Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:27]=[C:28]([CH2:30][OH:31])[N:29]=2)[C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][N:7]=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][C:33]1=[O:38].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[OH:31][CH2:30][C:28]1[N:29]=[C:3]2[C:2]([N:35]3[CH2:36][CH2:37][NH:32][C:33](=[O:38])[CH2:34]3)=[N:7][CH:6]=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[N:12][CH:13]=3)[N:4]2[CH:27]=1
Reactant: O=C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(Cl)c4nc(CO)cn34)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCNC(=O)C4)c4nc(CO)cn34)cn2)CC1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of compound 87c (90.0 mg, 0.202 mmol), piperazin-2-one (40.5 mg, 0.405 mmol) and K2CO3 (55.9 mg, 0.405 mmol) in 2.5 mL of DMF was stirred at 130° C. for 6 h under an Argon atmosphere. After cooling to rt, the mixture was treated with 30 mL of EtOAc and washed with saturated NH4Cl (20 mL), water (20 mL), brine (10 mL) and then dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (0-7 MeOH/DCM) to give compound 88a as an off white solid. 1H-NMR (CDCl3, 400 MHz): δ 8.34 (d, J=2.4 Hz, 1H), 7.67 (dd, J=8.8, 2.4 Hz, 1H), 7.54 (s, 1H), 7.30 (s, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.23 (br. s., 1H), 4.89 (s, 2H), 4.80 (d, J=5.4 Hz, 2H), 4.55 (t, J=5.3 Hz, 2H), 3.55-3.69 (m, 10H), 1.50 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calcd. for C25H32N8O4, 509.2 (M+H). found 509.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:11]=[C:12](/[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)\[C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-:3])=[O:2]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:11]=[C:12](\[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)/[C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-:3])=[O:2]
Reactant: COc1cc(/C(C#N)=C/c2ccc(Cl)c([N+](=O)[O-])c2)cc(OC)c1OC
Solvent: CC(C)=O
Product: COc1cc(/C(C#N)=C\c2ccc(Cl)c([N+](=O)[O-])c2)cc(OC)c1OC
Yield: 26.7 %

Procedure:
1.5 g of (Z)-3-(3-nitro-4-chlorophenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-ene-nitrile was dissolved in 500 ml of acetone and the solution was reacted in a photochemical apparatus (visible light) for 1 hour. The reaction mixture was concentrated and a half of it was purified on a silica gel plate to give 400 mg of the intended compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)ns1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCNCC2)ns1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
tert-Butyl 4-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (38.10 g, 65.95 mmol) was dissolved in CH2Cl2 (500 mL) and cooled to 0° C. TFA (25.40 ml, 329.7 mmol) was added over 5 minutes, keeping the internal temperature below 12° C. The reaction was then warmed to ambient temperature and stirred for 1 hour. More TFA (75 mL, 990 mmol) was added and the reaction was stirred for 2 hours. The reaction was concentrated and redissolved in 10% methanol in dichloromethane (450 mL) and saturated sodium bicarbonate was slowly added. The mixture was stirred for 1 hour and filtered. The solids were washed with water and dried in a vacuum oven to give N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-amine (29.7 g, 62.19 mmol, 94.29% yield).
Reaction SMILES: [OH:1][CH:2]([C:7]1[C:15]2[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20]C3CCCCO3)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=2[S:9][C:8]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=1)[CH2:3][CH:4]([CH3:6])[CH3:5]>Cl.CO>[OH:1][CH:2]([C:7]1[C:15]2[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:27])[N:11]([CH3:28])[C:10]=2[S:9][C:8]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:37])([F:38])[F:39])[CH:30]=1)[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)CC(O)c1c(-c2cccc(OC(F)(F)F)c2)sc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: Cl
Solvent: CO
Product: CC(C)CC(O)c1c(-c2cccc(OC(F)(F)F)c2)sc2c1c(=O)n(CCCO)c(=O)n2C
Yield: 47.4 %

