Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(Cl)cc(CCCBr)c1
Reaction time: 12 h
Yield: 80.9 %

Procedure:
Compound 35-2 (1.23 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (1.75 g) and N-bromosuccinimide (1.17 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.30 g) as a colorless oil.
Reaction SMILES: Cl.[C:2]([C@@H:5]1[CH2:9][C@H:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][NH:6]1)(=[O:4])N.[OH-:20].[Na+]>Cl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:10][C@@H:8]2[CH2:7][NH:6][C@H:5]([C:2]([OH:20])=[O:4])[CH2:9]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc(CS[C@@H]2CN[C@H](C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4.0 g of (2S,4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine hydrochloride were dissolved in 40 ml of 2N aqueous hydrochloric acid, and the resulting solution was stirred for 1.5 hours on an oil bath at 95°-100° C. At the end of this time, the solution was cooled to room temperature, and then about 40 ml of a 2N aqueous solution of sodium hydroxide were added to the solution, whilst stirring, to adjust its pH to a value of between 4 and 6. The crystals which separated were collected by filtration, washed with water and dried in the air, to yield 3.25 g of the title compound as crystals, melting at 198°-200° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:13])[N:9]=[C:10]([CH3:12])[CH2:11][C:3]=12.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH3:13][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:3]2[CH2:11][C:10]([CH3:12])=[N:9]1
Reactant: CC1=NN(C)c2ncnc(Cl)c2C1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=NN(C)c2ncnc(-c3ccccc3)c2C1
Temperature: 100 °C
Yield: 37.5 %

Procedure:
The 5-chloro-1,3-dimethyl-1,4-dihydropyridazino[3,4-d]pyrimidine (1.1 g), phenyl boronic acid (682 mg) and potassium carbonate (771 mg) were dissolved in toluene (15 mL) and water (1.5 mL). After the reaction mixture was degassed with nitrogen for 30 minute, Pd(PPh3)4 (323 mg) was added. The reaction mixture was again degassed with nitrogen for 20 minutes and then heated to 100° C. for 3 hours in a sealed tube. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (2×20 mL). The combined filtrate was washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography using MeOH/CHCl3 (0.8:9.2) as eluent to afford 1,3-dimethyl-5-phenyl-1,4-dihydropyridazino[3,4-d]pyrimidine (500 mg) as colorless viscous liquid. 1H NMR (DMSO-d6): δ 1.89 (s, 3H), 3.37 (s, 3H), 3.52 (s, 2H), 7.47-7.57 (m, 5H), 8.60 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][N:13]1[C:17](=[O:18])C2=CC=CC=C2C1=O.[OH2:24].NN.Cl>CO>[C:4]([O:24][C:17](=[O:18])[NH:13][CH2:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:12])([CH3:5])[CH3:3]
Reactant: O
Reactant: COc1ccc([N+](=O)[O-])cc1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CO
Product: COc1ccc([N+](=O)[O-])cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
To a mixture of the compound (357 mg) obtained in Example 117 and methanol (10 ml), hydrazine monohydrate (0.06 ml) was added and stirred at room temperature for 3 h. The reaction mixture was made acidic by addition of 2 N HCl and washed with ethyl acetate. The aqueous layer was made alkaline by addition of a 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate; then, the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the resulting residue in dimethylformamide (10 ml), di-t-butyl dicarbonate (274 mg) and triethylamine (0.17 ml) were added and stirred at room temperature for 3 h. Water and 2 N HCl were added to the reaction mixture and extraction was performed with ethyl acetate; then, the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1) to give 62 mg of the titled compound (yield, 20%).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2ccc(F)cc2)nc1
Temperature: 24 °C
Reaction time: 0.12 h
Yield: 98 %

