Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][SH:11])=[N:5][N:4]=[N:3]1.[N+:12]([C:15]1[CH:16]=[CH:17][C:18](Cl)=[N:19][CH:20]=1)([O-:14])=[O:13]>[OH-].[Na+].CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][S:11][C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][N:19]=2)=[N:5][N:4]=[N:3]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cn1nnnc1SCCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.9 %

Procedure:
1-Methyl-5-(3-mercaptopropyl)thio-1,2,3,4-tetrazole (1.9 g) is dissolved in 1 N aqueous sodium hydroxide (30 ml), and thereto is added dropwise a solution of 5-nitro-2-chloropyridine (1.9 g) in acetone (20 ml) under ice-cooling. After the addition, the mixture is stirred at room temperature for 3 hours. Acetone is distilled off and water is added to the residue. The mixture is extracted with ether, and the ether solution is washed with diluted aqueous sodium hydroxide and saturated aqueous sodium chloride and dried over sodium sulfate. After ether is distilled off, the residue is purified by column chromatography (Kieselgel 60), followed by eluting with n-hexane-ether (4:1) to give 1-methyl-5-[3-(5-nitro-2-pyridyl)thiopropyl]thio-1,2,3,4-tetrazole (1.4 g), pale brown liquid, nD29 =1.6289.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:11][C:12]([O:15][C:16](=O)[O:17]C(C)(C)C)([CH3:14])[CH3:13].C(N(CC)CC)C>CO>[OH:4][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][NH:1][C:16](=[O:17])[O:15][C:12]([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NC[C@H](O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.4 %

Procedure:
(R)-α-(Aminomethyl)benzenemethanol (1.70 g) and bis(1,1-dimethylethyl)carbonate (2.98 g) were dissolved in methanol (20 ml) and triethylamine (4.3 ml) added. The mixture was stirred at room temperature for 4 days and then concentrated to leave the sub-title compound as an oil (2.60 g).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.[OH:16][C:17]1C=CC(C=O)=CC=1.BrCC(OCC)=O>>[CH:17]([C:15]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)=[O:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)COc1cccc(C=O)c1
Agent: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(C=O)cc1
Yield: 52 %

Procedure:
In an analogous manner to compound 47, 4-hydroxy benzaldehyde (1 eq) and ethyl 2-bromoacetate (1.1 eq) were reacted to produce the desired product (52%) as a brown oil. NMR: δ 1.306 (t, J=6.8 Hz, 3H), 4.29 (q, J=7.2 Hz, 2H), 4.710 (s, 2H), 7.016 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H), 9.904 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][CH:14]([CH3:16])[CH3:15])[CH:4]=1.Cl[Si:18]([CH3:21])([CH3:20])[CH3:19].C([N-]C(C)C)(C)C.[Li+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][CH:14]([CH3:16])[CH3:15])[C:4]=1[Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1ccc(OC)cc1OC(C)C
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c([Si](C)(C)C)c1OC(C)C

Procedure:
More specifically, Scheme 3 shows compound of the formula 9 is prepared by adding a mixture methyl 4-methoxy-2-(l-methylethoxy)benzoate of the formula (10) and chlorotrimethylsilane to a -70° C. -78° C. tetrahydrofuran solution of lithium diisopropylamide to give methyl 4-methoxy-2-(1-methylethoxy)-3-(trimethylsilyl)benzoate (11) regioselectively.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1.[CH3:27][Sn:28](Cl)([CH3:30])[CH3:29]>CCOCC>[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[C:15]([Sn:28]([CH3:30])([CH3:29])[CH3:27])[CH:14]=1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: COc1ccc(NC(=O)OC(C)(C)C)c([Sn](C)(C)C)c1
Temperature: -20 °C
Reaction time: 5 h
Yield: 86.3 %

