Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>O1CCOCC1.O.C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C(=O)O)c(N)c1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)Nc2cc(C)ccc2C(=O)O)cc1
Reaction time: 18 h
Yield: 57.3 %

Procedure:
To a room temperature solution of 2-amino-4-methyl benzoic acid (1.93 g, 12.8 mmol) in 20 ml of dioxane:H2O (1:1) containing triethylamine (2.68 ml, 19.2 mmol), was added 4-methoxybenzenesulfonyl chloride (2.91 g, 14.1 mmol). The mixture was stired at rt for 18 hr. The resulting mixture was diluted with methylene chloride, washed with 1N HCl, H2O, brine, dried and concentrated. The crude liquid was triturated with 16 ml of EtOAc: hexane (1:3) to afford 2.358 g of the desired product as a white solid (57%). Electrospray Mass Spec 322 (M+H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([CH3:6])[CH2:9]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(CCc2ccccc2OC2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cccc(CCc2ccccc2OC2CCCN(C)C2)c1
Yield: 51.7 %

Procedure:
Following a procedure similar to that described in Example 38, 880 mg of 1-t-butoxycarbonyl-3-{2-[2-(3-methoxyphenyl)ethyl]phenoxy}piperidine [prepared as described in Example 51(a)] were reacted with 162 mg of lithium aluminum hydride. The mixture was then worked up as described in Example 38, and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 360 mg (yield 51%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:6].C([O:26][C:27](=[O:40])[CH2:28][CH2:29][C:30]1[CH:35]=[C:34]([Cl:36])[C:33]([CH:37]=O)=[C:32]([Cl:39])[CH:31]=1)(C)(C)C>>[Cl:36][C:34]1[CH:35]=[C:30]([CH2:29][CH2:28][C:27]([OH:40])=[O:26])[CH:31]=[C:32]([Cl:39])[C:33]=1[C:37]1[NH:1][C:2]2[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=3)[CH:18]=[CH:19][C:20]=2[N:21]=1
Reactant: Nc1ccc(C(=O)Nc2ccc(C(F)(F)F)nc2)cc1N
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(C=O)c(Cl)c1
Product: O=C(O)CCc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cc3[nH]2)c(Cl)c1

Procedure:
The title compound was prepared from 3,4-diamino-N-(6-trifluoromethylpyridin-3-yl)-benzamide (from Example 6-36) and 3-(3,5-dichloro-4-formylphenyl)-propionic acid tert butyl ester analogous to Example 6-25. 1H NMR (MeOD, 400 MHz): δ 9.07 (d, 1H), 8.54 (dd, 1H), 8.35 (s, 1H), 7.99 (dd, 1H), 7.84 (dd, 1H), 7.76 (d, 1H), 7.52 (s, 2H), 3.01 (t, 2H), 2.69 (t, 2H); MS (m/z) 523.01 (M+1), Retention time=1.06 min (Method 10).
Reaction SMILES: [Na].[CH2:2]1[O:4][CH:3]1[CH2:5][OH:6].[CH:7]([OH:10])([CH3:9])[CH3:8]>>[CH:7]([O:10][CH2:2][CH:3]([OH:4])[CH2:5][OH:6])([CH3:9])[CH3:8]
Reactant: OCC1CO1
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)OCC(O)CO
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Into a 3-L separable flask equipped with a stirrer and a condenser, 1200 g of isopropanol was introduced. Then 4.6 g of sodium was added and heated to 80° C. to dissolve. After complete dissolution of the sodium, 300 g of glycidol was dropped at 80° C. over 1 hour. After completion of the dropping, stirring was conducted for 3 hours. Then the stirring was stopped and the mixture was cooled to room temperature. At this time, the mixture separated into an upper layer and a lower layer. The upper layer was isolated and concentrated by an evaporator. Furthermore, 3-isopropoxy-1,2-propanediol (boiling point: 60° C./2 mmHg) was obtained through distillation under reduced pressure. 3-Isopropoxy-1,2-propanediol thus obtained is a model compound in the case where one molecule of glycidol reacted with a hydroxyl group of EVOH.
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23]CC)=[O:22])[CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:44]=[CH:43][C:37]2[C:38](=[O:42])[CH2:39][CH2:40][O:41][C:36]=2[C:35]=1[CH2:45][CH2:46][CH3:47])C.O.[OH-].[Li+].S(=O)(=O)(O)O.C(OCC)(=O)C>C1COCC1.O>[C:21]([C:17]1[CH:16]=[C:15]([C:13]([C:11]2[CH:10]=[CH:9][C:8]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]3[CH:44]=[CH:43][C:37]4[C:38](=[O:42])[CH2:39][CH2:40][O:41][C:36]=4[C:35]=3[CH2:45][CH2:46][CH3:47])=[C:7]([CH2:6][CH2:5][C:4]([OH:48])=[O:3])[CH:12]=2)=[O:14])[CH:20]=[CH:19][CH:18]=1)([OH:23])=[O:22]
Reactant: CCCc1c(OCCCCCCOc2ccc(C(=O)c3cccc(C(=O)OCC)c3)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 25.5 h