Procedure:
To a 2-L, 3-necked, round-bottomed flask equipped with a mechanical stirrer, a thermo couple, and a condenser was added DMF (194 mL), ethyl 6-chloronicotinate (100.00 g, 0.522 mol), and 4-fluorophenol (65.09 g, 0.575 mol). A brown solution formed after stirring for 5-10 min. To the solution was then added Cs2CO3 (189.19 g, 0.575 mol) in one portion. The reaction temperature increased from 20° C. to 30° C. over 10 min without external heating and then started cooling down. The resulting suspension was stirred at rt for 2-3 h and the internal reaction temperature cooled back to 23-25° C. The reaction mixture was then heated to 60° C. and stirred for 18-20 h. HPLC analysis indicated that the reaction was complete. The heating mantle was removed and the reaction mixture was allowed to cool to 25-30° C. To the mixture was added deionized water (145.5 mL) in a steady stream over 5 min and a slight exotherm was observed. The resulting suspension was stirred at rt for 15-20 min. Two additional portions of deionized water (145.5 mL each) were added and the suspension was stirred at rt for 15-30 min. The pH of the suspension was around 9-10. The solid product was collected by vacuum filtration, rinsed thoroughly with deionized water in portions. The filter cake as dried in a filter funnel by pulling through air for 24 h. The product was isolated as a white solid (133.6 g). mp: 68.0° C. (by DSC). 1H NMR (CDCl3): δ 8.81 (d, J=2.6 Hz, 1H), 8.22 (dd, J=8.5, 2.6 Hz, 1H), 7.12 (br s, 2H), 7.10 (d, J=1.0 Hz, 2H), 6.94 (d, J=8.5 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 4.38 (t, J=7.1 Hz, 3H). MS (ESI): M+H+=262.1.
Reaction SMILES: [C:1]([C:4]1[C:21](=[O:22])[C@:20]2([OH:23])[C@@H:7]([CH2:8][C@H:9]3[C:18](=[C:19]2[OH:24])[C:17](=[O:25])[C:16]2[C:15]([OH:26])=[C:14]([NH:27][C:28]([C@@H:30]4[CH2:34][CH2:33][CH2:32][N:31]4C(OCC4C=CC=CC=4)=O)=[O:29])[CH:13]=[C:12]([N:45]([CH3:47])[CH3:46])[C:11]=2[CH2:10]3)[C@H:6]([N:48]([CH3:50])[CH3:49])[C:5]=1[OH:51])(=[O:3])[NH2:2]>CO.[Pd]>[C:1]([C:4]1[C:21](=[O:22])[C@:20]2([OH:23])[C@@H:7]([CH2:8][C@H:9]3[C:18](=[C:19]2[OH:24])[C:17](=[O:25])[C:16]2[C:15]([OH:26])=[C:14]([NH:27][C:28]([C@@H:30]4[CH2:34][CH2:33][CH2:32][NH:31]4)=[O:29])[CH:13]=[C:12]([N:45]([CH3:46])[CH3:47])[C:11]=2[CH2:10]3)[C@H:6]([N:48]([CH3:50])[CH3:49])[C:5]=1[OH:51])(=[O:3])[NH2:2]
Reactant: CN(C)c1cc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Agent: [Pd]
Solvent: CO
Product: CN(C)c1cc(NC(=O)[C@@H]2CCCN2)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Reaction time: 1 h
Yield: 72.6 %

