Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=O.[CH2:9]1[CH:13]2[CH:14]3[CH:18]=[CH:17][CH:16]([CH:12]2[CH:11]=[CH:10]1)[CH2:15]3.O>>[CH2:9]1[CH:13]2[CH:14]3[CH:18]=[CH:17][CH:16]([CH:12]2[CH:11]=[CH:10]1)[CH2:15]3.[C:4]1(=[O:6])[O:8][C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: O=C(O)/C=C\C(=O)O
Solvent: C1=CC2C3C=CC(C3)C2C1
Solvent: O
Product: O=C1C=CC(=O)O1

Procedure:
The following example is for a case where an addition product of maleic acid to dicyclopentadiene produced from 1 mol (132 g) dicyclopentadiene, 1 mol (98 g) maleic anhydride and 1 mol (18 g) water is dehydrated and condensed with 0.6 mol (37.2 g) ethylene glycol. First, since the theoretic amount of the produced addition product of maleic acid to dicyclopentadiene is 1 mol, the weight is given by the equation: 132 g+98 g+18 g=248 g. Since there are 1.2 mol hydroxyl groups and 1 mol carboxyl groups, 1 mol water is eliminated with the condensation, and its weight is: 18×1=18 g. Therefore, the ratio of the dicyclopentenyl groups is given by the following equation: [133 g/(248 g+37.2 g-18 g)]×100=49.8 percent by weight.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][N:48]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:46]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and piperidin-4-yl-carbamic acid tert-butyl ester according to conditions described in general procedure C. Mp: 211-212° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.18-1.14 (m, 2 H), 1.34 (s, 9H), 1.57-1.61 (m, 8 H), 2.80 (t, J=12.8 Hz, 2 H), 3.21-3.34 (m, 6 H), 4.19 (bs, 1 H), 6.19 (d, J =5.5 Hz, 1 H), 6.76 (d, J=7.6 Hz, 1 H), 6.94-6.98 (m, 1 H), 7.14 (d, J=9.1 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.54-7.61 (m, 3 H), 7.81-7.83 (m, 1 H), 7.96-7.99 (m, 1 H), 8.24 (d, J=5.5 Hz, 1 H), 10.44 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH2:10].C([Li])CCC.CN(C)[CH:18]=[O:19].O>C1COCC1>[F:8][C:4]1[C:3]([CH:9]=[CH2:10])=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:18]=[O:19]
Reactant: C=Cc1c(F)cccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1c(F)cccc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-3-fluoro-2-vinylbenzene (900 mg) in THF (40 ml) was added dropwise, at −78° C., n-butyllithium (3.4 ml 1.6 M/hexane). After 60 minutes, N,N-dimethylformamide (0.69 ml) was added dropwise at −78° C. After stirring at −78° C. for 60 minutes, the reaction mixture was admixed with water and then warmed to room temperature. Then the mixture was admixed with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. Purification by column chromatography gives 3-fluoro-2-vinylbenzaldehyde (160 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(Cl)[Cl:12]>>[CH3:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([Cl:12])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: ClCCl
Product: CC(=O)c1ccc(O)c(Cl)c1

Procedure:
50 gm of p-hydroxyacetophenone were dissolved in 500 ml of hot methylene dichloride and filtered through a small pad of silica gel. The solution was allowed to cool and the methylene dichloride was stripped off to obtain 41.75 gm (0.31 mol) of crystals. These crystals were dissolved in about 1.5 liters of methylene dichloride. The reaction flask was placed in an ice bath and chlorine gas was bubbled through the solution. After about a total of 5 minutes of Cl2(g) bubbling, the methylene chloride was stripped off to yield more than 30 gm of white crystals (>90% pure) of 3-chloro-4-hydroxy acetophenone.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([CH:28]4[CH2:33][CH2:32][N:31]([CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[CH2:30][CH2:29]4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].C(Cl)Cl>>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([CH:28]4[CH2:33][CH2:32][N:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:30][CH2:29]4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1CCC(c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)CC1