Procedure:
A mixture of 0.144 g (0.70 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 0.371 g (0.70 mmol) of 2-[(6-bromohexyl)oxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, 0.479 g (3.47 mmol) of anhydrous granular potassium carbonate and 13.1 mL of 2-butanone was stirred and refluxed for 18 hr. The resulting slurry was filtered with suction and the solids washed thoroughly with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo and the residue was purified by flash chromatography on 75 g of silica gel, eluting with 3:1 hexane-ethyl acetate, giving 0.37 g (80.6%) of 2-[6-[(2,3-dihydro-4-oxo-8-propyl-4H-1-benzopyran-7-yl)oxy]hexyloxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester as a white solid, mp 58°-59.5° C. A mixture of 0.331 g (0.50 mmol) of this ester in 6 mL of THF and 6 mL of water was treated with 64.7 mg (1.54 mmol) of lithium hydroxide monohydrate and the resulting mixture was stirred for 25.5 hr at room temperature, before being acidified with 17 mL of 3N aqueous sulfuric acid. Work-up with ethyl acetate in the usual manner gave a crude product which was recrystallized from hexane-ethyl acetate affording 0.242 g (79.7%) of the title compound as a white solid, mp 169°-172° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.NC1C(C(NC)=O)=C(C)C(C2C=NN(CCCO)C=2)=CC=1>>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]([C:15](=[O:20])[NH:16][CH3:19])[C:18]=2[CH3:17])[CH:7]=[N:6]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c(C)c3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
Prepared analogously to Compound 1B replacing Compound C with 6-amino-3-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N,2-dimethyl benzamide (Compound 29C). 1H NMR (CD3OD, 400 MHz): δ=8.28 (s, 1H), 7.92 (s, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 6.92 (t, J=2.0 Hz, 1H), 6.60 (d, J=7.4 Hz, 1H), 4.35 (t, J=6.8 Hz, 2H), 4.00 (m, 4H), 3.89 (s, 3H), 3.60 (t, J=6.1 Hz, 2H), 3.16 (d, J=21.5 Hz, 2H), 2.85 (s, 3H), 2.37 (s, 3H), 2.12 (m, 2H), 1.22 (t, J=7.1 Hz, 6H). MS (ESI): m/z=706.58 [M+H]+. HPLC: tR=3.47 min (ZQ3: polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:17]=[CH:16][C:15]2[N:14]([CH3:18])[C:13](=[O:19])[C@@H:12]([CH2:20][CH3:21])[N:11]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:10]=2[N:9]=1.[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.O>[CH:22]1([N:11]2[C:10]3[N:9]=[C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[NH:1][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:17]=[CH:16][C:15]=3[N:14]([CH3:18])[C:13](=[O:19])[C@H:12]2[CH2:20][CH3:21])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1ccccc1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3N)nc2N1C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3NC(=O)c3ccccc3)nc2N1C1CCCC1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A mixture of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91, 1 eq), benzoic acid (3 eq), HATU (3 eq), and DIPEA (4 eq) in dry THF under Ar was stirred at 90° C. for 18 h. The mixture was cooled to rt and water was added and extracted with EtOAc. The organic layer was dried with Na2SO4, concentrated and the residue was purified by silica gel column to give the title compound. LCMS (0.05% TFA): 457.2 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 13.75 (s, 1H), 10.00 (bs, 1H), 8.55 (bs, 1H), 8.39 (d, 1H, J=5.0 Hz), 8.31 (s, 1H), 8.07 (m, 2H), 7.69 (m, 3H), 4.46 (m, 1H), 4.39 (m, 1H), 3.38 (s, 3H), 2.02-1.63 (m, 10H), 0.77 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH2:18])[N:6]=1)[CH:2]=[CH2:3].[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C.O>C(#N)C>[C:19]([NH:18][C:7]1[N:6]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCNc1nc(N)nc2ccc([N+](=O)[O-])cc12
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: C=CCNc1nc(NC(C)=O)nc2ccc([N+](=O)[O-])cc12
Yield: 80.7 %

