Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cccc2c(O)cc(=O)[nH]c12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1cccc2c(O)c([N+](=O)[O-])c(=O)[nH]c12
Temperature: 100 °C

Procedure:
A suspension of 4-hydroxy-8-methylcarbostyril (1.63g; 0.0093 mole), in glacial acetic acid (10 ml) was stirred during the addition of concentrated nitric acid (2.5 ml, d, 1.42) and the mixture warmed for 8 minutes at 100°C, after which time the solution had cleared and began to precipitate the yellow nitro derivative. After cooling, ethanol was added and the solid filtered and washed well with ethanol. On drying in vacuo over P2O5NaOH it had m.p. 266°-267°C (Found: C, 54.41; H, 3.80; N, 12.51; C10H8N2O4 requires; C, 54.55; H, 3.66; N, 12.75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19]CCCC)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)O)nn1
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
A solution of butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylate (reference example 11) (0.36 g, 1.0 mmol) in THF (4 ml) and methanol (4 ml) was treated with aqueous sodium hydroxide 1N (4 ml) and allowed to stand at ambient temperature for 1.5 hours. The reaction was evaporated to a small volume, diluted with water and acidified with acetic acid. After standing for 18 hours, the precipitate was filtered, washed with water and ether, and air dried to give the title compound as a white solid (0.26 g, 71%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[N:30]=[C:29]([C:31](O)=[O:32])[O:28][N:27]=2)[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:29]3[O:28][N:27]=[C:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[N:30]=3)=[O:32])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Reactant: O=C(O)c1nc(-c2cccnc2)no1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1nc(-c2cccnc2)no1

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.2 g, 0.72 mmol), 3-(pyridin-3-yl)-1,2,4-oxadiazole-5-carboxylic acid (0.137 g, 0.72 mmol), HOBt (0.145 g, 1.07 mmol), DIPEA (0.375 mL, 2.15 mmol) and EDCI (0.2 g, 1.07 mmol) using DMF as solvent using the method of Example 34(d). Yield 33.4 mg. 1H NMR (400 MHz; d6-DMSO): δ 1.23 (d, 3H), 4.41 (m, 2H), 4.52 (m, 1H), 6.79 (m, 1H), 7.65 (m, 1H), 7.78 (m, 1H), 7.95 (d, 1H), 8.03 (m, 1H), 8.38 (m, 1H), 8.83 (dd, 1H), 9.19 (dd, 1H), 9.51 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:21])[CH:9]=[C:8]([C:10]([NH:12][CH3:13])=[O:11])[C:7]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:6]=2[O:5]1.[CH3:22]I.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]1([CH3:21])[CH:9]=[C:8]([C:10]([N:12]([CH3:22])[CH3:13])=[O:11])[C:7]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:6]=2[O:5]1
Reactant: CNC(=O)C1=CC(C)(COC)Oc2ccc([N+](=O)[O-])cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1(C)C=C(C(=O)N(C)C)c2cc([N+](=O)[O-])ccc2O1
Temperature: 0 °C

Procedure:
To a mixture of 130 mg of 2-methoxymethyl-N,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamide, 83 μl of methyl iodide and 5 ml of dried N,N-dimethylformamide was added 21 mg of sodium hydride (60%) with stirring under ice-cooling and stirred at room temperature for 15 hours. Ice water was added to the reaction solution and it was extracted with ether. An organic layer was washed with water and dried, and the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 130 mg of 2-methoxymethyl-N,N,2-trimethyl-6-nitro-2H-1-benzopyran-4-carboxamide. Subsequently, 103 mg of a Lawesson's reagent and 8 ml of benzene were added therein and the resultant mixture was refluxed with heating for 1 hour. After the reaction solution was vacuum-condensed, the residue was purified according to silica gel column chromatography (developing solution, hexane:AcOEt=3:1) to obtain 140 mg of 2-methoxymethyl-N,N,2-trimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide. Subsequently, 290 μl of iodomethane, 104 mg of cyanamide and 8 ml of dried tetrahydrofuran were added therein and 96 mg of sodium hydride (60%) was added therein with stirring under ice-cooling, and the resultant mixture was stirred at room temperature for 15 hours. Ice water was added to the reaction product and it was extracted with ethyl acetate. an organic layer was washed with water and dried, and the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, hexane:AcOEt=2:3) to obtain 125 mg of N-cyano-2-methoxymethyl-N',N',2-trimethyl-6-nitro-2H-1-benzopyran-4-amidine with a melting point of 143°-146° C.
Reaction SMILES: C(OC([N:8]1[C:12](=[O:13])/[C:11](=[CH:14]\[OH:15])/[CH:10]2[CH2:16][C:17]3[C:22]([CH:9]12)=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)(C)(C)C.FC(F)(F)C(O)=O.[Na]>ClCCl>[OH:15]/[CH:14]=[C:11]1/[CH:10]2[CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]2[NH:8][C:12]/1=[O:13]
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\O)C2Cc3ccccc3C21
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC2c3ccccc3CC2/C1=C/O
Reaction time: 1 h
Yield: 102 %