Procedure:
A solution of compound 41g (0.20 g, 0.36 mmol) in TFA/CH2Cl2 (1:3, 3 mL) was stirred at rt for 2 h, and concentrated under reduced pressure. The resulting mixture was diluted with 10 mL of water. The solids formed were collected by filtration and washed with Et2O (2×30 mL). The crude solid product was then purified by re-crystallization from CH2Cl2:Et2O (1:10) to obtain the title compound 25 as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.48 (d, J=8.4 Hz, 1H), 8.24 (d, J=5.7 Hz, 1H), 8.06-8.03 (m, 2H), 7.87-7.80 (m, 2H), 7.70-7.65 (m, 1H), 6.41 (d, J=6.0 Hz, 1H), 4.19 (s, 2H), 4.08-3.95 (m, 4H), 3.82-3.64 (m, 7H), 3.42-3.29 (m, 2H), 2.70-2.57 (m, 2H), 2.23-2.19 (m, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H28N6O3: 497.2 (M+H). Found: 497.2.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:38][CH2:37][C@H:36]([F:39])[CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:38][CH2:37][C@H:36]([F:39])[CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: F[C@H]1CCN(C2CNC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CC[C@H](F)C4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.245 g, 0.627 mmol), (S)-1-azetidin-3-yl-3-fluoropyrrolidine (0.109 g, 0.752 mmol) and 4 Å molecular sieves (0.5 g) in DCE (5 mL). The reaction mixture was stirred for 90 min at room temperature. Sodium triacetoxyborohydride (0.266 g, 1.254 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 20:80) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 586 as an off-white solid (0.204 g, 63%). LCMS (Method I): RT=2.46 min, [M+H]+ 520.2 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.99 (m, 1 H), 7.65-7.61 (m, 1 H), 7.27-7.21 (m, 2 H), 5.19 (dt, J=55.8, 5.4 Hz, 1 H), 4.50-3.95 (m, 4 H), 3.87 (s, 2 H), 3.81-3.72 (m, 7 H), 3.40 (dd, J=7.1, 6.1 Hz, 2 H), 3.26 (q, J=7.4 Hz, 2 H), 3.21-3.12 (m, 1 H), 3.12-3.03 (m, 2 H), 2.79-2.65 (m, 2 H), 2.64-2.51 (m, 1 H), 2.34-2.25 (m, 1 H), 2.15-2.03 (m, 1 H), 1.76-1.95 (m, 1 H), 1.33 (t, J=7.4 Hz, 3 H)
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH:7]=O)[O:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CO>[Br:1][C:2]1[CH:6]=[C:5]([CH2:7][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[O:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:10]=1
Reactant: C1COCCN1
Reactant: O=Cc1cc(Br)c(-c2nc(-c3ccc(Cl)cc3)no2)o1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Clc1ccc(-c2noc(-c3oc(CN4CCOCC4)cc3Br)n2)cc1
Reaction time: 24 h
Yield: 16.6 %

