:11]=2)[CH2:4][O:3]1.CN1CCOCC1.Cl.[CH3:39][NH:40][OH:41]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1([CH3:30])[O:6][C@H:5]([CH2:7][O:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([C:19]([N:40]([OH:41])[CH3:39])=[O:20])[CH:17]=3)[N:12]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH:11]=2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](COCc2cn(Cc3ccc(F)cc3)c3cnc(C(=O)O)cc23)O1
Reactant: CNO
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CN(O)C(=O)c1cc2c(COC[C@@H]3COC(C)(C)O3)cn(Cc3ccc(F)cc3)c2cn1
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a solution of 3-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}methyl)-1-(4-fluorobenzyl)-1H -pyrrolo[2,3-c]pyridine-5-carboxylic acid (200 mg 0.4828 mmol) in anhydrous DMF (10 mL) was added CDMT (102 mg 0.5793 mmol 1.2 eq.) and NMM (0.064 mL, 0.5793 mmol 1.2 eq.). The mixture, under nitrogen, was stirred for 2 hours, during which it slowly darkened to a deep orange. N-Methylhydroxylamine Hydrochloride (202 mg 2.414 mmol 5.0 eq) was added and stirring continued for 10 hours. The reaction was judged to be complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. This oil was dissolved in EtOAc (30 mL) and washed with water (3×20 mL) and brine (20 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to afford the crude product which was purified by prep HPLC to give 95 mg (44%) of 3-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy)methyl)-1-(4-fluorobenzyl)-N -hydroxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide as a white powder. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, ESI, +mode): RT—2.278 min, m/e=444.2 (M+H+, base). 1H-NMR (400 MHz, CDCl3): δ=1.34 (s, 3H), 1.38 (s, 3H), 3.52 (m, 4H), 3.62 (m, 1H), 3.67 (m, 1H), 4.04 (m, 1H), 4.32 (m, 1H) 4.77 (q, 2H), 5.38 (s, 2H), 7.06 (m, 2H), 7.16 (m, 2H), 7.43 (s, 1H), 8.47 (s, 1H), 8.64 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]Br>C(Cl)(Cl)Cl>[Br:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: BrBr
Reactant: Nc1cccc(Cl)n1
Solvent: ClC(Cl)Cl
Product: Nc1nc(Cl)ccc1Br
Reaction time: 8 h
Yield: 26.7 %

Procedure:
6-Chloro-pyridin-2-ylamine (5 g, 38.89 mmol) is dissolved in chloroform (250 mL) and a solution of bromine (1.33 mL, 26 mmol) in chloroform (50 mL) is slowly added over a one hour period. During the addition a precipitate (hydrobromide salt of the starting material) forms. After stirring overnight the reaction mixture is filtered, the filtrate is evaporated and the residue is partitioned between ethyl acetate and 1 M sodium carbonate solution. The organic phase is separated, evaporated and the solid residue purified by flash chromatography (silica gel, 15% ethyl acetate in petroleum ether) affording the title compound (1.44 g, 17%) as a solid. The material is carried through the next three reaction steps.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:16][O:15][CH2:14]1)[C:5]([O:7]C)=[O:6].[OH-].[K+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:14][O:15][CH2:16]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC2COC2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OC2COC2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Crude methyl 3-fluoro-4-(oxetan-3-yloxy)benzoate from Step 1, MeOH (1 mL), and KOH (4.0 mL of 3.0 M, 12 mmol) were combined and the mixture was allowed to stir for 3 h at rt. The mixture was extracted with EtOAc and the organic layer was discarded. The aqueous layer was then treated with 1N HCl and the pH was adjusted to pH 3. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were dried over sodium sulfate and the solvent was removed. The crude acid was used without further purification. ESI-MS m/z calc. 212.1, found 213.0 (M+1)+; Retention time: 1.65 minutes (4 min run).
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:27])=[CH:29][CH:30]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc([N+](=O)[O-])cc12
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc([N+](=O)[O-])cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a mixture of 4-{[cyclohexyl(3-methyl-5-nitro-1-benzofuran-2-yl)methyl]amino}benzoic acid (1.54 g) synthesized above, ethyl 3-(methylamino)propanoate (593 mg), 1-hydroxybenzotriazole monohydrate (692 mg), triethylamine (1.26 mL) and N,N-dimethylformamide (15 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (867 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (1.41 g, 72%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.II.[I:22](O)(=O)(=O)=O>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[I:22]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: COC(=O)c1cc(N)c(F)c(-c2ccc(Cl)cc2)n1
Agent: II
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)c(F)c(N)c1I
Yield: 234 %

