Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:1]([C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[C:2]2[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=3)[N:3]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1c(N)nc2ccc([N+](=O)[O-])cc2c1NCc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc([N+](=O)[O-])cc3c(NCc3ccccc3)c2C#N)cc1
Yield: 97 %

Procedure:
A suspension of 3.5 g of 2-amino-3-cyano-4-benzylamino-6-nitroquinoline in 50 mL of dry pyridine was refluxed with 5.6 g of 4-methoxybenzoyl chloride for 3.5 hours. The solvent was evaporated in reduced pressure and the residue was suspended in 30 mL of a saturated solution of Na2CO3 in water. The suspension was extracted with 3×25 mL of CH2Cl2. The combined organic extract was evaporated to dryness, the residue was dissolved in diethyl ether and the solution was kept in a refrigerator for a night. The precipitate was filtered off, washed with diethyl ether to give 6.25 g of the title compound, m.p.: 145-148° C. LC-MS: MH+ 588; Ret. time: 7.00 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]CC)=[CH:12][CH:11]=2)[CH:3]=1.B(Cl)(Cl)Cl.Cl.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-ethoxy-benzyl)-benzene (10.0 g, 30.71 mmol) in dichloromethane (40.0 mL) cooled to 0 degrees Celsius under nitrogen was added drop-wise over 30 minutes a 1M solution of boron trichloride in dichloromethane (34 mL, 34.0 mmol). After the addition was complete, the reaction was allowed to warm to room temperature overnight (˜16 hours). The reaction mixture was cooled to 0 degrees Celsius and an aqueous solution of 1N hydrochloric acid was added. The resulting mixture was stirred for 30 minutes and then extracted using dichloromethane. The organic layer was separated and the aqueous layer was extracted two times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The TLC showed only 50% conversion. The crude material was redissolved in dichloromethane (40 mL), cooled to 0 degrees Celsius, and a 1M solution of boron tribromide in dichloromethane (31 mL, 31 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature over the weekend (˜55 hours). The reaction mixture was cooled to 0 degrees Celsius and an aqueous solution of 1N hydrochloric acid was added dropwise. The resulting mixture was stirred for 30 minutes and then extracted using dichloromethane. The organic layer was separated and the aqueous layer was extracted two times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The reaction was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (120 g silica gel column) and eluting with a gradient of 0 to 100% ethyl acetate in heptane. 9 g (98% yield) of the desired product obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O[C:14]1C=C(O)C=CC=1C(O)=O.CI.C(=O)([O-])[O-].[K+].[K+]>S1(CCCC1)(=O)=O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: O=C(O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: CI
Product: COC(=O)c1ccc(OC)cc1O
Reaction time: 8 h

Procedure:
Methyl 2,4-dihydroxybenzoate (prepared from 2,4-dihydroxybenzoic acid by the general method of Brunner (Monatsh. 1913, 34, 916) (12 g) was treated with methyl iodide (12.2 g) and anhydrous potassium carbonate (4.95 g) in dry sulpholane (140 ml) at 60°-70° C. After 8 hours, further methyl iodide (12.2 g) was added and heating was continued for 14 hours. The excess of methyl iodide was evaporated and the mixture was poured into a mixture of ice and water (1 liter) and the mixture was acidified with aqueous acetic acid (2N). The separated solid was filtered off and washed with water to give methyl 2-hydroxy-4-methoxybenzoate (10.8 g), m.p. 47°-50° C. [a sample of which, purified by chromatography on silica gel (eluting with chloroform), had the melting point 49°-51° C⟧ The said crude methyl 2-hydroxy-4-methoxybenzoate (2.0 g) was heated with benzyl chloride (1.88 g) and anhydrous potassium carbonate (0.76 g) in dry sulpholane (15 ml) at 100° C. for 16 hours and was then poured into a mixture of ice and water (300 ml). The mixture was extracted with diethyl ether and the extract was washed with several portions of aqueous sodium hydroxide solution (0.5N) at 0° C., and was then dried and evaporated to give crude methyl 2-benzyloxy-4-methoxybenzoate (2.5 g) in the form of an oil. This material was heated at reflux with a mixture of aqueous sodium hydroxide solution (2N; 100 ml) and ethanol (20 ml) for 3 hours. The mixture was then treated with water (100 ml) and then cooled and extracted with diethyl ether (2 × 50 ml). The aqueous layer was cooled to 10° C. and acidified to pH 2 by treatment with concentrated hydrochloric acid to give 2-benzyloxy-4-methoxybenzoic acid (1.6 g), m.p. 99°-101° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)=[CH:13][CH:12]=[N:11]1>C(O)(=O)C>[I:1][C:13]1[CH:12]=[N:11][N:10]([CH3:9])[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][N:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1nccc1-c1ccc(C(F)(F)F)cn1
Solvent: CC(=O)O
Product: Cn1ncc(I)c1-c1ccc(C(F)(F)F)cn1
Temperature: 70 °C

