Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[C:16](=[O:29])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N([O-])=[O:38].[Na+].C([O-])(O)=O.[Na+]>C(#N)C.O.OS(O)(=O)=O>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([N:15]2[C:16](=[O:29])[C:17]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]=3[N:19]=[C:14]2[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2](=[O:38])[NH:7][CH:6]=3)=[CH:9][CH:10]=2)=[CH:35][CH:34]=1
Reactant: Nc1ccc(-c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)cn1
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=c1ccc(-c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)c[nH]1
Temperature: 100 °C

Procedure:
To a solution of 6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (28.1 mg, 0.057 mmol) in acetonitrile (0.5 mL) is added a solution of NaNO2 (5.4 mg, 0.078 mmol) in H2O (0.5 mL) at 0° C., followed by addition of one drop of concentrated H2SO4. The reaction mixture is then heated at 100° C. for 30 minutes, cooled down to 0° C., neutralized by saturated NaHCO3 to pH= 4-5, and extracted with ethyl acetate. The organic layer is concentrated and purified by preparative LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.14 (d, 2H), 7.91 (dd, 1H), 7.75 (d, 1H), 7.52 (t, 2H), 7.44 (d, 2H), 7.36 (m, 5H), 7.13 (d, 2H), 6.88 (d, 1H); HPLC-MS calculated for C28H18ClN5O2 (M+H+) 492.1. Found: 492.1.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl[C:17]([O:19][CH3:20])=[O:18].O>O1CCCC1>[F:9][C:10]1[C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Fc1ccccn1
Reactant: COC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccnc1F
Temperature: -78 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
2 M lithium diisopropyl amide (11.3 mL, 22.5 mmol) is slowly added over a solution of 2-fluoropyridine (2 g, 20.5 mmol) in tetrahydrofuran (90 mL) under nitrogen atmosphere at −78° C. After 4 h at that temperature methyl chloroformate (1.9 mL, 24.6 mmol) is added and the mixture is stirred for an additional hour at −78° C. and allowed to reach room temperature overnight. Reaction mixture is slowly poured over water and extracted in diethyl ether. Organic layer is washed with brine, dried over sodium sulfate and solvent is evaporated in vacuo. Residue is purified by normal phase Isco chromatography eluting with hexane/diethyl ether (9/1) to give 495.2 mg of the title compound. MS (m/z): 156 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.CC1C=C(C)N2N=C(C=O)N=C2N=1.[CH:26]1([C:31]2([CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=3[O:49][CH3:50])[O:36][C:35](=[O:37])[CH:34]=[C:33]([OH:38])[CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:34]3[C:35](=[O:37])[O:36][C:31]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)([CH2:39][CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=4[O:49][CH3:50])[CH2:32][C:33]=3[OH:38])[N:10]=2)[CH:7]=1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)c(OC)c1
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(Cl)cn4n3)C(=O)O2)c(OC)c1

Procedure:
The title compound was prepared analogously to Example B(97), where 6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-Cyclopentyl-6-[2-(2,4-dimethoxy-phenyl)-ethyl]4-hydroxy-5,6-dihydro-pyran-2-one was substituted in place of 6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]6-cyclopentyl-dihydro-pyran-2,4-dione of that example. 1H NMR (400 MHz, DMSO-d6): δ 1.51–1.73 (m, 9H), 1.92–1.98 (m, 2H), 2.38–2.58 (m, 3H), 2.79 (d, J=16 Hz, 1H), 3.71 (s, 2H), 3.73 (s, 6H), 6.40–6.5 (m, 2H), 7.03 (d, J=8 Hz, 1H), 8.89 (d, J=2.6 Hz, 1H), 9.52 (d, J=2.6 Hz, 1H), 10.9 (s, 1H). Anal. Calcd. For C26H29ClN4O5.0.25H2O: C, 60.35; H, 5.75; N, 10.83. Found: C, 60.40; H, 5.65; N, 10.74. MS (ESI): 513 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([N+:28]([O-])=O)[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=3)[S:13][C:6]=12.[NH4+].[Cl-]>[Fe].CCO.O>[CH3:23][N:21]([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[S:13][C:6]3[C:7](=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:24]=[CH:25][C:26]([NH2:28])=[CH:27][C:2]=3[F:1])[CH:11]=2)=[N:19][CH:18]=1)[CH3:22]
Reactant: CN(C)Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(C)Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1
Yield: 123.2 %