Procedure:
A solution of 5-(1-hydroxy-3-methylbutyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 0.026 mmol) in concentrated HCl (1 mL) and MeOH (5 mL) was stirred at RT for 1 h. The reaction was concentrated to a residue which was purified by Prep HPLC to give 5-(1-hydroxy-3-methylbutyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (6 mg, 46.9% yield) as a white solid. 1H NMR (CDCl3) δ: 7.49 (t, J=8.0 Hz, 1H), 7.35 (d, J=7.7 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 5.39 (d, J=11.9 Hz, 1H), 4.85-4.65 (m, 1H), 4.26 (t, J=6.1 Hz, 2H), 3.70-3.49 (m, 5H), 2.89 (s, 1H), 2.06-1.89 (m, 3H), 1.76 (dt, J=13.4, 6.6 Hz, 1H), 1.43-1.33 (m, 1H), 0.80 (dd, J=9.3 and 6.7 Hz, 6H). LCMS: MH+ 487 and TR=2.971 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12](O)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Si:19]([O:26][CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:29]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Si:19]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:12](=[O:13])[C@H:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=2[CH3:18])[C@@H:15]([OH:17])[CH3:16])([C:32]([NH:34][NH2:35])=[O:33])[CH2:36][CH:37]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](C(=O)C2(C(=O)NN)C=CC(CO[Si](C)(C)C(C)(C)C)=CC2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (3 g, 11.16 mmol), 4-((tert-butyldimethylsilyloxy)methyl)benzohydrazide (3.44 g, 12.28 mmol) and anhydrous THF (250 mL) were placed in a 500 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (1.51 g, 11.16 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (3.21 g, 16.74 mmol) at −15° C. followed by triethylamine (2.33 mL, 16.74 mmol). The reaction mixture was maintained at −15° C. and stirred for 1 h after which, stirring continued overnight while the mixture slowly warmed to room temperature. After 19 h, the mixture was filtered under vacuum and the residue washed with THF (70 mL). The THF solution was concentrated to ca. 20 mL, whereupon EtOAc (100 mL) was added followed by water (50 mL). The phases were partitioned and the organic phase washed with water (30 mL), brine (30 mL) dried (Na2SO4), filtered and concentrated to furnish a light brown solid (5.82 g). This crude product was not chromatographed. 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.82 (d, J=9 Hz, 2H), 7.42 (d, J=8 Hz, 1H), 7.38 (d, J=8 Hz, 2H), 6.58 (d, J=8 Hz, 1H), 5.42 (d, J=8 Hz, 1H), 4.75 (s, 3H), 4.31-4.22 (m, 1H), 3.99-3.97 (m, 1H), 2.24 (s, 3H), 0.82 (s, 9H) and 0.01 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[C:22]([C:24]1[O:28][C:27]([C:29](Cl)=[O:30])=[CH:26][CH:25]=1)#[N:23].CCN(C(C)C)C(C)C>>[C:22]([C:24]1[O:28][C:27]([C:29]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH2:11][O:12][C:13](=[O:15])[CH3:14])=[O:10])=[CH:4][C:3]=2[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:30])=[CH:26][CH:25]=1)#[N:23]
Reactant: CC(=O)OCC(=O)Nc1ccc(N)c(N2CCCCC2)c1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)Nc1ccc(NC(=O)c2ccc(C#N)o2)c(N2CCCCC2)c1
Yield: 19.9 %