Procedure:
N-Iodosuccinimide (95%, 427 mg, 1.80 mmol) was added to a mixture of 2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyridine (C13) (390 mg, 1.72 mmol) and acetic acid (4 mL), and the reaction mixture was heated at 70° C. for 1 hour. The mixture was concentrated in vacuo and subjected to silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to afford the product as a white solid. Yield: 524 mg, 1.48 mmol, 86%. APCI m/z 353.8 (M+1). 1H NMR (400 MHz, CD3OD) δ 3.89 (s, 3H), 7.66 (s, 1H), 8.00 (br d, J=8 Hz, 1H), 8.17 (br dd, J=8, 2 Hz, 1H), 8.83 (br d, J=2 Hz, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[C:54]([O:58][C:59]([NH:61][CH:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:63](O)=[O:64])=[O:60])([CH3:57])([CH3:56])[CH3:55]>C1COCC1.C(Cl)Cl>[C:54]([O:58][C:59]([NH:61][CH:62]([C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)[C:63]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])=[O:64])=[O:60])([CH3:57])([CH3:55])[CH3:56]
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (500 mg, 1.50 mmol) in THF (15 ml) and DCM (5 ml), was added triethylamine (591 μl, 4.25 mmol), and the reaction was stirred at RT for 10 minutes. Then DCC (309 mg, 1.50 mmol), HOBT (203 mg, 1.50 mmol), and 2-(tert-butoxycarbonylamino)-2-phenylacetic acid (314 mg, 1.25 mmol) were added, and the reaction was stirred at RT for 15 hours. The solvent was evaporated, the residue was taken up with DCM, and the insoluble was removed by filtration. The organic solution was washed twice with 1N Na2CO3 and brine, dried over Na2SO4 and evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5) to obtain (R)-quinuclidin-3-yl 2-(2-(tert-butoxycarbonylamino)-2-phenylacetamido)-2-phenylacetate (210 mg, 34% yield).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f28) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6](Cl)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1COCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: C1CNCCN1
Reactant: Clc1ccc2c(c1)SCc1cccnc1C2Cl
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)SCc1cccnc1C2N1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
A slurry of 8,11-dichloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridine (3.79 g, 13.43 mmol) in THF (25 ml) was added dropwise to piperazine (3.53 g, 157 mmol) in THF (50 ml) over 45 minutes. The mixture was stirred at room temperature for 5 hours and the reaction was then quenched with the slow addition of NaOH (200 ml, 2.5N) and extracted with CH2Cl2 (400 ml and 4×100 ml). The combined organic layers were washed with brine, dried (Na2SO4), decanted and concentrated; the crude product was purified by flash chromatography (10%acetone/CH2Cl2 to 10%MeOH/CH2Cl2 /NH4OH) and obtained as a white solid (4.08 g, 91%); MS (FAB, M+H)=332; found: C, 61.73; H, .5.60; N, 12.40; C17H18ClN3S requires: C, 61.53; H, 5.47; N, 12.66.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)(=[O:17])[CH3:16]>S1(CCCC1)(=O)=O>[C:15]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)[CH2:21][CH2:20]1)(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1ccncc1
Reactant: Cc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CC(=O)NC1CCN(c2cccc(C)n2)CC1
Reaction time: 24 h
Yield: 28 %