Procedure:
To a solution of 402 (308 mg, 0.72 mmol) and NH4Cl (33 mg, 061 mmol) in 2:1 EtOH/water (9 mL) was added iron powder (345 mg, 6.17 mmol) and the suspension was heated to reflux for 1 hour. The reaction mixture was filtered through celite and concentrated to provide title compound 397 (350 mg, quantitative yield), that was used without further purification. MS (m/z): (M+1) 395.1 (100%).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:21]([NH2:23])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[NH:25]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@H:26]([C:31](ON1C(=O)CCC1=O)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29].C(N(CC)CC)C>CN(C=O)C>[NH:25]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@H:26]([C:31]([NH:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:21]([NH2:23])=[O:22])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)N[C@@H](C(N)=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C(N)=O)c1ccccc1
Yield: 76 %

Procedure:
5.0 g (14.0 mmoles) of H-Asp(OtBu)-D-Phg-NH2.HCl, prepared as described in Example 1, Step 4, and 5.13 g (14.2 mmoles) of Z-Leu-OSu are dissolved in 60 ml of DMF, and 1.96 ml (14.0 mmoles) of triethylamine are added to the solution. Next day the reaction mixture is evaporated in vacuo, and the residue is triturated with water. The resulting crude product, weighing 7.32 g, is recrystallized from ethanol under decolourizing. 6.05 g (77.7%) of Z-Leu-Asp(OtBu)-D-Phg-NH2 are obtained; m.p.: 192°-194° C., Rf4 : 0.75. A sample of the product melts as 195°-196° C. after recrystallization from ethanol; [α9 D : -69.5° (c: 1.0, in dimethyl formamide).
Reaction SMILES: Br.Br[CH:3]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:4]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])=O.[CH3:19][C:20]1[N:25]=[C:24]([NH:26][C:27]([NH2:29])=[S:28])[CH:23]=[CH:22][CH:21]=1>C(O)C>[CH3:19][C:20]1[N:25]=[C:24]([NH:26][C:27]2[S:28][C:3]([N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)=[C:4]([C:6]3[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=3)[C:9]#[N:10])[N:29]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1cccc(C(=O)C(Br)n2cncn2)c1
Reactant: Cc1cccc(NC(N)=S)n1
Agent: Br
Solvent: CCO
Product: Cc1cccc(Nc2nc(-c3cccc(C#N)c3)c(-n3cncn3)s2)n1
Temperature: 90 °C

Procedure:
3-(2-Bromo-2-[1,2,4]triazol-1-yl-acetyl)-benzonitrile hydrobromide (500 mg, 1.34 mmol) is dissolved in ethanol (5 ml). (6-Methyl-pyridin-2-yl)-thiourea (208 mg, 1.34 mmol) is added and the reaction heated to 90° C. for 2 hours. The precipitate is collected and washed with ethanol twice. The solid is suspended in water and basified with concentrated ammonium hydroxide and the resulting precipitate collected and washed with water to give the title compound after drying. Mass Spec (APCI+) 360.0, m.p. 236–237° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[C:12]([C:16]1[C:17](=[O:33])[CH2:18][CH:19]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([NH2:31])[C:24]=2[CH3:32])[CH2:20][C:21]=1[OH:22])(=[O:15])[CH2:13][CH3:14]>C(Cl)Cl>[C:12]([C:16]1[C:17](=[O:33])[CH2:18][CH:19]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([NH:31][S:8]([CH3:7])(=[O:10])=[O:9])[C:24]=2[CH3:32])[CH2:20][C:21]=1[OH:22])(=[O:15])[CH2:13][CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(N)c2C)CC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(NS(C)(=O)=O)c2C)CC1=O
Reaction time: 8 h

Procedure:
Pyridine (0.53 ml, 6.6 mmol) followed by methane sulfonyl chloride (0.52 ml, 6.6 mmol) was added to a stirred solution of 2-propionyl-3-hydroxy-5-(3-amino-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.0 g, 3.3 mmol)in methylene chloride (10 ml). Stirring was continued at 20° for 8 hr. The organic layer was washed with water, dilute hydrochloric acid and further water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield the crude product. The crude material was purified by column chromatography on silica gel (elution with an increasing gradient of methanol in methylene chloride) to give 2-propionyl-3-hydroxy- 5-(3-methylsulphonamido-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as a yellow waxy solid (0.6 g, 50%). The compound was characterized by proton magnetic resonance spectroscopy (CDCl3 ; δ in ppm): 1.17 (3H,t); 2.35 6H, s); 2.46 (3H,s); 3.0 (3H,s); 2.4-4.1 (7H,m); 6.78 (1H,s); 6.89 (1H,s); 18.15 (1H,brs).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:37]=[C:25]1[CH2:26][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=2)=[N:7][C:8]2[CH:13]=[C:12]([N:14]3[CH2:15][CH2:16][S:17][CH2:18][CH2:19]3)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=2[NH:24]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C2=Nc3cc(N4CCSCC4)c(C(F)(F)F)cc3NC(=O)C2)ccn1