Procedure:
A solution of 3-[1-hydroxy-meth-(Z)-ylidene]-2-oxo-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]pyrrole-1-carboxylic acid tert-butyl ester D1 (0.400 g, 1.32 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (2 mL) at 0° C. The solution was stirred for 1 h. A saturated solution of sodium hydrogenocarbonate was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with a saturated solution of sodium hydrogenocarbonate, dried and concentrated in vacuo to give 3-[1-Hydroxy-meth-(Z)-ylidene]-3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one C1 (White solid, 271 mg, quant.). C12H11NO2; MW: 201.23; LCMS (method A) RT 1.18 min; ES: 256 (MH++MeCN), 224 (MNa+), 202 (MH+); IR: 3264, 1678 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 10.00 (1H, s), 7.16-7.38 (4H, m), 7.13 (1H, d), 4.94 (1H, d), 3.68-3.82 (1H, m), 3.31 (2H, dd), 3.01 (1H, dd) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@H:7]([C@H:12]1[CH2:16][O:15]C(C)(C)[O:13]1)[CH2:6][CH2:5]2.O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@H:7]([C@H:12]([OH:13])[CH2:16][OH:15])[CH2:6][CH2:5]2
Reactant: CC1(C)OC[C@H]([C@@H]2CCc3cc(F)ccc3O2)O1
Solvent: O
Solvent: CC(=O)O
Product: OC[C@@H](O)[C@@H]1CCc2cc(F)ccc2O1
Temperature: 65 °C
Yield: 42.8 %

Procedure:
(S)-6-fluoro-3,4-dihydro-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2H-chromene (1.10 g, 4.4 mmol) was dissolved in acetic acid (9 ml) and demi water (3 ml). The reaction mixture was stirred vigorously and heated to 65° C. After 2.5 h at 60° C. the reaction mixture was cooled to 25° C. The solution was then concentrated in vacuo to obtain a vetrous oil. Chromatographic separation on silica of the crude, using a mixture of heptane:ethyl acetate 1:1 as eluent, furnished 0.40 g of (R)-1-((S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethane-1,2-diol as a white solid (43% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[N:12]=[C:11](Cl)[N:10]=[C:9]([CH3:14])[N:8]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:6][C:7]1[N:8]=[C:9]([CH3:14])[N:10]=[C:11]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[N:12]=1
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: COCCN
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COCCNc1nc(C)nc(Cl)n1
Reaction time: 0.08 h
Yield: 31.8 %