Procedure:
A solution of t-butyllithium in pentane (1.70M, 148 mL, 251 mmol, 2.50 equiv) was added via cannula to a solution of tert-butyl 4-methoxycarbanilate (22.4 g, 100 mmol, 1 equiv) in ether (500 mL) at -20° C., producing a cloudy yellow solution. After stirring at -20° C. for 5 h, the reaction mixture was cooled to -78° C. and a solution of trimethyltin chloride (50.0 g, 251 mmol, 2.50 equiv) in ether (50 mL) was added via cannula. After the addition, the reaction mixture was warmed to -20° C. and was stirred at that temperature for 30 min, then was stirred in an ice bath for 30 min. The product solution was partitioned between aqueous phosphate buffer solution (pH 7, 0.05M in sodium hydrogen phosphate and 0.05M in potassium dihydrogen phosphate, 600 mL) and ether (400 mL). The aqueous layer was separated and further extracted with ether (2×400 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The product was purified by flash column chromatography (15% ethyl acetate-hexanes) to afford tert-butyl 4-methoxy-2-(trimethylstannyl)carbanilate (7) as a yellow oil (33.3 g, 85%). ##STR19##
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[P:2](=[O:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].[H-].[Na+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C=O)C>[CH2:15]([O:14][P:10]([CH:1]([P:2]([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:9])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([O:11][CH2:12][CH3:13])=[O:17])[CH3:16]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(CC(=O)OC(C)(C)C)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a solution of tetraethyl methylenebisphosphonate (3.00 g, 10.4 mmol) in dry DMF (9 mL) was added NaH (60% suspension in mineral oil, 0.46 g, 11.5 mmol) portionwise. The resulting slurry was stirred for 30 min at room temperature, after which t-butyl bromoacetate (1.7 mL, 11.5 mmol) was quickly added neat. The reaction mixture was stirred for 1 h and quenched by adding 2 mL of a saturated solution of NH4Cl. The reaction mixture was evaporated and purified by flash chromatography on silica gel eluting with 5% methanol/ethyl acetate to give pure 40 (2.1 g, 50%) as a clear colourless oil. 1H NMR (400 MHz, CDCl3) δ 1.33 (bt, J=7.0, 12H), 1.46 (s, 9H), 2H), 2.76 (dt, J=16.0, 6.1, 2H), 3.07 (tt, J=24.0, 6.1, 1H), 4.10-4.25 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]=[N+]=[N-])=[N:6][C:5]=1[Cl:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[N:6][C:5]=1[Cl:14]
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])nc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN)nc1Cl
Temperature: 45 °C

Procedure:
To a solution of 6-azidomethyl-2-chloro-nicotinic acid methyl ester (4.75 g, 21 mmol) in THF (189 mL) and water (3.6 mL) was added triphenylphosphine (11 g, 42 mmol), the reaction mixture was heated at 45° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue azeotroped with methanol. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane) to afford the title compound as a yellow solid. LCMS (method B): RT=2.65 min, [M+H]+=201.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(O[CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:20]1([CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CC(=O)OC(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccccc2c1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 88.6 %

Procedure:
Boron trifluoride-ether complex (0.65 ml, 5.29 mmol) was added to a solution of ethyl indole-2-carboxylate (10.0 g, 52.9 mmol) in 100 ml of methylene chloride, and a solution of benzhydryl acetate (11.4 g, 50.2 mmol) in 50 ml of methylene chloride was dropwise added thereto, followed by stirring at room temperature for 40 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution for neutralization followed by extraction with chloroform. The resulting organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a crude product. The obtained crude product was washed with diisopropyl ether to give 15.8 g (yield: 84%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[N:7]2>C(O)C.[Ni]>[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]2[C:8](=[CH:9][C:10]=1[C:15]([OH:17])=[O:16])[N:7]=[C:6]([C:18]([F:21])([F:19])[F:20])[CH:5]=[CH:4]2
Reactant: Cc1c([N+](=O)[O-])c(C(=O)O)cc2nc(C(F)(F)F)ccc12
Agent: [Ni]
Solvent: CCO
Product: Cc1c(N)c(C(=O)O)cc2nc(C(F)(F)F)ccc12
Reaction time: 12 h
Yield: 71.5 %

Procedure:
A solution of 5-Methyl-6-nitro-2-trifluoromethyl-quinoline-7-carboxylic acid (1.40 g, 4.66 mmol) in ethanol (100 ml) is hydrogenated at atmospheric pressure and ambient temperature in the presence of Raney-nickel catalyst. TLC analysis after 12 hr shows reaction completion. The mixture is filtered over hyflo and the filtrate concentrated in vacuo. The residue is recrystallised from hexane/ethyl acetate to give 0.9 g (71%) of the title compound as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[C:14]([CH3:16])[S:13][C:12]=2Br)=[O:10])=[C:4]([OH:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](=[O:10])[C:11]3[CH:15]=[C:14]([CH3:16])[S:13][C:12]=3[O:18][C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)Nc2ccc(F)cc2O)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc2c(s1)Oc1cc(F)ccc1NC2=O