Procedure:
A suspension of (S)-benzyl 2-((5aR,6aS,7S,10aS)-9-carbamoyl-4,7-bis(dimethylamino)-1,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-ylcarbamoyl)pyrrolidine-1-carboxylate (200 mg, 0.29 mmol) and 10% Pd on charcoal in methanol (10 mL) was hydrogenated over 1 h. The reaction mixture was filtered through a pad of celite and the filtrate was poured into ether containing HCl to get (S)—N-((5aR,6aS,7S,10aS)-9-carbamoyl-4,7-bis(dimethylamino)-1,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl)pyrrolidine-2-carboxamide (120 mg, 72%).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:8]=1)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+].[Cl-].[Li+]>CN(C)C=O>[CH2:16]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[NH:5][C:4](=[O:19])[C:3]([C:1]2[NH:22][N:21]=[N:20][N:2]=2)=[CH:8][CH:7]=1)[CH2:17][CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCOc1ccccc1-c1ccc(C#N)c(=O)[nH]1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCOc1ccccc1-c1ccc(-c2nnn[nH]2)c(=O)[nH]1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 3-cyano-6-(2-propoxyphenyl)-2(1H)-pyridinone (1.85 g), sodium azide (0.59 g), ammonium chloride (0.49 g) and lithium chloride (0.39 g) in dry dimethylformamide (75 ml) was heated at 120° C. for 72 hours. The reaction mixture was evaporated to dryness and the resultant residue treated with water (100 ml) and acidified with glacial acetic acid to afford a precipitate which was collected and dissolved in warm dilute aqueous potassium bicarbonate. The aqueous solution was allowed to stand overnight at room temperature, was filtered and the filtrate was acidified with concentrated hydrochloric acid to afford a yellow precipitate, 1.80 g, m.p. 226°-230° C. This was recrystallized from ethanol (with charcoal) to afford the pure title compound, 1.08 g, m.p. 229°-231° C.
Reaction SMILES: Cl.[NH+]1C=CC=CC=1.N1(C2SC3C=CC([OH:23])=CC=3N=2)CCNCC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[F:37][C:38]([F:58])([F:57])[C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:47]2[S:48][C:49]3[CH:55]=[CH:54][C:53](O)=[CH:52][C:50]=3[N:51]=2)[CH2:43][CH2:42]1)=[O:40]>FC(F)(F)C(O)=O.CC(O)(C)C>[F:37][C:38]([F:58])([F:57])[C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:47]2[S:48][C:49]3[C:55]([OH:23])=[CH:54][CH:53]=[CH:52][C:50]=3[N:51]=2)[CH2:43][CH2:42]1)=[O:40]
Reactant: Oc1ccc2sc(N3CCNCC3)nc2c1
Reactant: O=C(N1CCN(c2nc3cc(O)ccc3s2)CC1)C(F)(F)F
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)(C)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(N1CCN(c2nc3cccc(O)c3s2)CC1)C(F)(F)F
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
The thiourea obtained from the reaction of 3-methoxyphenyl isothiocyanate (5.02 g, 30.4 mmol) with piperazine (13.01 g, 151 mmol) in refluxing t-BuOH was cyclized with K3Fe(CN)6 and subsequently deprotected with molten pyridinium hydrochloride at about 160° C. according to the procedure described for Preparation 84, but without the chromatographic separation of the 5- and 7- isomers. The resulting 2-(piperazinyl)-benzothiazol-5-ol and -7-ol mixture (2.35 g, 10 mmol) was dissolved in trifluoroacetic acid (20 mL) and chilled to about 0-5° C. Trifluoroacetic anhydride (3.4 mL, 24 mmol) was added dropwise over several minutes. After stirring for about 3 h. at about 20° C. the mixture was concentrated in vacuo at about 35° C. and then redissolved in H2O (50 ml) with adjustment of the pH to 6-7 by careful addition of saturated aqueous K2CO3. The mixture was stirred for about 30 min. at about 20° C., diluted with H2O (60 mL) and extracted with 5% MeOH in CH2Cl2 (1×100 mL, 2→40 mL). Pooled organic extracts were dried over Na2SO4 (s) and concentrated in vacuo to afford a mixture of the 2-(4-trifluoroacetylpiperazin-1-yl) benzothiazol-5-ol and -7-ol isomers as a foamy solid (2.12 g; GC-MS m/z 331). The isomers were resolved by flash chromatography on silica (35% EtOAc/hexanes) to yield 820 mg of the pure 2-(4-trifluoroacetyl-piperazin-1-yl)benzothiazol-7-ol as the faster eluting isomer.
Reaction SMILES: O=[C:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[NH2:17][CH:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[CH:18]([N:17]=[C:2]1[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][O:5][C:4]3[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=3)[CH2:19]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C1c2ccccc2OCc2ncccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: c1ccc2c(c1)OCc1ncccc1C2=NC1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.5 %

Procedure:
In this example, 2.1 g of 5-oxo-5,11-dihydro[1]benzoxepino[3,4-b]pyridine and 8.8 g of 3-aminoquinuclidine were dissolved in 50 ml of anhydrous benzene. Then, a solution of 1.1 g of titanium tetrachloride in 20 ml of anhydrous benzene was added dropwise thereto under ice cooling. The mixture was stirred under ice cooling for 3 hours and at room temperature for an additional two days. After completion of the reaction, the precipitate formed was filtered away, and the filtrate was concentrated under the reduced pressure. Then, 150 ml of ethyl acetate and 30 ml of water were added thereto and the mixture was shaken. The separated aqueous layer was removed, and the ethyl acetate layer was dried and concentrated. Purification of the residue by chromatography on silica gel, followed by concentration of the main fraction, gave 1.35 g of 5-(3-quinuclidinyl)imino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine as crystals. This product was dissolved in 20 ml of methanol and pH of the solution was adjusted to 5 with hydrochloric acid. Then, 1.0 g of sodium borocyanohydride was added thereto, and the mixture was heated at 40°-50° C. for 8 hours. After addition of 30 ml water, pH was adjusted to 12 with 1N aqueous sodium hydroxide solution, and the alkaline solution was extracted twice with 100 ml ethyl acetate. The ethyl acetate layer was dried and concentrated under reduced pressure, and the residue was purified by chromatography on silica gel. The main fraction was concentrated, whereby 1.0 g of 5-(3-quinuclidinyl)amino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine (compound 25) as a diastereomeric mixture was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])[O:6][CH:7]=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31].CN(C)C=O.[H-].[Na+]>O>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][CH2:8][C:5]1[O:6][CH:7]=[C:3]([CH2:2][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[N:4]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCc1nc(CCl)co1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccccc1OCc1coc(CCc2nc(-c3ccccc3)oc2C)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.1 %