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-thiomorpholin-4-yl-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M26) (265 mg, 0.5 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (111 mg).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][C:22]=1O.C(N(CC)CC)C>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][C:22]=1[O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9]
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 65.5 %

Procedure:
Trifluoromethanesulphonic anhydride (2.67 mL, 16.29 mmol) was added dropwise to a stirred solution of methyl 2-(3-fluoro-4-hydroxyphenyl)acetate (85% by LCMS) (2 g, 10.86 mmol) in DCM (47.1 mL) cooled to 0° C., over a period of 5 minutes under nitrogen. Triethylamine (4.54 mL, 32.58 mmol) was added dropwise over 5 minutes (keeping internal temperature between 5-10° C.) and the resulting solution stirred at room temperature for 4 hours under nitrogen. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with water (100 mL), saturated NaHCO3 (100 mL), and water (100 mL). The organic layer was dried by passing through a phase seperating cartridge and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(3-fluoro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (2.250 g, 65.5%) as a straw yellow oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:5]=2[CH:6]=1.[O-:16][C:17]#[N:18].[Na+].C(O)(=O)C(C1C=CC=CC=1)O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:1]1[CH:2]=[CH:3][C:4]2[N:15]([C:17]([NH2:18])=[O:16])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:5]=2[CH:6]=1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: N#C[O-]
Agent: O=C(O)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Yield: 90 %

Procedure:
A suspension of 10 g of iminostilbene in 100 ml toluene was treated with 20.2 g of sodium cyanate and 27.5 g of mandelic acid and was heated to reflux for about 10 hrs. The reaction mixture was cooled to room temperature and charged with sodium hydroxide solution and maintained for 8 hrs. The resulting suspension was filtered, washed with water and dried to give 11 g of carbamazepine.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[CH3:11][C:12]1[CH:17]=[C:16]([O:18][C:2]2[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=2[CH:4]=[O:5])[CH:15]=[C:14]([CH3:19])[N:13]=1
Reactant: O=Cc1cc(I)ccc1F
Reactant: Cc1cc(O)cc(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccc(I)cc2C=O)cc(C)n1
Yield: 93.1 %

Procedure:
In a manner similar to the method described in Example 50a, 2-fluoro-5-iodobenzaldehyde (2 g, 8 mmol) (Aldrich) was reacted with 2,6-dimethyl-4-hydroxypyridine (1.08 g, 8.8 mmol) and K2CO3 in N,N-dimethylacetamide to give 2-(2,6-dimethyl-pyridin-4-yloxy)-5-iodo-benzaldehyde as a yellow solid (Yield 2.63 g, 92%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:27]3[N:23]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39](=[O:50])[N:40]([CH:47]([CH3:49])[CH3:48])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:19]2=[O:51])=[N:9]1)=O)(C)(C)C.Cl>O1CCOCC1.CCOC(C)=O>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:27]3[N:23]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39]([N:40]([CH:47]([CH3:48])[CH3:49])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:50])[C:19]2=[O:51])=[N:9]1
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
To a solution of 3-{6-[(isopropyl-phenyl-carbamoyl)-methyl]-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indazole-1-carboxylic acid tert-butyl ester (391.9 mg, 0.674 mmol) in dioxane (8 mL) was added 4M HCl in dioxane (6 mL). The reaction was stirred at room temperature for 24 hours and was diluted with EtOAc. The organic solution was washed with aqueous NaHCO3 and brine, was dried (MgSO4), filtered and concentrated in vacuo. Purification by medium pressure chromatography eluting with a solvent gradient (EtOAc to 10% MeOH in EtOAc) provided 260.9 mg of 2-[4-(1H-indazol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide as a racemic mixture. 1H NMR (CD3OD) δ 7.90 (d, 1H), 7.65 (d, 2H), 7.34-7.54 (m, 12H), 7.22 (t, 1H), 7.13 (t, 1H), 6.99 (d, 1H), 4.74 (m, 1H), 465 (d, 1H), 4.42 (t, 1H), 3.92-4.12 (m, 3H), 0.99 (m, 6H); MS 582.7 (M+1), 580.4 (M−1).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[F:10][C:11]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>O>[N+:6]([C:17]1[C:18]([F:21])=[C:19]([F:20])[C:11]([F:10])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Reaction time: 0.75 h
Yield: 77.5 %