Procedure:
0.042 mole of 2-chloro-6-methylpyridine, 0.056 mole of anhydrous potassium carbonate and 0.052 mole of 4-acetamidopyridine in 75 ml of sulfolane are heated to 150° C. with stirring for 24 hours, then the sulfolane is concentrated up to 1.5 of its volume, the mixture is poured into 100 ml of water and extraction is effected four times with 150 ml of diethyl ether. The organic phase is washed with water, it is dried over anhydrous sodium sulfate, concentrated to dryness and the residue is crystallised in 40 m of ethyl acetate. Thus, the 4-acetamido-1-(6-methyl-2-pyridyl)piperidine is obtained; m.p. 145° to 147° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23](O)=[O:24])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:38][CH2:37][C@@H:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:34][CH2:35][C@@H:36]([NH:39][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]=3[NH:22][CH:21]=2)=[O:24])[CH2:37][CH2:38]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A75) and cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH:12]([O:14]C(=O)C)[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[OH-].[Li+].O.C(Cl)(Cl)Cl>C1COCC1.CO.O>[Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)OC1C=CC(O[Si](C)(C)C(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
Dissolve (-)-acetic acid 4-tert-butyldimethylsilyloxy-cyclopent-2-enyl ester (2.3 mmol, prepared in example 10) in THF/methanol/water (2.7/0.9/0.9 mL). Add lithium hydroxide monohydrate (2.5 mmol) with stirring. After stirring for about 3 hours at room temperature, dilute the reaction with water (10 mL) and extract with tert-butyl methyl ether. Combine the organic phases, dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (silica gel, 20% ethyl acetate/hexane) to provide the title compound (452 mg, 92% yield), [α]20D =+21.80, (c=1.02, chloroform).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH:9]2[CH2:13][CH2:12][CH:11]([O:14]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:10]2)[C:4](=[O:26])[N:3]=1.C[O-].[Na+]>>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[C:4](=[O:26])[N:3]=1
Reactant: Nc1nc(=O)n(C2CCC(OC(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1F
Agent: C[O-]
Agent: [Na+]
Product: Nc1nc(=O)n(C2CCC(O)C2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A solution of 4-Nitro-benzoic acid 3-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-cyclopentyl ester (1.27 g, 3.50 mmol) in anhydrous sodium methoxide (0.5 M in methanol, 20 mL, 10 mmol). The mixture was stirred under nitrogen at room temperature for 2 hours, and the solvent was removed in vacuo. The residue was dry-loaded onto silica gel and purified by silica gel plug filtration (20 g SiO2, CH2Cl2/Methanol/ammonium hydroxide: 88/12/0.25) to afford 4-Amino-5-fluoro-1-(3-hydroxy-cyclopentyl)-1H-pyrimidin-2-one 29 as an off-white solid (0.346 g, 46%).
Reaction SMILES: C=O.[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][C:13]1[N:14]=[C:15](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:16][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:26](OCC)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2[N:14]=[C:15](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:16][C:17]=2[CH2:26]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)NCCc1coc(/C=C/c2ccccc2)n1
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2nc(/C=C/c3ccccc3)oc2C1

Procedure:
Paraformaldehyde (54.5 mg) and p-toluenesulfonic acid (7.2 mg) were added to a solution of 4-[2-(tert-butoxycarbonylamino)ethyl]-2-(trans-styryl)oxazole (190 mg) in toluene (15 ml) at room temperature. After heating under reflux for 1 hour, the reaction mixture was allowed to cool, and ethyl acetate (15 ml) and a saturated aqueous solution (15 ml) of sodium hydrogen-carbonate were added to the reaction mixture to separate an organic layer. After the water layer was extracted with ethyl acetate (10 ml), the resultant organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1→2:1) to obtain the title compound (153 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([NH:13]C(=O)C2C=CC=CC=2)[CH:3]=1>Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([NH2:13])[CH:3]=1
Reactant: O=C(Nc1cc(Cl)c2ccc(Cl)cc2n1)c1ccccc1
Agent: Cl
Product: Nc1cc(Cl)c2ccc(Cl)cc2n1
Temperature: 25 °C

Procedure:
A mixture of example 289B (5.0 g, 15.8 mmol) and hydrochloric acid (22%, 150 mL) was heated to reflux for 24 hours, cooled to room temperature, filtered. Filtrate was basified with 50% sodium hydroxide. Pale green solid was collected by filtration, washed with large quantity of water and dried under vacuum. MS (ESI(+)Q1MS m/z 291 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:33][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)=[O:18])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:24])=[O:25]
Reactant: Nc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)Nc4cccnc4)cc3)oc2C)cc1
Yield: 55.1 %

Procedure:
Method E. Reaction of oxalyl chloride (100 λL, 1.1 mmol) and benzoic acid 4 (207 mg, 0.6 mmol) with subsequent coupling to 3-aminopyridine (58 mg, 0.6 mmol) gave benzamide 5 (148 mg, 59%) as a white powder: mp (EtOAc) 248-250° C.; 1H NMR δ 10.56 (s, 1 H, CONH), 8.94 (d, J=2.2Hz, 1 H, H-2′), 8.33 (dd, J=4.7, 1.5 Hz, 1 H, H-6′), 8.20 (ddd, J=8.3, 2.5, 1.5 Hz, 1 H, H-4′), 8.10 (br d, J=8.6 Hz, 2 H, H-2, H-6), 7.97 (br d, J=8.6 Hz, 2 H, H-3, H-5), 7.69 (br d, J=8.3Hz, 2 H, H-2″, H-6″), 7.38-7.45 (m, 3 H, H-5′, H-3″, H-5″), 4.65 (s, 2 H, CH2SO2), 2.41 (s, 3 H, CH3), 2.16 (s, 3 H, CH3); 13C NMR δ 165.0, 157.9, 150.1, 144.7 (2), 144.5, 142.1, 135.6, 135.5, 129.7 (2), 129.3, 128.6 (2), 128.3 (2), 127.4, 126.1, 125.5 (2), 123.5, 53.0, 21.1, 9.7; MS m/z 448.7 (MH+, 100%). Anal. calcd for C24H21N3O4S: C, 64.41; H, 4.73; N, 9.39. Found: C, 64.18; H, 4.74; N, 9.39%.
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH2:10][C@@H:9]([C:12]([CH3:14])=[CH2:13])[CH2:8][C:7]1=[CH:6][C:5](=[O:15])[CH2:4][CH2:3]2.S(=O)(=O)(O)[OH:17]>C(O)=O>[CH3:1][C:2]12[CH2:11][CH2:10][C@@H:9]([C:12]([OH:17])([CH3:14])[CH3:13])[CH2:8][C:7]1=[CH:6][C:5](=[O:15])[CH2:4][CH2:3]2
Reactant: O=S(=O)(O)O
Reactant: C=C(C)[C@@H]1CCC2(C)CCC(=O)C=C2C1
Solvent: O=CO
Product: CC12CCC(=O)C=C1C[C@H](C(C)(C)O)CC2

