Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[CH2:7][CH2:6][N:5](C(=O)C)[CH2:4][CH2:3]1.[OH-].[Na+]>Cl>[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1[C:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]=1
Reactant: CC(=O)N1CCC(O)(c2ccc3ccccc3c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C1=C(c2ccc3ccccc3c2)CCNC1
Yield: 77.9 %

Procedure:
1-(4-Hydroxy-4-naphthalen-2-yl-piperidin-1-yl)ethanone (3.40 g, 13 mmol) was dissolved in hydrochloric acid (50 ml, 6M) and the solution refluxed for 12 hours. The resultant mixture was cooled in ice, basified with sodium hydroxide solution (32 ml, 10M) and extracted with dichloromethane (2×100 ml). The extracts were combined, dried (MgSO4) and concentrated to give 4-naphthalen-2-yl-1,2,3,6-tetrahydropyridine (2.12 g, 78% ) as a tan solid; δH (CDCl3) 2.60 (2H, m, tetrahydropyridinyl CH2), 3.20 (2H, t, J 5.6 Hz, tetrahydropyridinyl CH2), 3.60 (2H, m, tetrahydropyridinyl CH2), 6.30 (1H, m, CH=CR), 7.45 (2H, m, ArH), 7.60 (1H, dd, J 8.4, 1.4 Hz, ArH), and 7.80 (4H, m, ArH).
Reaction SMILES: [NH:1]1[C:5](=O)[CH2:4][C:3]2([CH2:18][CH2:17][N:9]3[C:10]4[C:15]([CH:16]=[C:8]3[CH2:7]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:2]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[NH:1]1[CH2:5][CH2:4][C:3]2([CH2:18][CH2:17][N:9]3[C:10]4[C:15]([CH:16]=[C:8]3[CH2:7]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:2]1
Reactant: O=C1CC2(CCn3c(cc4ccccc43)C2)C(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)cc1n2CCC2(CCNC2)C1
Yield: 69.7 %

Procedure:
A solution of 100 mg of 7,9-dihydrospiro[pyrido[1,2-a]indole-8(6H),3'-pyrrolidine]-2',5'-dione in 10 ml of THF was added dropwise to a suspension of 152 mg of lithium aluminium hydride in 20 ml of THF. After completion of the addition the mixture was heated at reflux for 20 hours. 20 ml of water were added to the cooled mixture and the resulting mixture was extracted with diethyl ether. The etheral extracts were washed with water, dried and concentrated. There were obtained 62 mg of 7,9-dihydrospiro[pyrido[1,2-a]indole-8(6H),3'-pyrrolidine].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:22])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15](/[CH:18]=[CH:19]/[CH2:20]Cl)[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:23][NH:24][CH2:25][CH2:26][CH3:27]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:22])[N:10]([CH3:11])[C@H:12]2[CH2:17][CH2:16][C@H:15](/[CH:18]=[CH:19]/[CH2:20][N:24]([CH3:23])[CH2:25][CH2:26][CH3:27])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCCNC
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](/C=C/CCl)CC1
Solvent: CO
Product: CCCN(C)C/C=C/[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 80 mg (0.23 mmol) of trans-(1E)-[4-(3-Chloro-propenyl)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester in 4.3 ml of methanol was treated with 0.24 ml (2.34 mmol) N-methylpropylamine and stirred over night at RT. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 95:5) gave 46 mg (52%) of trans-(1E)-Methyl-{4-[3-(methyl-propyl-amino)-propenyl]-cyclohexyl}-carbamic acid 4-chloro-phenyl ester, MS: 379 (MH+, 1Cl).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:38][C:39]1[CH:40]=[C:41]([NH2:45])[CH:42]=[N:43][CH:44]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:45][C:41]5[CH:42]=[N:43][CH:44]=[C:39]([F:38])[CH:40]=5)=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cncc(F)c1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3cncc(F)c3)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.5 %