Procedure:
To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3×200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78% yield; m.p.; 1H-NMR (400 MHz; DMSO) δ 14.29 (broad s, 1H), 8.43–8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) δ 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) δ −120.50 to −120.63 (m), −131.133 to −131.27 (m), −153.63 to −153.74 (m).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].O>C1COCC1>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1[O:1][CH2:2][CH2:3][CH2:4][CH:5]=1)[CH2:22][CH2:23][CH3:24]
Reactant: C1=COCCC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)C1=CCCCO1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3,4-dihydro-2H-pyran (500 mg, 5.94 mmol) in THF (10 mL) was brought to −78° C. followed by the addition of tert-butyllithium (12.2 mL, 20.8 mmol, 1.7 M in pentane). The resulting yellow solution was brought to 0° C. and stirred for 15 min. The reaction was then cooled to −78° C. and tributyltin chloride (4.8 mL, 17.8 mmol) was slowly added. The reaction was monitored by TLC. Upon completion by TLC, water was added (20 mL) to the reaction. The organic phase was separated, washed with water, dried over MgSO4, concentrated and chromatographed on silica gel using hexanes (500 ml hexanes and 0.5 mL triethylamine). The title compound was obtained as a colorless oil. MS m/z: 375 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][N:11]([C:25]([NH:24][CH2:22][CH3:23])=[O:26])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: CCN=C=O
Reactant: Clc1ccc(C=CC2=NCCNc3ccccc32)cc1Cl
Product: CCNC(=O)N1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 41.2 %

Procedure:
A solution of 32 mg (0.1 mmol) of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1H-benzo-1,4-diazepine and 10 mg (0.14 mmol) of ethyl isocyanate was heated at 85° C. for 48 hours, a further 10 mg of ethyl isocyanate being added after 6 hours and again after 30 hours. The solvent was removed by evaporation and the residue chromatographed on silica gel using dichloromethane/methanol (19:1) for the elution. The product was recrystallized from diethyl ether. There was obtained 16 mg of (E)-5-(3,4-dichlorostyryl)-N-ethyl-2,3-dihydro-1H-1,4-benzodiazepine-1-carboxamide as an off-white solid. MS: m/e 387.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@@:10]([CH2:47][CH:48]=O)([CH2:34][CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:28][CH2:29]3)(=[O:25])=[O:26])[C:11](=[O:33])[C@@:10]([CH2:47][CH2:48][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)([CH2:34][CH2:35][O:36][Si:37]([CH:38]([CH3:40])[CH3:39])([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](CC=O)(CCO[Si](C(C)C)(C(C)C)C(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@](CCO[Si](C(C)C)(C(C)C)C(C)C)(CCN2CCOCC2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
N-((S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-(2-oxoethyl)-3-(2-((triisopropylsilyl)oxy)ethyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (Example 408, Step F) and morpholine were combined according to a procedure similar to the one described in Example 91, Step F. Purification by chromatography on silica gel (eluent: 50 to 100% EtOAc/DCM, gradient elution over 15 min) provided the title compound as a clear, colorless glass.
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(=O)(O)[O-].[Na+].Cl[CH2:16][C:17]([O:19][CH3:20])=[O:18]>O>[CH3:20][O:19][C:17](=[O:18])[CH2:16][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([CH2:2][F:1])[CH:4]=1
Reactant: Nc1cccc(CF)c1
Reactant: COC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)CNc1cccc(CF)c1
Temperature: 90 °C
Yield: 48.1 %

Procedure:
3-Fluoromethyl aniline (containing 37% 3-methylaniline, 13.6 g≡68 mmol) was mixed with dry acetonitrite (10 ml), sodium bicarbonate (15.4 g, 183 mmol) and methyl chloroacetate (12 ml, 137 mmol) and heated to 90° C. under nitrogen for 14 h. The cooled reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (4×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give an orange oil. The crude product was purified by chromatography on silica (Merck 9385, 1.5 kg) eluted with ether-hexane 1:4 to give Intermediate 54 (6.45 g, 48%) as a white crystalline solid, m.p. 47°-47.5°.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([Cl:21])(C1C=CC(C)=CC=1)(=O)=O>N1C=CC=CC=1>[C:1]1([C:7]#[C:8][CH2:9][Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC#Cc1ccccc1
Solvent: c1ccncc1
Product: ClCC#Cc1ccccc1
Temperature: 0 °C
Yield: 63 %

Procedure:
1-Phenyl-1-propyn-3-ol (5 g), 5.1 g of tosyl chloride and 20 ml of pyridine were stirred at room temperature for 1 hour. The reaction mixture was poured into 100 ml of ice water and extracted with ethyl acetate. The oil layer was washed with 1N hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give 2.54 g of 3-phenyl-2-propynyl chloride as a pale yellow, oily substance.