Procedure:
A 250 mL round bottom flask was loaded with methyl 4-amino-6-(4-chlorophenyl)-5-fluoropicolinate (25 g, 0.08906 mol), iodine (18 g, 0.07125 mol), and periodic acid (H5IO6; 7.3 g, 0.03206 mol). CH3OH (100 mL) was added. The reaction mixture was stirred at reflux for 16 h. The reaction mixture was concentrated under vacuum and then dissolved in Et2O (500 mL). The ether solution was washed with 10% sodium thiosulfate (3×100 mL), water (3×100 mL) and then brine. The organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give an orange solid. Crystallisation from EtOAc-hexane (3:7) gave a pale orange solid (30.5 g, 83%): mp 113.7-115.2° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 6.73 (br s, 2H), 3.87 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 167.50, 151.48 (d, JF-C=5 Hz), 145.95 (d, JF-C=13 Hz), 144.05 (d, JF-C=257 Hz), 140.75 (d, JF-C=9 Hz), 134.56, 133.42 (d, JF-C=5 Hz), 130.63 (d, JF-C=6 Hz), 129.02, 112.44 (d, JF-C=5 Hz), 77.52, 53.05; 19F NMR (376.5 MHz, DMSO-d6) δ −140.62; ESIMS m/z 407 ([M]+). Anal. Calcd. For C13H9ClFIN2O2: C, 38.40; H, 2.23; N, 6.89. Found: C, 38.40; H, 2.31; N, 6.85.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:4].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:35])[CH:34]=1)[C:29](Cl)=[O:30]>>[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:35])[CH:34]=1)[C:29]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:30]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)CN)C3)CC2)cn1
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cc(F)cc(F)c4)C3)CC2)cn1

Procedure:
The title compound was prepared as yellow solid from coupling of 2-amino-N-{1-[4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-acetamide, as prepared in Step D of Example 16, and 3,5-difluorobenzoyl chloride using the procedure described in Example 18.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([CH2:20][CH3:21])=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[Si:31]([O:19][CH2:18][CH2:17][N:13]1[C:14]([CH2:15][CH3:16])=[C:10]([S:9][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Br:8])[CH:5]=2)[C:11]([CH2:20][CH3:21])=[N:12]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: CCc1nn(CCO)c(CC)c1Sc1cc(Br)cc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCc1nn(CCO[Si](C)(C)C(C)(C)C)c(CC)c1Sc1cc(Br)cc(Br)c1
Temperature: 20 °C
Reaction time: 15 h
Yield: 72.9 %

Procedure:
A solution of 2-{4-[(3,5-dibromophenyl)sulfanyl]-3,5-diethyl-1H-pyrazol-1-yl}ethanol (1.3 g, 3 mmol) (Example 93) in dimethylformamide (3 ml) was treated with imidazole (270 mg, 4 mmol) and tert-butyl(chloro)dimethylsilane (500 mg, 3.3 mmol) and stirred at 20° C. for 15 hours. The mixture was partitioned between diethyl ether (70 ml) and citric acid solution (5% weight:volume in water, 150 ml). The aqueous layer was further extracted with diethyl ether (70 ml) and the combined organic layers were washed with brine (2×70 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with pentane:dichloromethane (1:1, by volume) to provide the title compound (1.2 g) as a colourless oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14].CN(C)C=O>O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([CH2:12][N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:14])=[CH:16][CH:17]=1
Reactant: CC(C)Nc1ccccc1
Reactant: O=C(CCl)c1ccc(F)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(CC(=O)c1ccc(F)cc1)c1ccccc1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
562.9 g. (4.08 moles) of N-isopropylaniline is rapidly added to a solution of the crude product of Step 1 in 500 ml. of dimethylformamide stirred at 50° C. under nitrogen. The reaction mixture is stirred at 100° C. under nitrogen for 10 hours and allowed to cool to room temperature overnight. The reaction mixture is heated to 60° C., 2 l of water is added, and the mixture is cooled to 10° C. The obtained solids are collected, washed twice with 500 ml. portions of water and dissolved in 550 ml. of 95% ethanol at 75° C. The solution is cooled to 0° C., and the obtained solids are collected, washed three times with 100 ml. portions of 95% ethanol and vacuum dried at 35°-40° C. for 4 hours to obtain the 95.3% pure yellow product (466 g. (80.2% (two steps))), m.p. 78°- 81° C.
Reaction SMILES: C([O:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32])=[O:24])=[O:10])C1C=CC=CC=1.O1CCCC1>[C].[Pd]>[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32])=[O:24])([OH:10])=[O:8]
Reactant: O=C(CCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 15 h
Yield: 0.1 %