Procedure:
A solution of the product of Example 19C (259 mg, 0.488 mmol) in anhydrous tetrahydrofuran (5 mL) was treated with the product of Example 224C (60.2 mg, 0.537 mmol) and diisopropylethylamine (0.128 mL, 0.732 mmol), and stirred at room temperature under a nitrogen atmosphere for 15 hours. The solvent was removed by rotary evaporation in vacuo, and the residue was taken up in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (25 mL), water (2×25 mL), and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration with 3% methanol/methylene chloride provided the title compound as a yellow solid (176 mg, 60%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH3:8])=[C:5]([CH:9]=[O:10])[C:4]([CH3:11])=[N:3]1.O.[Mn]([O-])(=O)(=O)=[O:14].[K+].[OH-].[NH4+]>CO.CC(C)=O.C(O)(=O)C>[CH3:1][N:2]1[C:6]([O:7][CH3:8])=[C:5]([C:9]([OH:14])=[O:10])[C:4]([CH3:11])=[N:3]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1c(C=O)c(C)nn1C
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: COc1c(C(=O)O)c(C)nn1C
Reaction time: 3 h
Yield: 58 %

Procedure:
2.5 g (0.0162 mole) of 1,3-dimethyl-5-methoxy-4-pyrazole carboxaldehyde (prepared as described in Khim. Farm. Zh, 4, 19 (1970) [CA, 73, 3844 w, (1970)] was dissolved in a solution containing 50 ml of water, 2 ml of acetic acid and 0.6 ml of acetone. 2.56 g (0.0162 mole) of potassium permanganate was added in several portions. The reaction was stirred for 3 hours before decomposing the excess potassium permanganate with 3 ml of methanol and then made alkaline with ammonium hydroxide, heated on the steam bath for 1/2 hour, and filtered. The filtrate was evaporated to approximately 30 ml of solution which was then acidified to pH4 with concentrated HCl. The solid was then collected. 1.6 g (58% yield) was obtained, m.p. 179°-180° C., white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:29])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23]O)[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)([Cl:32])=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:27]([CH3:29])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][Cl:32])[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: O=S(Cl)Cl
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CCl)cs3)c1)=N2
Temperature: 40 °C

Procedure:
A mixture of 8-chloro-7-dimethylamino-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one (0.38 g) (Example 19) and thionyl chloride (0.1 mL) in CH2Cl2 was heated to 40° C. for 2 h. The heterogeneous mixture was evaporated in vacuum and the residue was triturated with AcOEt to give the title compound (0.44 g) as a light-brown solid, MS (ISP) 445.1 [(M+H)+].
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[NH2:10][C:11]1[N:15]([CH2:16][CH2:17][OH:18])[N:14]=[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=1.[OH-].[Na+]>CCOC(C)=O>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2](=[O:3])[NH:10][C:11]1[N:15]([CH2:16][CH2:17][OH:18])[N:14]=[C:13]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:12]=1
Reactant: CC(C)(C)c1cc(N)n(CCO)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Temperature: 0 °C
Reaction time: 5 h
Yield: 17.8 %

Procedure:
2,2,2-Trichloroethyl chloroformate (3.24 mL, 23.5 mmol) was added dropwise over 5 min to a solution of Intermediate 110a (4.11 g, 22.4 mmol) in NaOH (1M in water, 33.6 mL, 33.6 mmol) and EtOAc (35 mL) cooled at 0° C. under argon atmosphere. The reaction mixture was stirred at RT for 5 h. Additional 2,2,2-trichloroethyl chloroformate (462 μL) was added and stirring at RT was continued for 16 h. Additional NaOH (1M in water, 15 mL) and 2,2,2-trichloroethyl chloroformate (462 μL) were added and stirring at RT was continued for 1 h. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was dissolved in cyclohexane (100 mL) and left to stand for 5 days. The resulting suspension was filtered and the solid collected by filtration washing with additional cyclohexane affording the title compound (3.64 g, 45%) as a white solid. The filtrate was concentrated in vacuo and the resultant residue was purified by FCC on silica, using a mixture of 50% EtOAc in cyclohexane, then partitioned between DCM and water. The organic layer was dried through a phase separator and concentrated in vacuo to afford additional title compound (1.43 g, 18%) as an orange gum. LCMS (Method 3): Rt 3.72 min, m/z 358 [MH+].
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:35]=[CH:36]/[C:37]([O:39]CC2C=CC=CC=2)=[O:38])=[C:13]([C:15]2[CH2:19][C:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=2)[CH:14]=1)C1C=CC=CC=1>[Pd].C1COCC1>[C:23]([O:22][C:20]([C:18]1([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[O:17][N:16]=[C:15]([C:13]2[CH:14]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=2[CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:19]1)=[O:21])([CH3:25])([CH3:26])[CH3:24]
Reactant: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2/C=C/C(=O)OCc2ccccc2)=NO1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(O)ccc2CCC(=O)O)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.9 %