Procedure:
Similar reaction is carried out using N-(4-fluoro-2-hydroxyphenyl)-2-bromo-5-methyl-3-thiophenecarboxarnide and potassium carbonate to give 8-fluoro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].C=O.[CH3:20]COCC>CO>[ClH:1].[CH2:20]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]=2[CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][NH:2]1
Reactant: COC(=O)C(CN)c1c[nH]c2ccccc12
Reactant: CCOCC
Agent: C=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CNCc2[nH]c3ccccc3c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
2.04 g of methyl 3-amino-2-(indol-3-yl)propionate hydrochloride are dissolved in 60 ml of methanol. 0.83 g of 35% formalin is added thereto, and the mixture is stirred at room temperature for 18 hours. After the reaction, ether is added to the mixture and crystalline precipitates are collected by filtration and dried, whereby 2.04 g of methyl (4RS)-1,2,3,4-tetrahydro-β-carboline-4-carboxylate hydrochloride are obtained as colorless needles. Yield: 95%
Reaction SMILES: FC1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([O:17]C)=O)[C:8]2=[O:22])=CC=1.C1(CN2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)CC1.[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][NH2:52]>>[CH:5]1([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([NH:52][CH2:51][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][N:45]=3)=[O:17])[C:8]2=[O:22])[CH2:23][CH2:24]1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCc1ccccn1
Agent: COC(=O)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Product: O=C(NCc1ccccn1)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Yield: 71 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinate to react with pyridin-2-ylmethanamine, 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-2-ylmethyl)isonicotinamide was obtained as a colorless solid in 71% yield: mp 122-123° C.; 1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.53 (d, J=5.1 Hz, 1H), 8.34 (d, J=5.1 Hz, 1H), 7.77-7.63 (m, 2H), 7.43-7.34 (m, 2H), 7.23-7.18 (m, 1H), 4.74 (d, J=5.1 Hz, 2H), 4.05 (t, J=8.1 Hz, 2H), 3.59 (t, J=8.1 Hz, 2H), 3.16 (d, J=7.2 Hz, 2H), 1.00-0.87 (m, 1H), 0.57-0.50 (m, 2H), 0.25-0.20 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 166.1, 156.9, 155.7, 153.3, 148.4, 148.2, 142.9, 137.6, 122.7, 122.6, 115.5, 109.5, 48.6, 44.5, 41.6, 41.5, 9.1, 3.4; MS (ES+) m/z 352.3 (M+1).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[CH:7]=[CH:6][N+:5]([O-])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:13])=O.P(Cl)(Cl)(Cl)(Cl)Cl>O>[Cl:13][C:6]1[CH:7]=[C:2]([C:1]([OH:10])=[O:9])[CH:3]=[CH:4][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1cc[n+]([O-])cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: O=C(O)c1ccnc(Cl)c1
Reaction time: 8 h
Yield: 66 %

Procedure:
87 g of isonicotinic acid N-oxide, 350 ml of phosphorus oxychloride and 192 g of phosphorus pentachloride were mixed and refluxed for 3 hours. The reaction mixture was poured into water and left to stand overnight. The resulting precipitate was collected by filtration, and recrystallized from ethanol to give 65 g (66%) of 2-chloro-4-pyridinecarboxylic acid.
Reaction SMILES: [OH-].[Na+].C(=O)(O)O.[NH2:7][C:8]([NH2:10])=[NH:9].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH2:18]([O:25][C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([N:33]=[C:34]=[O:35])=[C:28]([CH3:36])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[ClH:37].CO>C1COCC1.CO>[ClH:37].[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH3:36])[C:29]([NH:33][C:34]([NH:9][C:8](=[NH:10])[NH2:7])=[O:35])=[C:30]([CH3:32])[CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1N=C=O
Reactant: N=C(N)N
Agent: Cl
Agent: O=C(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)NC(=N)N
Reaction time: 1 h