Procedure:
To a mixture of 4-[2-(4-chloromethyl-2-oxazolyl)ethyl]-5-methyl-2-phenyloxazole (0.50 g), methyl 2-(2-hydroxyphenyl)acetate (0.25 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.07 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water, 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-oxazolyl]methoxy]phenyl]acetate as a colorless oil (0.43 g, 66%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:30])[CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[N:18][CH:17]=2)=[C:10](Cl)[CH:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[Cl:22][C:20]1[CH:21]=[C:16]([C:15]2[O:28][C:10]3[CH:9]=[C:8]([O:7][CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:30])[N:13]=[CH:12][C:11]=3[N:14]=2)[CH:17]=[N:18][C:19]=1[O:23][CH2:24][CH:25]1[CH2:27][CH2:26]1
Reactant: CC(=O)N[C@@H](C)COc1cc(Cl)c(NC(=O)c2cnc(OCC3CC3)c(Cl)c2)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cnc(OCC4CC4)c(Cl)c3)nc2cn1
Temperature: 160 °C
Reaction time: 3 h
Yield: 18.3 %

Procedure:
A suspension of N-(6-(((2S)-2-acetamidopropyl)oxy)-4-chloropyridin-3-yl)-5-chloro-6-(cyclopropylmethoxy)nicotinamide (910 mg), potassium carbonate (555 mg) and copper(I) iodide (38.2 mg) in DMF (10 mL) was stirred at 160° C. for 3 hr under microwave irradiation. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was washed with ethyl acetate/hexane to give the title compound (153 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][CH2:23][CH2:24][O:25][CH2:26][C:27](O)=[O:28].CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C>[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])=[O:28]
Reactant: O=C(COCCO)OCc1ccccc1
Reactant: O=C(O)COCCOC1CCCCO1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Product: O=C(COCCOC1CCCCO1)OCCOCC(=O)OCc1ccccc1
Yield: 82 %

Procedure:
A solution of the alcohol 4 (685 mg, 3.26 mmol), the acid 2 (932 mg, 4.57 mmol), DIC (680 μl, 4.57 mmol) and DMAP (39 mg, 0.32 mmol) was stirred overnight at room temperature. The mixture was then filtered and concentrated. Flash chromatography on silica gel (EtOAc/pentane 1/1) afforded compound 5 as an oil (1.06 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:12][CH2:13][O:14][CH3:15])[C:9]([OH:11])=O)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:12][CH2:13][O:14][CH3:15])[C:9]([NH:26][C:27]2[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=2)=[O:11])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COCCC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: COCCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
417 mg (purity 76%, 0.83 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) were reacted with 177 mg (0.91 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate according to General Method 5A. Yield: 438 mg (92% of theory)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:7]1[O:11][N:10]=[C:9]([NH2:12])[CH:8]=1)([CH3:6])[CH3:5].C(C1C=C(N[C:22](=[O:30])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)ON=1)(C)C>>[CH3:1][O:2][CH2:3][C:4]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:22](=[O:30])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:8]=1)([CH3:6])[CH3:5]
Reactant: COCC(C)(C)c1cc(N)no1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Product: COCC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Yield: 98 %

Procedure:
Prepared from 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine (30 mg, 0.176 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as an oil (50 mg, 98%). 1H NMR (300 MHz, CDCl3) δ 8.04 (brs, 1H), 7.42-7.43 (m, 2H), 7.31 (m, 1H), 7.18-7.21 (m, 2H), 6.63 (s, 1H), 3.45 (s, 2H), 3.33 (s, 3H), 1.35 (s, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:20])[CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][CH2:12][CH2:11][CH2:10]1.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>CC(C)=O.O>[CH3:7][N:8]([CH3:20])[CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C1CCCNc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Yield: 97.1 %

Procedure:
38.8 g of potassium carbonate was added to a solution of 50 g of 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 400 ml of acetone and 200 ml of water. To the solution was added 40 g of p-nitrobenzoyl chloride with ice-cooling and stirring. The resulting mixture was stirred overnight at room temperature. The reaction mixture was mixed with an appropriate amount of water. The resulting crystals were collected by filtration and dried to obtain 71 g of 5-dimethylamino-1-(4-nitro-benzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: C([O:5][C:6](=[O:23])[CH2:7][N:8]1[CH2:17][C:16]2[N:15]=[CH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]=2[CH2:10][CH2:9]1)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[CH2:21]([O:20][C:18]([C:13]1[CH:14]=[N:15][C:16]2[CH2:17][N:8]([CH2:7][C:6]([OH:23])=[O:5])[CH2:9][CH2:10][C:11]=2[CH:12]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cnc2c(c1)CCN(CC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2c(c1)CCN(CC(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 7-(2-tert-butoxy-2-oxoethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylate (657 mg, 2.05 mmol) in dioxane (10 mL) is added 4 N HCl in dioxane (5 ml, 20 mmol) and the mixture is stirred at rt overnight. The solvent is removed and the residue is washed with ether to give the title compound as a white solid. MS (M+1): 265.1.