Procedure:
2-methoxyethanamine (Aldrich, 0.350 g, 4.66 mmol) was added to a solution of 2,4-dichloro-6-methyl-1,3,5-triazine (0.80 g, 4.88 mmol) in dioxane (10 mL). Heat was generated. Hünig's base (1.0 mL, 5.73 mmol) was added and the mixture was stirred for 5 min. The mixture was partitioned between DCM (15 mL) and water. The organic phase was dried over Na2SO4 and concentrated. The resulting yellow oil was purified by chromatography on silica using EtOAc in hexane (20-80%) to give the desired product as a yellow solid (300 mg). LCMS (ES, pos.): calcd for C7H11ClN4O: 202.1. found: 203.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 5.93 (br. s., 1H); 3.60-3.70 (m, 2H); 3.49-3.58 (m, 2H); 3.38 (s, 3H); 2.42 (d, 3H).
Reaction SMILES: Br[C@@:2]1([C:14](=[O:16])[CH3:15])[C@:10]2([CH3:11])[C@H:5](/[C:6](=[CH:12]/[Br:13])/[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3]1.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+].O>CN(C)C=O>[Br:13]/[CH:12]=[C:6]1\[CH2:7][CH2:8][CH2:9][C@@:10]2([CH3:11])[C@H:5]\1[CH2:4][CH:3]=[C:2]2[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)[C@@]1(Br)CC[C@H]2/C(=C/Br)CCC[C@@]21C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)C1=CC[C@H]2/C(=C/Br)CCC[C@]12C
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
1-{(E,1R,3aS,7aS)-1-bromo-4-(bromomethylene)-octahydro-7a-methyl-1H-indene-1-yl}ethanone (Compound 12: 100 mg, 0.369 mmol) was dissolved in dimethylformamide (1.6 ml), and lithium bromide (35.8 mg, 0.412 mmol) and lithium carbonate (27.4 mg, 0.371 mmol) were added thereto. The resulting mixture was heated to 100° C. and stirred for 3 hours. After cooling the reaction solution to room temperature, water was added thereto, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over sodium sulfate, and evaporated to obtain a crude product. The product was purified by flash column chromatography to obtain 1-{(3aS,7E,7aR)-7-(bromomethylene)-3a,4,5,6,7,7a-hexahydro-3a-methyl-1H-indene-3-yl}ethanone (71.6 mg, 94.0%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:28])[CH2:22][N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:28])[CH2:22][N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=1
Reactant: Fc1cccc(CCl)c1
Reactant: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Product: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Yield: 87 %

Procedure:
The procedure described in Example 3 was repeated using N-[(2R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide (obtained as described for in Example 50, preparation of starting materials) and 3-fluorobenzyl chloride to give the title compound in 87% yield; NMR spectrum (DMSO-d6) 1.36 (d, 3H), 1.93 (s, 3H), 3.04 (s, 3H), 3.27 (1H obscured by H2O), 4.22 (dd, 1H), 5.07 (m, 1H), 5.25 (s, 2H), 7.16 (t, 1H), 7.29 (m, 5H), 7.45 (m, 1H), 7.65 (dd, 1H), 7.71 (t, 1H), 8.09 (d, 1H), 8.46 (s, 1H), 9.93 (s, 1H); Mass Spectrum MH+ 509.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:28]1([C:34]2[CH:35]=[C:36]([C:43]([OH:45])=O)[S:37][C:38]=2[C:39]([F:42])([F:41])[F:40])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:43]([C:36]3[S:37][C:38]([C:39]([F:40])([F:41])[F:42])=[C:34]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:35]=3)=[O:45])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3cc(-c4ccccc4)c(C(F)(F)F)s3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH:10]1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:11][CH:10]1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CC(CO)CCC1NCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC(NCc3ccccc3)C(C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(4-Benzylamino-3-methyl-cyclohexyl)-methanol (0.1 g, 3.00 mmol) in DCM (30 mL) and pyridine (3 mL) is treated with TsCl (0.86 g, 4.50 mmol) and the resulting mixture is stirred at RT overnight. The reaction mixture is partitioned between DCM and water and the organic portion is separated, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with iso-hexane:EtOAc (1:2 increasing to 1:4) affords the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (2H, d), 7.50 (2H, d), 7.30 (4H, m), 7.20 (1H, m), 3.80 (2H, d), 3.63 (2H, q), 2.41 (4H, m), 2.01 (1H, m), 1.72 (2H, m), 1.58 (1H, m), 1.49 (2H, m), 1.20 (1H, m), 1.02 (1H, m), 0.85 (1H, m), 0.81 (3H, d).
Reaction SMILES: [CH2:1]([C:3]1([CH3:21])[N:15]([CH3:16])[C:14]([CH2:18][CH3:19])([CH3:17])[CH2:13][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]2=[O:12])[CH:4]1[CH3:20])[CH3:2].[H-].[Na+].CI.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:3]1([CH3:21])[N:15]([CH3:16])[C:14]([CH2:18][CH3:19])([CH3:17])[CH2:13][C:5]2([N:9]([CH3:26])[C:8](=[O:10])[N:7]([CH3:11])[C:6]2=[O:12])[CH:4]1[CH3:20])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC1(C)CC2(NC(=O)N(C)C2=O)C(C)C(C)(CC)N1C
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCC1(C)CC2(C(=O)N(C)C(=O)N2C)C(C)C(C)(CC)N1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.95 g of Compound 64, obtained as described in Example 5, in 10 ml of dimethylformamide was added 0.67 g of 52.9% sodium hydride; the mixture was stirred overnight at room temperature. 2.26 g of methyl iodide were then added and the mixture was heated at 100° C for 15 hours, with stirring. After cooling the mixture, 100 ml of ice-water and 20 ml of a 20% aqueous potassium carbonate solution were added in turn; the mixture was then extracted with ethyl acetate. The extract was washed with water and dried over potassium carbonate. After removing the solvent from the extract, the residue was purified by column chromatography on silica gel (eluent: chloroform containing 2.5% of methanol), giving 2.9 g of Compound 136 as a white powder melting at 77° - 88° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](Cl)[CH:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1)[CH3:8]>>[CH3:8][CH2:7][N:9]1[C:18]2[CH:17]=[C:16]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[C:15]([F:20])=[CH:14][C:13]=2[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1
Reactant: C1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21