Procedure:
A 50% NaOH aqueous solution (8.0 g) is added to a suspension of guanidine carbonate (9.0 g) in 200 ml of THF. The mixture is stirred for one hour, after which 15.0 grams of anhydrous Na2SO4 are added and the mixture stirred an additional hour. A solution of 4-benzyloxy-2,6-dimethylphenyl isocyanate (12.7 g) in 100 ml HTF is added to the mixture over a period of 4 hours. The reaction mixture is allowed to stand overnight, filtered, and the filtrate concentrated under vacuum. The filtrate is partitioned between H2O and CHCl3. The two layers are filtered to remove insoluble materials and then separated. The aqueous layer is extracted with CHCl3 and the combined CHCl3 extracts dried and concentrated under vacuo to give a tan solid. This solid is dissolved in methanol and acidified with HCl/methanol. Methanol is removed under vacuo to give a solid which is crystallized from methanol/acetonitrile to give after filtering and vacuum drying 9.8 grams of the desired amidinourea hydrochloride, M.P. 181°-183° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:8][CH2:7][CH2:6][C:5]2[C:9]([NH:18]C(=O)C)=[C:10]([Cl:17])[CH:11]=[C:12]([C:13]([O:15]C)=[O:14])[C:4]=2[O:3]1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:22])[CH2:8][CH2:7][CH2:6][C:5]2[C:9]([NH2:18])=[C:10]([Cl:17])[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:4]=2[O:3]1
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OC(C)(C)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCCc2c(N)c(Cl)cc(C(=O)O)c2O1

Procedure:
To a solution of 5.46 g (16.8 mmol) of methyl 2,2-dimethyl-6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate in 10 ml of methanol is added 10 ml of a 10% aqueous sodium hydroxide solution in a single portion at room temperature. The solution is heated to reflux and refluxing maintained for 2 hours. After cooling, methanol is removed in vacuo and the residue is diluted with water. The pH of this solution is adjusted to 7 with 1N HCl. The neutral solution is extracted with CH2Cl2 and the combined organic extracts are dried over MgSO4, filtered and concentrated. Flash chromatography (30% EtOAc/hexanes) provides 2,2-dimethyl-6-amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:10]=[C:11]([F:13])[CH:12]=1>O>[F:13][C:11]1[CH:10]=[C:9]2[C:8](=[C:7]([F:6])[CH:12]=1)[C:17](=[O:19])[CH2:16][CH2:15][CH2:14]2
Reactant: O=C(O)CCCc1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCCc2cc(F)cc(F)c21
Temperature: 45 °C
Yield: 64.4 %