Procedure:
After 100 mg (0.41 mmol) of 4-allylamino-2-amino-6-nitroquinazoline was dissolved in 10 ml of acetonitrile, 84 mg (0.82 mmol) of acetic anhydride and 0.06 ml (0.45 mmol) of triethylamine were added thereto, and then the reaction mixture was subjected to heating under reflux overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate, washing successively with a saturated aqueous sodium hydrogen carbonate solution and brine and drying over anhydrous sodium sulfate. The solvent was distilled off, followed by recrystallization from ethyl acetate-hexane to give 95 mg (80.7%) of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[C:16]2[C:12](=[CH:13][N:14]([CH3:17])[N:15]=2)[C:11]([CH:18]2[CH2:20][CH:19]2[C:21](OCC)=[O:22])=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:7][C:8]1[C:16]2[C:12](=[CH:13][N:14]([CH3:17])[N:15]=2)[C:11]([CH:18]2[CH2:20][CH:19]2[CH2:21][OH:22])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1CC1c1ccc(F)c2nn(C)cc12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc2c(C3CC3CO)ccc(F)c2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
To a suspension of lithium aluminum hydride (695 mg, 18.3 mmol) in tetrahydrofuran (30 mL) was added a solution of ethyl 2-(7-fluoro-2-methyl-2H-indazol-4-yl)cyclopropanecarboxylate (1.20 g, 4.58 mmol) obtained in Reference Example 81 in tetrahydrofuran (15 mL) under nitrogen atmosphere at 0° C., and the mixture was stirred at 0° C. for 15 min. Sodium sulfate decahydrate (7.0 g) was added under ice-cooling, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/hexane=15/85→100/0) to give the title compound (961 mg, yield 95%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]1([C:27]3[C:18](=[CH:19][C:20]4[O:25][CH2:24][CH2:23][O:22][C:21]=4[CH:26]=3)[O:17][CH2:16]1)[C:8](=[O:15])[N:9]2[CH3:14])=O.[C:28]([NH2:31])(=[S:30])[CH3:29]>O1CCOCC1>[CH3:14][N:9]1[C:10]2[C:6](=[C:5]([C:3]3[N:31]=[C:28]([CH3:29])[S:30][CH:2]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2([C:27]3[C:18](=[CH:19][C:20]4[O:25][CH2:24][CH2:23][O:22][C:21]=4[CH:26]=3)[O:17][CH2:16]2)[C:8]1=[O:15]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)CBr)cccc21
Reactant: CC(N)=S
Solvent: C1COCCO1
Product: Cc1nc(-c2cccc3c2C2(COc4cc5c(cc42)OCCO5)C(=O)N3C)cs1
Temperature: 80 °C
Yield: 32.8 %