Procedure:
In Canadian patent 1,178,961 piperazine is condensed with 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid to give norfloxacin. Canadian patent 1,214,466 claims the process of making the ester analogues of norfloxacin by the condensation of piperazine with the ester of the above compound. Hydrolysis of the ester leads to norfloxacin. Canadian patent 1,273,936 relates only to the synthesis of the quinolone carboxylic acid by cyclocondensation of a 2-benzoyl-3-amino-acrylonitrile followed by hydrolysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C@H:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][O:10][C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C@H:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: C[C@@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@@H]1Cn2c(cc(OCc3ccc(F)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,4-difluorophenyl)methanol and (R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:11]=[C:12]([C:16]4[O:17][CH2:18]C(C)(C)N=4)[CH:13]=[CH:14][CH:15]=3)[C:4]=2[CH:3]=[CH:2]1.S(=O)(=O)(O)[OH:24].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=3)[C:16]([O:17][CH3:18])=[O:24])[C:4]=2[CH:3]=[CH:2]1
Reactant: CC1(C)COC(c2cccc(-c3cccc4occc34)c2)=N1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(-c2cccc3occc23)c1

Procedure:
A mixture of 2-[3-(benzofuran-4-yl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole (1.4 g), concentrated sulfuric acid (0.8 ml) and water (1 ml) in methanol (20 ml) was refluxed for 48 hours. After evaporating the solvent, the residue was dissolved in a mixture of ethyl acetate (50 ml) and water (50 ml). The organic layer was successively washed with 10% sodium carbonate aqueous solution, brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with toluene. The fractions containing the desired products were collected and evaporated in vacuo to afford methyl 3-(benzofuran-4-yl)benzoate (0.77 g).
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[SH:5][C:6]1[CH:7]=[C:8]([B:12]([OH:14])[OH:13])[CH:9]=[CH:10][CH:11]=1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>C(OCC)C>[OH:4][C@@H:2]([CH3:3])[CH2:1][S:5][C:6]1[CH:7]=[C:8]([B:12]([OH:14])[OH:13])[CH:9]=[CH:10][CH:11]=1
Reactant: CC1CO1
Reactant: OB(O)c1cccc(S)c1
Agent: [Al+3]
Agent: [O-2]
Solvent: CCOCC
Product: C[C@H](O)CSc1cccc(B(O)O)c1
Yield: 90 %