Procedure:
A mixture of concentrate sulfuric acid (10.21 kg) and crude 4-(3,5-difluoro-phenyl)-butyric acid (2.8 kg) was stirred at 45° C. until the cyclization reaction was complete by HPLC. The reaction mixture was diluted with water (6.15 kg), and the product was extracted with THF/methylene chloride (2.71/7.33 kg) mixture. The organic layer was sequentially washed with water (4 liters), saturated aqueous sodium bicarbonate (2.64 kg), water (3.0 kg) and 50% diluted brine (8.4 kg). Removal of the solvents provided 1.64 kg (62% yield) of 6,8-difluoro-3,4-dihydro-2H-naphthalen-1-one as a light yellow solid (92.75% pure by HPLC): MP=58.1-58.8° C.; MS (M+1)=183; H1 NMR (300 MHz): δ (DMSO): 2.00 (2H, p, J=6.4 Hz), 2.57 (2H, t, J=6.40 Hz), 2.96 (2H, t, J=6.40 Hz), 7.08-7.20 (2H, m, J=2.26 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1I.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[F:58][C:59]([F:70])([F:69])[C:60]1[CH:65]=[CH:64][C:63]([C:66](=[O:68])[CH3:67])=[CH:62][CH:61]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:67][C:66]([C:63]1[CH:64]=[CH:65][C:60]([C:59]([F:58])([F:69])[F:70])=[CH:61][CH:62]=1)=[O:68]
Reactant: Clc1ccc(I)c(Cl)c1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Cc1ccc(Cl)cc1Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A solution of 6 g of 2,4-Dichloro-1-iodo-benzene, 15.7 g of Cs2CO3, 63 mg of Pd(dba)2 (Bis(dibenzylidenacetonpalladium), 127 mg of Xantphos (9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene) and 8.3 g of 1-(4-Trifluoromethyl-phenyl)ethanone in 45 ml of dioxane was heated under argon for 30 min at 150° C. by microwave irradiation. After cooling to room temperature and dilution with saturated aqueous sodium hydrogen carbonate solution, the reaction mixture was filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 9.1 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH:3]=[C:2]([CH3:1])[CH:7]=1)[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1
Reactant: Cc1cc(C)c([N+](=O)[O-])c(F)c1
Reactant: Nc1ccc(CCO)cc1
Product: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(CCO)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 4,6-dimethyl-2-fluoronitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@H:13]([CH3:16])[C@H:12]([CH2:17][NH2:18])[CH2:11]2)=[CH:4][CH:3]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH:29]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:39][N:38]1[C:34]([C:30]2[CH:29]=[C:28]([NH:27][C:26]([NH:18][CH2:17][C@H:12]3[C@@H:13]([CH3:16])[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:11]3)=[O:25])[CH:33]=[CH:32][CH:31]=2)=[N:35][N:36]=[N:37]1
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: C[C@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CNC(=O)Nc1cccc(-c2nnnn2C)c1
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A solution of cis-1-[2-(4-fluorophenyl)ethyl]-4-methyl-piperidin-3-ylmethylamine (54 mg, 215 μmol) and [3-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (64 mg, 215 μmol) in N,N-dimethylformamide (2 mL) was treated with triethylamine (60 μL, 431 μmol). After 18 hours, the mixture was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 3% methanol in dichloromethane containing 0.3% aqueous ammonium hydroxide, to provide an amorphous solid (73 mg, 75%). 1H NMR (300 MHz, CDCl3) δ7.95 (s, 1H), 7.64 (d, J=7 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 7.29 (m, 1H), 7.11 (m, 2H), 6.97 (t, J=9 Hz, 2H), 4.17 (s, 3H), 3.42 (m, 1H), 3.26 (m, 1H), 3.1-2.5 (m, 8H), 2.1-1.6 (m, 4H), 0.99 (d, J=7 Hz, 3H). Mass spec (AP+) m/z 452.1 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]2[C:7]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:8][C:9]3[CH:10]=[CH:11][NH:12][C:13](=[O:15])[C:14]=3[C:5]=2[CH:4]=1)#[CH:2].[N:25]([Si](C)(C)C)=[N+:26]=[N-:27]>CN(C=O)C.CO.O.[Cu]I>[NH:25]1[CH:2]=[C:1]([C:3]2[CH:24]=[CH:23][C:6]3[C:7]([NH:16][CH:17]([CH3:22])[C:18]([CH3:20])([CH3:19])[CH3:21])=[N:8][C:9]4[CH:10]=[CH:11][NH:12][C:13](=[O:15])[C:14]=4[C:5]=3[CH:4]=2)[N:27]=[N:26]1
Reactant: C#Cc1ccc2c(NC(C)C(C)(C)C)nc3cc[nH]c(=O)c3c2c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(Nc1nc2cc[nH]c(=O)c2c2cc(-c3c[nH]nn3)ccc12)C(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
9-ethynyl-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (150 mg, 0.47 mmol) was dissolved in DMF/MeOH (2.0 mL) in a sealed tube. To the solution was added CuI (5.0 mg, 0.020 mmol) and azidotrimethylsilane (270 mg, 2.4 mmol) under an argon atmosphere. The mixture was stirred at 100° C. in a sealed tube for 8 h. The resulting solution was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate, filtered, and purified by preparative TLC to afford 9-(1H-1,2,3-triazol-4-yl)-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (400 MHz, MeOD) δ 10.28 (s, 1H), 8.38 (d, J=8.4 Hz, 2H), 8.30 (d, J=6.4 Hz, 1H), 7.38 (d, J=7.2 Hz, 1H), 6.64 (d, J=7.2 Hz, 1H), 4.78 (m, 1H), 1.28 (d, J=6.8 Hz, 3H), 1.04 (s, 9H). LRMS calculated for C20H22N6O [M+H]+, 363; found 363.