Procedure:
Using a procedure similar to Example 4, step (c), acetic acid (4-amino-3-piperidin-1-yl-phenylcarbamoyl)-methyl ester (80 mg, 0.27 mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (42 mg, 0.27 mmol) in the presence of DIEA (0.10 mL, 0.59 mmol) to afford 22 mg (20%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 9.66 (s, 1H), 8.40 (d, 1H, J=9.0 Hz), 7.73-7.76 (m, 2H), 7.27-7.28 (m, 1H), 7.22 (d, 1H, J=2.7 Hz), 7.08 (dd, 1H, J=2.3, 8.7 Hz), 4.68 (s, 2H), 2.84-2.86 (m, 4H), 2.24 (s, 3H), 1.82-1.84 (m, 4H), 1.68 (br s, 2H); Mass spectrum (ESI, m/z): Calcd. for C21H22N4O5, 411.1 (M+H), found 411.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].N1C=CC=CC=1>ClCCl>[Cl:15][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[Cl:14])[N:10]=[C:11]([O:12][CH3:13])[C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[N:3]2
Reactant: CCOC(=O)Cl
Reactant: COc1nc2cc(Cl)c(Cl)cc2nc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
2-Amino-6,7-dichloro-3-methoxyquinoxaline (1.16 g, 4.75 mmol) and ethyl chloroformate (1.03 g, 9.50 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (751 mg, 9.50 mmol) was added. The mixture was stirred at room temperature for 24 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 1.29 g of the titled compound (yield, 86%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:26]([NH:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:11][C:12](=[O:14])[NH2:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[CH3:37][CH:38]([CH2:40][C@H:41]([NH:54][C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])[C:42](OC1C=CC([N+]([O-])=O)=CC=1)=[O:43])[CH3:39]>CN(C)C=O>[NH:54]([C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])[C@H:41]([C:42]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:26]([NH:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:11][C:12](=[O:14])[NH2:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:43])[CH2:40][CH:38]([CH3:39])[CH3:37]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(N)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
26.5 g of H-Asn-Asn-Phe-NHNH-BOC are dissolved in 58 ml of warm dimethylformamide, a solution of 24.2 g of Z-Leu-ONP in 16 ml of dimethylformamide is added at room temperature, and the mixture is stirred until it solidifies. After standing overnight the mixture is triturated with ether, filtered off, dissolved in 190 ml of dimethylformamide, and the product reprecipitated by adding dropwise to 1.5 liters of ether. The product is filtered off and washed with ether until free of nitrophenol. Rf = 0.45 in the system chloroform-methanol (7:3) on silica gel.
Reaction SMILES: I[C:2]1[N:7]=[N:6][C:5]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:4]=2[CH:3]=1.[F:16][C:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)([F:19])[F:18].C(N(CC)CC)C.CN(C)C=O>[Cu](I)I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)(=O)C>[F:16][C:17]([F:18])([F:19])[O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:2]2[N:7]=[N:6][C:5]3[O:8][C:9]4[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=4[O:11][C:4]=3[CH:3]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(OC(F)(F)F)cc1
Reactant: Ic1cc2c(nn1)Oc1ccccc1O2
Agent: I[Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(C#Cc2cc3c(nn2)Oc2ccccc2O3)cc1

Procedure:
To a sealed reaction container were added 3-iodo[1,4]benzodioxino[2,3-c]pyridazine (200 mg) synthesized in Production Example 9 to be mentioned later, 4-ethynylphenyl trifluoromethyl ether (0.15 mL), copper iodide (6 mg), triethylamine (64 mg), bis(triphenylphosphine)palladium (II) dichloride (22 mg) and dimethylformamide (5 mL), and the mixture was stirred at 120° C. for 0.5 hr. Ethyl acetate and water were added, the organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3-{[4-(trifluoromethoxy)phenyl]ethynyl}[1,4]benzodioxino[2,3-c]pyridazine (100 mg).
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([CH2:20][C:21](Cl)=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:1]([C:5]1[C:6]([NH:14][C:21](=[O:22])[CH2:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: O=C(Cl)CC1CCCC1
Product: CC(C)(C)c1c(NC(=O)CC2CCCC2)nn2cccnc12