Procedure:
A mixture of tert-butyl 3-(5-(benzyloxy)-2-((1E)-3-(benzyloxy)-3-oxoprop-1-en-1-yl)phenyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (260 mg), 10% Pd/C (containing about 55% water, 26 mg), and THF (3 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was combined with 10% Pd/C (containing about 55% water, 52 mg) and THF (3 mL), and the obtained mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure to obtain the title compound (214 mg).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH:12]=[C:7]12.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:13]2[CH:12]=[C:7]3[C:8]4[C:3]([CH2:4][CH2:5][N:6]3[C:16](=[O:17])[CH2:15][N:14]=2)=[C:2]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:11]=[CH:10][CH:9]=4)[CH:23]=[CH:22][CH:21]=1
Reactant: C1COCCN1
Reactant: COc1cccc(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cccc(C2=NCC(=O)N3CCc4c(cccc4N4CCOCC4)C3=C2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.5 %

Procedure:
A solution of Pd(OAc)2 (4.0 mg, 0.017 mmol), and BINAP (10.5 mg, 0.017 mmol) in toluene (5 mL) was stirred at RT under N2 for 10 min, and then transferred to a mixture of 9-iodo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (Example 30) (150 mg, 0.34 mmol), morpholine (35 μL, 0.41 mmol) and Cs2CO3 (550 mg, 1.69 mmol) in toluene (5 mL). The reaction was stirred at RT under N2 for 5 min, and then heated to reflux for 24 h. The mixture was allowed to cool to RT, and then filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, hexane to hexane/AcOEt 1:1) and the brown solid obtained was recrystallized from hexane to give the title compound (83 mg) as a beige solid. UPLC-MS: MS 404.5 (M+H+); UPLC rt 1.09 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 2.84-3.03 (m, 6 H); 3.76-3.95 (m, 6 H); 3.87 (s, 3H); 4.51 (br. s., 2 H); 6.92 (s, 1 H); 7.00 (dd, J=8.21, 2.74 Hz, 1 H); 7.14 (d, J=7.82 Hz, 1 H); 7.28-7.51 (m, 5 H).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=O)[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.Cl.Cl.[NH2:28][OH:29].[OH-].[Na+].O>CO>[N:28](=[C:20]1[CH2:22][CH2:23][C@:9]2([OH:24])[C@:10]34[CH2:11][CH2:12][N:13]([CH2:14][CH:15]5[CH2:17][CH2:16]5)[C@@H:8]2[CH2:7][C:6]2[CH:1]=[CH:2][C:3]([OH:25])=[C:4]([O:19][C@@H:18]13)[C:5]4=2)[OH:29]
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: ON=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reaction time: 15 h