Procedure:
To a suspension of 4′-(bromoacetyl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.25 g, 0.57 mmol) in p-dioxane (15 mL) was added thioacetamide (0.047 g, 0.63 mmol) and the reaction mixture, which became homogeneous upon heating, was heated at 80° C. for 1 h. The reaction mixture was allowed to cool to ambient temperature and was concentrated to dryness in vacuo. The crude product was purified by column chromatography and eluted with a 0% to 100% gradient of ethyl acetate in hexanes to afford 1′-methyl-4′-(2-methyl-1,3-thiazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.076 g, 33%) as an off-white solid: mp 219-220° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.42-7.36 (m, 1H), 7.32-7.27 (m, 1H), 6.91 (d, J=7.7 Hz, 1H), 6.54 (s, 1H), 6.36 (s, 1H), 6.22 (s, 1H), 4.81-4.71 (m, 2H), 4.21-4.07 (m, 4H), 3.29 (s, 3H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.4, 165.2, 156.1, 151.8, 144.4, 137.7, 133.2, 129.2, 128.6, 124.7, 122.2, 116.6, 111.2, 108.2, 99.1, 78.3, 77.4, 64.7, 64.0, 58.8, 27.0, 19.1; MS (ES+) m/z 406.9 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17]C(=O)OC(C)(C)C)[S:9][C:10]=1[C:11]([CH2:13][CH2:14][O:15][CH3:16])=[O:12]>FC(F)(F)C(O)=O>[CH3:16][O:15][CH2:14][CH2:13][C:11]([C:10]1[S:9][C:8]([NH2:17])=[N:7][C:6]=1[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: COCCC(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccco1
Solvent: O=C(O)C(F)(F)F
Product: COCCC(=O)c1sc(N)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Compound 409 (124 mg, 0.343 mmol) was dissolved in trifluoroacetic acid (3 mL), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford the entitled Compound 410 (79.0 mg, 87%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[S:17][C:18]([C:21]4[O:25][N:24]=[CH:23][CH:22]=4)=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:26][N:27](C)[C:28](=O)OC(C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.[ClH:42]>C(O)C>[ClH:42].[F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[S:17][C:18]([C:21]4[O:25][N:24]=[CH:23][CH:22]=4)=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:26][NH:27][CH3:28])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(-c3ccno3)s2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(-c3ccno3)s2)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
tert-Butyl ({5-(2-fluoropyridin-3-yl)-1-[(5-isoxazol-5-yl-2-thienyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (80 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 50° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from a mixed solvent of ethyl acetate-diethyl ether (1:1) to give the title compound as colorless crystals (yield 23 mg, 33%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][CH2:22][C:23]1[O:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:28]([C:26]3[N:27]=[C:23]([CH2:22][CH2:21][O:20][CH3:19])[O:24][C:25]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:29])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: COCCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: COCCc1nc(C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-(2-methoxy-ethyl)-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.0 min; [M+H]+=435.31.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)(=O)=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1O)[CH:27]=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)[CH:27]=[O:28]
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reactant: O=Cc1ccc(O)c(Cl)c1
Product: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)c(Cl)c1
Yield: 34.5 %

Procedure:
Using a similar protocol as described in Example 9A but employing 1C (500 mg, 1.55 mmol) and 3-chloro-4-hydroxybenzaldehyde (250 mg, 1.60 mmol) as starting materials gave 205 mg (34%) of 10A as a solid. 1H NMR (500 MHz, CD3OD): δ 4.33 (m, 1H), 4.6-4.9 (m, 2H), 5.23 (m, 1H), 5.36 (m, 1H), 7.07 (d, 1H), 7.5-7.7 (m, 3H), 7.8-9.0 (m, 4H), 9.86 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[NH:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].P(Cl)(Cl)(Cl)=O.CN(C)[CH:23]=[O:24]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([OH:14])=[C:12]([CH:23]=[O:24])[C:11]([CH3:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(=O)n(-c2ccc(C)c(C)c2)[nH]1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-n2nc(C)c(C=O)c2O)cc1C
Temperature: 100 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
1.86 g (9.16 mmol) of 1-(3,4-dimethylphenyl)-3-methyl-3-pyrazolin-5-one was dissolved in 3.6 ml of dry dimethylformamide, and 1.02 ml (11.0 mmol) of phosphorus oxychloride was added gradually under cooling with ice at 20° C. or below. After the addition, the mixture was heated at 100° C. for 2 hours, then cooled to room temperature and poured into 30 ml of ice-cold water. Then, it was washed with 10 ml of water and 10 ml of dimethylformamide. The mixed solution was stirred for 18 hours, and the precipitated solid was collected by filtration, washed with 20 ml of water and dried to obtain 1.03 g of the above-identified desired product as a pale brown solid (yield 49%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.O>C(OCC)C>[O:4]=[C:1]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: C1CCNC1
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCCC1
Temperature: -50 °C
Reaction time: 12 h