Procedure:
The product from Example 105B and cyclopentylacetyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.13-1.24 (m, 2H), 1.45-1.65 (m, 13H), 1.71-1.82 (m, 2H), 2.19-2.28 (m, 3H), 6.99 (dd, J=7.1, 4.1 Hz, 1H), 8.48 (dd, J=3.9, 1.9 Hz, 1H), 8.92 (dd, J=7.0, 1.9 Hz, 1H), 9.64 (br s, 1H); MS (DCI) m/z 301 (M+H)+.
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C=C(OC(=O)C(C)(C)C)C=CC=2C1)C.N12CCC(COC3C=CC(C=O)=CC=3)(CC1)CC2.[N:47]12[CH2:54][CH2:53][C:50]([CH2:55][O:56][C:57]3[CH:91]=[CH:90][C:60]([CH2:61][CH2:62][CH2:63][NH:64][C:65]4[CH:70]=[C:69]([O:71][CH3:72])[CH:68]=[CH:67][C:66]=4[CH:73]4[CH2:82][CH2:81][C:80]5[CH:79]=[C:78]([O:83]C(=O)C(C)(C)C)[CH:77]=[CH:76][C:75]=5[CH2:74]4)=[CH:59][CH:58]=3)([CH2:51][CH2:52]1)[CH2:49][CH2:48]2>>[N:47]12[CH2:54][CH2:53][C:50]([CH2:55][O:56][C:57]3[CH:58]=[CH:59][C:60]([CH2:61][CH2:62][CH2:63][NH:64][C:65]4[CH:70]=[C:69]([O:71][CH3:72])[CH:68]=[CH:67][C:66]=4[CH:73]4[CH2:82][CH2:81][C:80]5[CH:79]=[C:78]([OH:83])[CH:77]=[CH:76][C:75]=5[CH2:74]4)=[CH:90][CH:91]=3)([CH2:51][CH2:52]1)[CH2:49][CH2:48]2
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(OCC34CCN(CC3)CC4)cc2)c1
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: O=Cc1ccc(OCC23CCN(CC2)CC3)cc1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC34CCN(CC3)CC4)cc2)c1
Yield: 69.6 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester and 4-(1-azabicyclo[2.2.2]oct-4-ylmethoxy)benzaldehyde according to an analogous synthetic method to Example 212, pivalic acid 6-{2-{[4-(1-azabicyclo[2.2.2]oct-4-ylmethoxy)benzyl]ethylamino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) was used according to an analogous synthetic method to Example 217 to provide the title compound (18 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=O)=[CH:4][CH:3]=1.[F:10][C:11]1[C:16]([F:17])=[CH:15][C:14]([NH2:18])=[C:13]([I:19])[CH:12]=1.CCOC(C)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:18][C:14]2[CH:15]=[C:16]([F:17])[C:11]([F:10])=[CH:12][C:13]=2[I:19])=[CH:4][CH:3]=1
Reactant: O=Nc1ccc(Cl)cc1
Reactant: Nc1cc(F)c(F)cc1I
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Fc1cc(I)c(N=Nc2ccc(Cl)cc2)cc1F
Temperature: 0 °C
Yield: 25.6 %

Procedure:
Chloro-4-nitroso-benzene (9.1 g, 64 mmol; [932-98-9]) was added to a solution of 4,5-difluoro-2-iodo-phenylamine (10.9 g, 43 mmol; [847685-01-2]) in acetic acid (430 ml). The reaction mixture was heated under reflux conditions for 14 h. Ice water (1 l) and EtOAc (1 l) was added, the layers were separated and the aqueous layer was extracted two times with EtOAc. The combined extracts were washed with water and brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, CH2Cl2/heptane) to give the title compound (4.34 g, 11 mmol; 27%) as orange solid. MS: m/e=377.9 [M+].
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]=[C:30]1[C:34](=[CH:35][C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[S:33][C:32](=[S:44])[NH:31]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:40][C:39]3[CH:38]=[CH:37][C:36](/[CH:35]=[C:34]4/[C:30](=[O:29])[NH:31][C:32](=[S:44])[S:33]/4)=[CH:43][CH:42]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(C=C2SC(=S)NC2=O)cc1
Product: O=C1NC(=S)S/C1=C\c1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 610.0.
Reaction SMILES: [C:1]1(=O)O[C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1(=O)OC(=O)C=[CH:13]1>CC1C=CC=CC=1C>[CH:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:1]=[CH:13][CH:12]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1C
Product: c1ccc2ccccc2c1

Procedure:
A process for the continuous isolation of phthalic anhydride and maleic anhydride from the reaction gases obtained by catalytic oxidation of o-xylene or naphthalene with air, wherein the reaction gases are treated with a hydrocarbon of boiling range from 115° to 175° C. as the solvent in a column, and are then treated with an organic solvent of boiling range from 180° to 290° C. in a second column, the phthalic anhydride and maleic anhydride being isolated from the liquid bottom product of the first column.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][C:15](=O)[CH2:14]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:15]1([CH2:16][CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC1CCCC(=O)C1
Solvent: C1CCNC1
Solvent: CO
Product: CC1CCCC2(CC(=O)c3cc(Br)ccc3O2)C1
Reaction time: 8 h
Yield: 124.7 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (10 g, 46.7 mmol), 3-methylcyclohexanone (10.5 g, 93.4 mmol) and pyrrolidine (6.3 g, 88.8 mmol) in methanol (200 mL) was stirred overnight. The reaction mixture was concentrated in vacuo, and then H2O was added. The resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 6-bromo-3′-methylspiro[chroman-2,1′-cyclohexan]-4-one (18 g, 100%). 1HNMR (CDCl3): 0.86 (m, 3H), 0.91 (m, 2H), 1.02 (m, 2H), 1.30 (m, 2H), 1.52 (m, 2H), 1.65 (m, 4H), 1.80 (m, 7H), 2.01 (m, 4H), 2.22 (m, 1H), 2.48 (m, 1H), 2.60 (s, 2H), 2.72 (t, 3H), 6.81 (m, 1H), 7.50 (m, 1H), 7.91 (m, 1H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]([CH:13]([CH3:15])[CH3:14])[NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:21][CH:20]=1>>[CH2:2]([O:9][C:10](=[O:16])[C@H:11]([CH:13]([CH2:14][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:23][CH:24]=1)[CH3:15])[NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Agent: Cl
Product: CC(CCc1ccc(-c2ccccc2C#N)cc1)[C@H](N)C(=O)OCc1ccccc1