Procedure:
S-(−) Propylene oxide (152 μL) was added to a mixture of 500 mg of 3-mercaptophenylboronic acid and aluminum oxide (˜30 eq, neutral, activated, ˜150 mesh) in diethyl ether at room temperature. The reaction was monitored by LC/MS until complete. The reaction mixture was evaporated, and then added 1N HCl. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over MgSO4, filtered and evaporated to give 3-((S)-2-hydroxypropylthio)phenylboronic acid (414 mg, 90%). The crude product was directly used for next step reaction without purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[NH:33][C:34]3[CH:40]=[C:39]([C:41]([O-])=[O:42])[CH:38]=[CH:37][C:35]=3[N:36]=2)=[CH:28][CH:27]=1)#[N:25]>>[OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([NH:20][C:41]([C:39]4[CH:38]=[CH:37][C:35]5[N:36]=[C:32]([C:29]6[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=6)[NH:33][C:34]=5[CH:40]=4)=[O:42])=[CH:19][C:13]=3[N:12]=2)=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(-c2nc3ccc(C(=O)[O-])cc3[nH]2)cc1
Reactant: Nc1ccc2nc(-c3ccc(N(CCO)CCO)cc3)[nH]c2c1
Product: N#Cc1ccc(-c2nc3ccc(C(=O)Nc4ccc5[nH]c(-c6ccc(N(CCO)CCO)cc6)nc5c4)cc3[nH]2)cc1

Procedure:
Compound 293 was prepared according to the procedure similar to that described in Scheme V from 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5-aminobenzimidazole and 2-(4-cyanophenyl)benzimidazole-5-carboxylate. [M+H]+ calcd for C32H25N7O3: 558.22; found: 557.99.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([OH:11])[CH:5]=1.[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:11][C:6]1[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=[CH:8][C:7]=1[NH:10][C:20]([NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)c1ccc(N)c(O)c1
Product: COC(=O)c1ccc(NC(=O)Nc2ccccc2)c(O)c1
Yield: 90.7 %

Procedure:
N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenyl urea was prepared from methyl-4-amino-3-hydroxybenzoate (200 mg, 1.19 mmol) and phenyl isocyanate (1.19 mmol) according to the procedure noted above in General Method A. The product was purified by precipitation from toluene, and filtering, to afford the titled compound (309 mg, 90%). mp: 188.4-188.8° C.; 1H NMR (CD3OD/CDCl3): δ 8.15 (d, 1H, J=8.25 Hz), 7.70 (s, 1H), 7.51 (d, 1H, J=8.25 Hz), 7.43 (d, 2H, J=8.25 Hz), 7.30 (t, 2H, J=8.25 Hz), 7.01 (t, 1H, J=8.25 Hz), 3.87 (s, 3H), EI-MS m/z 286 (M+H)+ ; Anal. (C15H14N2O4) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18][NH:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I.Cl>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18][N:19]([CH3:31])[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(CNc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1ncc(C(=O)O)n1-c1ccc(F)cc1)c1c(F)ccc(F)c1F
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-(((2,3,6-trifluorophenyl)amino)methyl)-1H-imidazole-5-carboxylate (23) (56 mg, 0.14 mmol) in DMF (2 mL) was added sodium hydride (60% in mineral oil, 7 mg, 0.28 mmol) and stirred for 30 minutes. To the solution was added methyl iodide (18 μL, 0.28 mmol) and again stirred overnight at room temperature. Ethyl acetate was added and the reaction was acidified with 2N HCl. The ethyl acetate was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-(4-fluorophenyl)-2-((methyl(2,3,6-trifluorophenyl)amino)methyl)-1H-imidazole-5-carboxylic acid (24).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]([CH3:18])[C:8]2[O:13][C:12]([CH3:15])(O)[CH2:11][CH2:10][C:9]=2[C:16]=1[CH3:17])(=[O:3])[CH3:2].[ClH:20]>CCOCC>[C:1]([O:4][C:5]1[C:6]([CH3:19])=[C:7]([CH3:18])[C:8]2[O:13][C:12]([Cl:20])([CH3:15])[CH2:11][CH2:10][C:9]=2[C:16]=1[CH3:17])(=[O:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(O)O2
Solvent: CCOCC
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(Cl)O2
Yield: 40.2 %

Procedure:
A mixture of 10 g (37.9 mmol) of rac-3,4-dihydro-6-acetyloxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ol and 10 g of 4A molecular sieves in 200 mL of anhydrous ether was stirred with ice-bath cooling while HCl gas was bubbled in for 30 min. The mixture was filtered and the filtrate concentrated in vacuo. The residue was taken up in 600 mL of hexane and anhydrous CaCl2 was added. The mixture was stirred for 1 hr then filtered and the filtrate was concentrate in vacuo giving 4.3 g (40.2% yield) of rac-2-chloro-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol acetate as a colorless solid, mp 102°-106° C., which was unstable to column or thin layer chromatography.