Procedure:
Acryloyl chloride (9 g, 0.1 mole) was added by syringe to ethyl ether (40 ml) and the solution cooled to -50° C. A solution of pyrrolidine (7.1 g, 0.1 mole) in ethyl ether (20 ml) was added dropwise. A solution of triethylamine (15.3 ml) was added slowly over 10 minutes. The reaction was slowly allowed to warm to room temperature and stirred for 12 hours. Water (50 ml) was added, the layers were separated and the aqueous Iayer extracted with ethyl ether (100 ml) and methylene chloride (2×ml), and combined with the organic layer above, dried over sodium sulfate, filtered, and the solvents removed to give an oil. The product was purified by chromatography on silica. The structure was confirmed by NMR.
Reaction SMILES: BrC1C=CC([N+]([O-])=O)=C(C=1)N.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([N+:21]([O-])=O)=[C:17]([CH:20]=1)[C:18]#[N:19].NC1C=CC=CC=1.N([O-])=O.[Na+].Cl>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:21])=[C:17]([C:18]#[N:19])[CH:20]=1
Reactant: N#Cc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Nc1cc(Br)ccc1[N+](=O)[O-]
Agent: O=N[O-]
Solvent: Nc1ccccc1
Product: N#Cc1cc(Br)ccc1N

Procedure:
5-bromo-2-nitroaniline is converted into 5-bromo-2-nitrobenzonitrile by treating the aniline derivative with sodium nitrite and hydrochloric acid and reacting the resulting diazonium salt with cuprous cyanide as in Example 2. The nitro group is reduced with stannous chloride and hydrochloric acid to give 4-bromo-2-cyanoaniline.
Reaction SMILES: OC1C2C(=C(C)C(OC)=CC=2)N=C(C2SC=C(C(C)C)N=2)C=1.[CH:23]([C:26]1[N:27]=[C:28]([C:31]2[CH:40]=[C:39]([O:41][CH:42]3[CH2:59][CH:58]4[CH:44]([C:45](=[O:65])[N:46]([CH3:64])[CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH:53]5[C:55]([C:61]([OH:63])=[O:62])([NH:56][C:57]4=[O:60])[CH2:54]5)[CH2:43]3)[C:38]3[C:33](=[C:34]([CH3:68])[C:35]([O:66][CH3:67])=[CH:36][CH:37]=3)[N:32]=2)[S:29][CH:30]=1)([CH3:25])[CH3:24]>>[CH:23]([C:26]1[N:27]=[C:28]([C:31]2[CH:40]=[C:39]([O:41][CH:42]3[CH2:59][CH:58]4[CH:44]([C:45](=[O:65])[NH:46][CH2:64][CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH:53]5[C:55]([C:61]([OH:63])=[O:62])([NH:56][C:57]4=[O:60])[CH2:54]5)[CH2:43]3)[C:38]3[C:33](=[C:34]([CH3:68])[C:35]([O:66][CH3:67])=[CH:36][CH:37]=3)[N:32]=2)[S:29][CH:30]=1)([CH3:25])[CH3:24]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NCCCCCC=CC5CC5(C(=O)O)NC(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from intermediate 79 and quinoline 36 following the procedure (Steps D-F) reported for the preparation of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo-[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (46): m/z=647 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:9]=[C:10](/[CH:16]=[C:17](/[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)\[C:18]([OH:20])=[O:19])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[CH3:28]O>>[CH3:28][O:19][C:18](=[O:20])/[C:17](/[C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)=[CH:16]\[C:10]1[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=[C:8]([O:7][CH3:6])[CH:9]=1
Reactant: CO
Reactant: COc1cc(/C=C(\C(=O)O)c2ccc(O)cc2)cc(OC)c1
Agent: O=S(=O)(O)O
Product: COC(=O)/C(=C\c1cc(OC)cc(OC)c1)c1ccc(O)cc1
Yield: 35 %

Procedure:
Concentrated sulfuric acid. (10 drops) was added to a stirred methanol suspension of thoroughly dried 19 (0.60 g, 2.0 mmol) under argon and heated at reflux for 18 h. Methanol was evaporated under reduced pressure, residue was taken up in ethyl acetate (20 mL) and washed with water (20 mL), saturated aqueous Na HCO3 (10 mL) and brine (10 mL). The organic layer was dried on anhydrous magnesium sulfate, filtered and the solvent was evaporated. The crude product obtained was purified by chromatography over silica gel and eluted with hexane-ethyl acetate (7:3) to yield 20 as white solid (0.24 g, 35%): 1HNMR (400 MHz, CDCl3) δ 7.26 (d, J=8.4 Hz, 2H), 6.82 (s, 1H), 6.76 (d, J=8.4 Hz, 2H), 6.45 (d, J=2.0 Hz, 2H), 6.34 (t, J=2.0 Hz, 1H), 4.97 (s, 1H), 3.73 (s, 3H), 3.72 (s, 6H).