Procedure:
L-valine benzyl ester hydrochloride is N-alkylated with 4-bromomethyl-2′-cyanobiphenyl, the product 4-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester so formed is N-acylated with valeryl chloride to give N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester. N-[2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester is treated with tributyltin azide to give valsartan benzyl ester. Valsartan benzyl ester is subjected to catalytic hydrogenation using for example palladium-charcoal as catalyst to give valsartan.
Reaction SMILES: [Cl:1][C:2]1[CH:7]([O:8][CH:9]([C:11]([O:13]CC)=[O:12])[CH3:10])[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])([N+:16]([O-:18])=[O:17])[CH:5]=[CH:4][C:3]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:46]([O-:48])=[O:47])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:45])([F:44])[F:43])[CH:32]([O:49][CH:50]([C:52]([O:54]CC)=[O:53])[CH3:51])[C:31]=1[Cl:57].[OH-].[K+].C(O)C.S(=O)(=O)(O)O>O.CCOCC.O1CCOCC1>[Cl:1][C:2]1[CH:7]([O:8][CH:9]([C:11]([OH:13])=[O:12])[CH3:10])[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])([N+:16]([O-:18])=[O:17])[CH:5]=[CH:4][C:3]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:46]([O-:48])=[O:47])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:45])([F:44])[F:43])[CH:32]([O:49][CH:50]([C:52]([OH:54])=[O:53])[CH3:51])[C:31]=1[Cl:57]
Reactant: CCOC(=O)C(C)OC1C(Cl)=C(OC2=C(Cl)C(OC(C)C(=O)OCC)C(c3ccccc3C(F)(F)F)([N+](=O)[O-])C=C2)C=CC1(c1ccccc1C(F)(F)F)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(OC1C(Cl)=C(OC2=C(Cl)C(OC(C)C(=O)O)C(c3ccccc3C(F)(F)F)([N+](=O)[O-])C=C2)C=CC1(c1ccccc1C(F)(F)F)[N+](=O)[O-])C(=O)O
Yield: 40.1 %

Procedure:
2-Chloro-α,α,α-trifluoro-p-tolyl-3-(1-carbethoxyethoxy)-4-nitrophenyl ether (8.6 g. 0.02 mol), potassium hydroxide 86% (2.6 g. 0.04 mol), ethanol (8 ml.), dioxane (8 ml.), and water (100 ml.) are heated at 90°-95° C. for 30 minutes. Ether (200 ml.) and water (200 ml.) are added and the mixture acidified with dilute sulfuric acid, the water layer extracted three times with ether (200 ml. each), dried, and the ether removed to give 2-chloro-α,α,α-trifluoro-p-tolyl-3-(1-carboxyethoxy)-4-nitrophenyl ether (6.4 g. 79%) m.p. 108°-109° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([O:11]CC2C=CC=CC=2)=[O:10])[CH2:4][CH2:3]1>CO.[Pd]>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:6][CH2:7]1
Reactant: O=C(CN1CCC(O)CC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CN1CCC(O)CC1
Reaction time: 1 h
Yield: 94.2 %

Procedure:
A mixture of benzyl 2-(4-hydroxypiperidin-1-yl)acetate (1.0 g, 4.0 mmol) and Pd/C (0.1 g) in methanol (20 mL) was hydrogenated for 1 h at ambient temperature. The Pd/C was filtered off and the filtrate was concentrated to dryness to afford 2-(4-hydroxypiperidin-1-yl)acetic acid (0.6 g, 94% yield).