Procedure:
In Scheme V, treatment of (6R/S,9R)-6-methyl-9-(1-methylvinyl)-bicyclo[4,4,0]dec-1-ene-3-one (1) with mixture of sulfuric acid and formic acid at room temperature produces (6R/S,9R)-6methyl-9-(1-hydroxyisopropyl)-bicyclo[4.4.0]-dec-1-ene-3-one (14). Compound (14) reacts with organometallic reagent such Grignard reagent or organolithium reagent to form compound of formula (15) and the reaction is conducted in diethylether, tetrahydrofuran or any other solvent that does not interfere with the reaction at room temperature or cooled with ice bath or ice-salt mixture. Cyclization of compound of formula (15) to form compound of formula (Ie) is carried out in acidic medium, optionally with inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid in any solvent that does not interfere with the reaction such as water, methanol, ethanol, diethylether, benzene, toluene, methylene chloride, chloroform, ethylacetate, tetrahydrofuran, or a mixture thereof, particularly benzene-water, diethylether-water mixture. The reaction temperature is usually room temperature or lower.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:28])=[C:9]([NH:11][C:12]2[C:21]3[C:16](=[C:17](Cl)[N:18]=[CH:19][CH:20]=3)[C:15]3[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=3[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C([O-])(O)=[O:31].[Na+]>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:28])=[C:9]([NH:11][C:12]2[C:21]3[CH:20]=[CH:19][NH:18][C:17](=[O:31])[C:16]=3[C:15]3[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=3[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: Cc1ccc(C(C)(C)C)cc1Nc1nc2ccc(F)cc2c2c(Cl)nccc12
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)C)cc1Nc1nc2ccc(F)cc2c2c(=O)[nH]ccc12
Temperature: 25 °C

Procedure:
N-(5-tert-butyl-2-methylphenyl)-1-chloro-9-fluorobenzo[c]-2,6-naphthridin-5-amine (110 mg, 0.28 mmol) was taken up in THF (3.5 mL) and 6 N HCl (3.5 mL) and heated to 85° C. for 2 hr. The reaction was cooled to room temperature, neutralized with saturated NaHCO3 and extracted with EtOAc. The organic layers were dried over Mg2SO4, filtered, and concentrated. Column chromatography on silica gel (100% hexane to 100% EtOAc) provided the title compound.
Reaction SMILES: [O:1]=[C:2]([CH2:7][Cl:8])[CH2:3][C:4]([OH:6])=[O:5].[C-:9]#[N:10].[Na+].Cl>O>[C:9]([C:2]([OH:1])([CH2:7][Cl:8])[CH2:3][C:4]([OH:6])=[O:5])#[N:10]
Reactant: O=C(O)CC(=O)CCl
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CC(O)(CCl)CC(=O)O
Yield: 82 %

Procedure:
68.8 g of 3-oxo-4-chlorobutyric acid (94.2 percent purity by NMR) (0.476 mols) was mixed with 200 ml of distilled water in a three neck flask fitted with a thermometer, dropping funnel, stirrer and connected via an ice condenser to a nitrogen bubbler which was connected to a NaOH trap in series. Sodium cyanide (24.5 g) (0.50 mol) was dissolved in 75 ml of water and placed in the dropping funnel. The contents of the flask were cooled in an ice bath and the NaCN solution added at 10°-15°C to give a pH of 8. The mixture was brought to a pH of 0.8 with 46 ml (0.568 mol) concentrated HCl and then extracted with five 100 ml. portions of ether. The combined ether extract was dried with anhydrous MgSO4. After filtering off the drying agent and washing the solids with ether, the ether was evaporated on a rotary evaporator at 35°-40°C. Assay of the 78.3 g of product by NMR showed 80.6 percent 3-cyano-3-hydroxy-4-chlorobutyric acid, 8.22 percent water, 3.53 percent acetoacetic acid and 7.6 percent ether. The last traces of ether and water were quite difficult to remove. The yield was 82 percent.