Procedure:
A mixture of naltrexone hydrochloride (1.34 g, 3 mmol) and hydroxylamine hydrochloride (0.28 g, 4 mmol) was dissolved in 20 mL of MeOH and 2.8 mL of aqueous NaOH added. The mixture was stirred for 15 h. Water was added (100 mL) and the mixture extracted with 150 mL CHCl3 (3×50 mL). The combined extracts were dried (MgSO4) and evaporated. The residue obtained was chromatographed on a column of silica gel (approx. size 40 microns) using ethyl acetate-ethanol-NH4OH (300:1.5:2) as eluent. The combined fractions were evaporated and the residue recrystallized from CH2Cl2 -petroleum ether. Yield: 0.54 g (50.5%) mp 235-236° C. IR (KBr): No C=O absorption at 1720 cm-1. 1H NMR (CDCl3) δ6.7 (2d, 2H, J=10 Hz) 5 (s,C5H); Rf: silica gel 60 in ethylacetate-EtOH-NH4OH (100:1:1) 0.22. Anal. Calcd for C20H24N2O4 : C, 67.40; H, 6.79; N, 7.86. Found: C, 67.12; H, 6.88; N, 7.63.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:23])=[CH:5][C:6]=1[C:7]1[N:8]=[C:9]2[N:13]([C:14]=1[CH2:15][C:16]([OH:18])=O)[C:12]1[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=1[S:10]2.[CH3:24][NH2:25]>O1CCCC1>[CH3:1][C:2]1[S:3][C:4]([CH3:23])=[CH:5][C:6]=1[C:7]1[N:8]=[C:9]2[N:13]([C:14]=1[CH2:15][C:16]([NH:25][CH3:24])=[O:18])[C:12]1[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=1[S:10]2
Reactant: Cc1cc(-c2nc3sc4ccccc4n3c2CC(=O)O)c(C)s1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Cc1c(-c2cc(C)sc2C)nc2sc3ccccc3n12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 1.5 g (0.0044 mole) of 2-(2,5-dimethylthien-3-yl)imidazo[2,1-b]benzothiazole-3-acetic acid in 30 ml of anhydrous tetrahydrofuran is treated, at room temperature, with 0.85 g (0.005 mole) of N,N'-carbonyldiimidazole for 30 minutes. The solution which has become clear is cooled to 0° C. and a stream of methylamine is passed through it for 30 minutes. The mixture is allowed to return to room temperature, the stirring is continued for 3 h, the solvent is evaporated under reduced pressure, the residue is taken up in 10 ml of water, it is extracted with dichloromethane, the organic phase is separated, it is washed with water, it is dried over sodium sulphate, the solvent is evaporated under reduced pressure, and the residue is crystallized from ethyl acetate. 1 g of pale yellow crystals is finally obtained. Melting point: 238°-239° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[S:9][CH2:10][C:11](=[O:13])[N:12]=1.C(O[Na])(C)=O.[CH:19]([C:21]1[N:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]([C:31]#[N:32])=[C:24]2[O:33][CH:34]([CH3:36])[CH3:35])=O>CC(O)=O>[CH:34]([O:33][C:24]1[C:23]2[C:28](=[CH:29][CH:30]=[C:21]([CH:19]=[C:10]3[S:9][C:8]([NH:7][CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[N:12][C:11]3=[O:13])[N:22]=2)[N:27]=[CH:26][C:25]=1[C:31]#[N:32])([CH3:36])[CH3:35]
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Reactant: O=C1CSC(NCc2cccs2)=N1
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NCc4cccs4)=NC3=O)nc12
Temperature: 80 °C
Yield: 50.8 %

Procedure:
To a mixture of 2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one (34.0 mg, 0.16 mmol, (prepared as described below), AcONa (160 mg, 1.95 mmol), and 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (57.9 mg, 0.24 mmol) (see Example 1) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 80° C. (oil bath) for 5 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water. The solid was then suspended in AcOEt (20 mL) and filtered. The solid was washed with AcOEt and dried to give 4-isopropoxy-6-{4-oxo-2-[(thiophen-2-ylmethyl)-amino]-4H-thiazol-5-ylidenemethyl}-[1,5]naphthyridine-3-carbonitrile as a light brown solid (35.4 mg, 50.8%). HR-ES (+) m/e calcd for C21H17N5O2S2 (M+H)+ 436.0897. found 436.0895.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][CH2:14][CH:10]3[CH2:9][C:8](=[O:16])[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][CH:14]=[C:10]3[CH2:9][C:8](=[O:16])[N:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[CH:23]=1
Reactant: CC1=NCC2CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N12
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Cc1ncc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2

Procedure:
A mixture of 7.2 g (0.022 moles) of 8-chloro-1-methyl-6-phenyl-3,3a,4,6-tetrahydro-5H-imidazo[1,5-a][1,5]benzodiazepin-5-one, 45 g of activated manganese dioxide and 1.5 l. of toluene was stirred and refluxed for 45 minutes. The manganese dioxide was filtered off and washed well with tetrahydrofuran and methylene chloride. The filtrate was evaporated and the residue was crystallized from ethyl acetate to yield end product with mp 276°-278° C.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:7]([CH2:8]O)[O:6][C:4](=[O:5])[CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:33]([CH2:8][C@H:7]1[O:6][C:4](=[O:5])[CH2:3][C@@H:2]1[CH3:1])=[N+:34]=[N-:35]
Reactant: C[C@H]1CC(=O)O[C@@H]1CO
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C[C@H]1CC(=O)O[C@@H]1CN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,3-dideoxy-3-C-methyl-D-erythro-pentono-1,4-lactone (490 mg, 3.76 mmol) in methylene chloride (10 mL) cooled in an ice-bath were added 2,6-lutidine (501 mL, 4.30 mmol) and trifluoromethanesulfonic anhydride (682 mL, 4.05 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, diluted with methylene chloride, washed with water, 2N hydrochloric acid, saturated sodium hydrogencarbonate solution, saturated brine solution, dried (Na2SO4), and evaporated. The crude product was taken up in DMF (6 mL) and treated with sodium azide (856 mg, 13.2 mmol) at room temperature for 30 minutes. The mixture was diluted with ethyl acetate, washed with water, dried (Na2SO4), and evaporated. The pure title compound was obtained after flash silica gel chromatography eluting with 25% ethyl acetate in hexane; yield 358 mg (61%); 1H NMR (400 MHz, CDCl3): δ1.15 (d, 3H), 2.21 (dd, 1H), 2.42 (m, 1H), 2.74 (dd, 1H), 3.44 (dd, 1H), 3.60 (dd, 1H), 4.15 (m, 1H); mass spectrum: 128 (M+1-N2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[Al+3].[Cl-].[Cl-].[Cl-].[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([O:8][CH3:9])=[C:6]([C:21]([C:20]2[CH:24]=[CH:25][C:17]([F:16])=[CH:18][CH:19]=2)=[O:22])[CH:7]=1
Reactant: COc1ccc(Cl)c(OC)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(OC)c(C(=O)c2ccc(F)cc2)cc1Cl
Temperature: 0 °C