Procedure:
In 15 ml of tetrahydrofuran N-(13-benzyloxycarbonyltridecanoyloxy)succinimide (2.28 g, 5.12 mmoles) was dissolved. To the obtained solution, were added 228 mg of 10% palladium carbon and the mixture was stirred for 15 hours under an atmosphere of hydrogen. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethanol, to give N-(13-carboxytridecanoyloxy)succinimide (1.71 mg, 94%) having the following properties.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][N:10]2[CH2:17][CH:16]3[O:18][CH:12]([CH2:13][N:14]([CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:15]3)[CH2:11]2)=[CH:7][CH:6]=1)#[N:4].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[CH2:28]([N:21]([CH2:20][CH2:19][N:14]1[CH2:15][CH:16]2[O:18][CH:12]([CH2:11][N:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:27][CH:26]=3)[CH2:17]2)[CH2:13]1)[S:22]([CH3:25])(=[O:24])=[O:23])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)NCCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(CCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a suspension of NaH (60% in oil, 0.039 g, 1.64 mmol) in dry DMF (10 mL) was added N-{2-[7-(4-cyanobenzyl)-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl]ethyl}methanesulfonamide (0.3 g, 0.82 mmol; see Preparation M above) at 0° C. The reaction mixture was stirred for 1 h at room temperature. Benzyl bromide (0.155 g, 0.9 mmol) was added at 0° C. and the reaction mixture stirred at rt for 2 h. The reaction quenched with water, extracted with dichloromethane, washed with water, brine and then dried over sodium sulfate. Solvent evaporation under reduced pressure, followed by column chromatography of the residue over silica gel (using 5% methanol in chloroform as eluent) gave 160 mg of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2]>[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: [Pd]
Product: NCc1ccc2c(c1)CC(=O)N2
Reaction time: 24 h
Yield: 107.2 %

Procedure:
A slurry of 5-cyanoindolin-2-one (5 g, 31.64 mmol) and 10% palladium on carbon (500 mg), was hydrogenated under 40 psi at ambient temperature temp. for 24 hours. Filtration through a pad of celite and concentration afforded 5-aminomethylindolin-2-one (5.5 g) as an orange oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[C:12]([F:22])=[C:13]3[C:18](=[CH:19][C:20]=2[F:21])[N:17]=[CH:16][CH:15]=[CH:14]3)[CH3:10])[C:5]([NH2:23])=[N:4][CH:3]=1.[N:24]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH:9]([C:11]3[C:12]([F:22])=[C:13]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]=[CH:16][CH:15]=[CH:14]4)[CH3:10])[N:24]=[N:23][C:5]2=[N:4][CH:3]=1
Reactant: O=N[O-]
Reactant: CC(Nc1nc(Br)cnc1N)c1c(F)cc2ncccc2c1F
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(c1c(F)cc2ncccc2c1F)n1nnc2ncc(Br)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of 6-bromo-N2-(1-(5,7-difluoroquinolin-6-yl)ethyl)pyrazine-2,3-diamine (450 mg, 1.2 mmol) in acetic acid (12 mL) was added a solution of sodium nitrite (82.0 mg, 1.2 mmol) in water (2 mL). After stirring at rt for 2 hours, the solvent was removed in vacuo. The residue was diluted with NaHCO3 (aq.), extracted with DCM. The organic layer was separated and washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a yellow solid (423 mg, 91%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.01 (dd, 1H), 8.95 (s, 1H), 8.52 (d, 1H), 7.75 (d, 1H), 7.64 (dd, 1H), 6.77 (q, 1H), 2.30 (d, 3H). LCMS (method A): [MH]+=391/393, tR=5.59 min.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([C:20](=[O:22])[CH3:21])[S:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O1CCCC1>[CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([OH:22])[CH3:21])[S:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(=O)c1nc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)ns1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1ccc(Oc2ncc(-c3nsc(C(C)O)n3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of Example 100C (1.7 g, 0.0047 mol) in a mixture of methanol and tetrahydrofuran (1:1) was added sodium borohydride (0.36 g, 0.0094 mol) and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified on silica gel (ethyl acetate/hexane, 10˜50%) to give 1.43 g of product as a white solid (84% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=5.88 Hz, 6H) 1.70 (d, J=6.62 Hz, 3H) 2.87 (s, 1H) 4.45-4.61 (m, 1H) 5.27 (q, J=6.62 Hz, 1H) 6.87-6.98 (m, 2 H) 7.16-7.25 (m, 2H) 7.94 (s, 1H). MS (ESI), M/Z: 364.0 (M+H)+.
Reaction SMILES: C([C:3](=[C:9]([O:15][CH2:16][CH3:17])[CH:10]=[CH:11][N:12](C)[CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#N.CC(O)=[O:20]>>[CH2:16]([O:15][C:9]1[CH:10]=[CH:11][NH:12][C:13](=[O:20])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:17]
Reactant: CCOC(=O)C(C#N)=C(C=CN(C)C)OCC
Reactant: CC(=O)O
Product: CCOC(=O)c1c(OCC)cc[nH]c1=O
Yield: 66.6 %

Procedure:
A mixture of ethyl 2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate (150 g, 0.63 mol) and HOAc (600 mL) was refluxed overnight. The mixture was concentrated to dryness under high vacuum and the residue treated with water (300 mL). The mixture was extracted with EtOAc (2×250 mL) to remove the impurities. The pH of the aqueous was adjusted with NaHCO3 to pH ˜9-10. The mixture was extracted with CH2Cl2 (3×300 mL). The combined organics were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to afford ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (90 g, 66.6% yield).