Procedure:
Chloro-2,4-Dimethoxy-benzene (5.00 g, 29.0 mmol) and AlCl3 (4.63 g, 1.2 eq.) were dissolved in 290 ml of CH2Cl2 and cooled down to 0° C. 4-Fluoro-benzoyl chloride (3.47 mL, 1.0 eq.) was slowly added via dropping funnel and the mixture allowed to react for 2 additional h at ambient temperature. Pouring onto crashed ice, twofold extraction with AcOEt, washing with brine, drying over sodium sulfate, and evaporation of the solvents left 8.41 g of the title compound used crude for the next step.
Reaction SMILES: C1COCC1.[OH-].[Na+].[F:8][C:9]1[CH:14]=[C:13]([C:15](=[O:38])[NH:16][C:17]2[S:18][C:19]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[CH2:30][CH2:31][CH:32]([O:36][CH3:37])[CH2:33][CH2:34][CH3:35])[C:20]=3[N:21]=2)[CH:12]=[C:11]([F:39])[C:10]=1[CH:40]=[C:41]([CH3:47])[C:42]([O:44]CC)=[O:43].Cl>CO>[F:39][C:11]1[CH:12]=[C:13]([C:15](=[O:38])[NH:16][C:17]2[S:18][C:19]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[CH2:30][CH2:31][CH:32]([O:36][CH3:37])[CH2:33][CH2:34][CH3:35])[C:20]=3[N:21]=2)[CH:14]=[C:9]([F:8])[C:10]=1[CH:40]=[C:41]([CH3:47])[C:42]([OH:44])=[O:43]
Reactant: CCCC(CCc1cccc2c1CCc1sc(NC(=O)c3cc(F)c(C=C(C)C(=O)OCC)c(F)c3)nc1-2)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(CCc1cccc2c1CCc1sc(NC(=O)c3cc(F)c(C=C(C)C(=O)O)c(F)c3)nc1-2)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
A mixture of THF (40 mL), methanol (40 mL), and 2N sodium hydroxide aqueous solution (40 mL) of 3-{2,6-difluoro-4-[4,5-dihydro-6-(3-methyloxyhexyl)naphtho[1,2-d]thiazol-2-ylcarbamoyl]phenyl}-2-methylacrylic acid ethyl ester (8) (7.0 g), was stirred at room temperature for 3 h. The reaction mixture was acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate to obtain the compound (A1) 5.5 g.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([C:10]1[CH:15]=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:12][C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:9])[CH3:8].Br[CH2:29][C:30]1[C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[C:34]([O:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:33]([C:51]([F:54])([F:53])[F:52])=[CH:32][CH:31]=1.O>CN(C)C=O>[C:7]([C:10]1[CH:15]=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:12][C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:29][C:30]2[C:35]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[C:34]([O:43][C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[C:33]([C:51]([F:52])([F:53])[F:54])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1)(=[O:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Cesium carbonate (209 mg, 0.644 mmol) was added to a solution of methyl (2-acetyl-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (122 mg, 0.429 mmol) obtained in Example (40-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (181 mg, 0.429 mmol) obtained in Example (28-5) in N,N-dimethylformamide (4 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate (three times). After the organic layer was successively washed with water (three times) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to give tert-butyl 6-[({2′-acetyl-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (93 mg, yield: 34%).