Procedure:
To a stirring solution of 5-(3-bromo-5-formyl-furan-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole (60 mg, 0.170 mmol), sodium cyanoborohydride (10.5 mg, 0.167 mmol), acetic acid (10.0 μL, 0.173 mmol), and methanol (2.0 mL) under argon was added morpholine (50 μL, 0.57 mmol). The solution was stirred for 24 h and concentrated to dryness. The product was purified by column chromatography (2:1, hexane:ethyl acetate) to yield 12 mg (17%) of 5-(3-bromo-5-morpholinomethyl-furan-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole as a white solid. 1H NMR (CDCl3): 8.12 (d, J=8.51 Hz, 2H), 7.49 (d, J=8.52 Hz, 2H), 6.60 (s, 1H), 3.74 (t, J=4.67 Hz, 4H), 3.67 (s, 2H), 2.56 (t, J=4.67 Hz, 4H); and to also yield 12 mg (20%) of 5-(3-bromo-5-hydroxymethyl-furan-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole as a white solid. 1H NMR (CDCl3): 8.11 (dd, J=8.79, 2.20 Hz, 2H), 7.49 (dd, J=8.79, 2.20 Hz, 2H), 6.67 (s, 1H), 4.77 (d, J=6.32 Hz, 2H), 2.09 (t, J=6.46 Hz, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:24][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCN
Reactant: Cc1ccc2nc(-c3cc([N+](=O)[O-])ccc3F)oc2c1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2ccc(C)cc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-6-methylbenzoxazole (250 mg, 0.9 mmol) and propylamine (400 μL, 5.0 mmol) the subtitle compound was obtained (262 mg, 94%). 1H NMR (DMSO) δ 9.21(t, 1H), 8.78(d, 1H), 8.19(dd, 1H), 7.70–7.66(m, 2H), 7.25(d, 1H), 7.03(d, 1H), 3.43(q, 2H), 2.47(s, 3H), 1.73(m, 2H), 1.01(t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:72]=[CH:71][C:69]([NH2:70])=[CH:68][CH:67]=1>C(Cl)Cl>[NH2:65][C:66]1[CH:72]=[CH:71][C:69]([NH:70][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[CH:68][CH:67]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(N)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (300 mg, 0.66 mmol) in methylene chloride (10 mL), HATU (Aldrich, 266 mg, 0.66 mmol) was added followed by the addition of DIPEA (0.30 mL) and 4-amino-aniline (Aldrich, 143 mg, 1.32 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 40-85% EtOAc/hexanes) to give an off-white solid. 298 mg.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
2-(4-Bromo-phenoxy)-ethanol (5 g, 23 mmol) is dissolved in dichloromethane (40 mL). Triethylamine (2.8 g, 28 mmol) and 4-dimethylaminopyridine (140 mg, 1.15 mmol) were then added followed by tert-butyldimethylsilyl chloride (3.65 g, 24.3 mmol) as a solution in dichloromethane (10 mL). The reaction is allowed to stir at ambient temperature for 18 hours. The reaction mixture is washed with 10% aqueous citric acid, the organic layer is separated and concentrated in vacuo to afford 7.5 g (98% yield) of the title compound. 1H NMR (CDCl3) 0.05 (s, 6H), 0.85 (s, 9H), 3.85-3.94 (m, 4H), 6.72 (d, 2H, J=6.90 Hz), 7.28 (d, 2H, J=6.90 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[CH2:16][NH2:17].C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]([F:25])([F:26])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1)[CH2:16][NH:17][CH2:4][C:3]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=1[Br:1]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Fc1ccc(Br)c(CBr)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-bromo-5-fluoro benzyl bromide (0.5 g, 1.86 mmol) and 3,5-bis(trifluoromethyl)benzylamine (0.45 g, 1.86 mmol) in methylene chloride (10 ml) at 0° C., triethyl amine (0.39 ml, 2.80 mmol) was added. The solution was slowly warmed to room temperature and stirred for 18 h. The solvent was removed under reduced pressure. The title compound was obtained by flash column chromatography using EtOAc/hexane (2:8) as the eluant. 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 2H), 7.80 (s, 1H), 7.53 (dd, J=8.8, 5.3 Hz, 1H), 7.18 (dd, J=9, 3.3 Hz, 111), 6.91 (dt, J=8.5, 3.3 Hz, 1H), 3.98 (s, 2H), 3.90 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][NH2:8])=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([CH3:12])=[N:3]1.[CH3:13][O:14][C:15]1[C:16]([O:28][CH3:29])=[CH:17][C:18]2[NH:24][C:23](=[O:25])[CH2:22][CH2:21][C:20](=O)[C:19]=2[CH:27]=1.O>C(O)(=O)C>[CH3:1][N:2]1[C:6]([NH:7][N:8]=[C:20]2[CH2:21][CH2:22][C:23](=[O:25])[NH:24][C:18]3[CH:17]=[C:16]([O:28][CH3:29])[C:15]([O:14][CH3:13])=[CH:27][C:19]2=3)=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([CH3:12])=[N:3]1
Reactant: COc1cc2c(cc1OC)C(=O)CCC(=O)N2
Reactant: Cc1nn(C)c(NN)c1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C(=NNc1c([N+](=O)[O-])c(C)nn1C)CCC(=O)N2
Temperature: 70 °C
Yield: 12.2 %

Procedure:
1,3-Dimethyl-4-nitro-1H-pyrazol-5-yl-hydrazine (0.073 g, 0.4 mmol) was added to a suspension of 7,8-dimethoxy-1H-[1]benzazepin-2,5(3H, 4H)-dione (0.100 g, 0.4 mmol) in acetic acid (5 ml) with stirring under argon. The mixture was heated at 70° C. for 2 days, cooled and water (5 ml) added. The precipitate was then filtered off to give the title compound as a yellow solid (0.019 g, yield 11.5%); 1H-NMR (DMSO-d6, 300 MHz): δ (ppm)=12.8 (v br s; 1 H), 9.59 (s; 1H), 7.2 (s; 1H), 6.63 (s; 1H), 3.96 (s; 3H), 3.75-3.77 (s, 6H), 3.05 (br t, 2H), 2.57 (br t, 2H), 2.35 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].O=[C:15]([CH2:21][CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[CH2:19]([O:18][C:16]([CH:15]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:21][CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)=[O:17])[CH3:20]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1cccs1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1cccs1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4 g of type 4A molecular sieves (powdered) are added to a mixture of L-alanyl-L-proline (0.93 g) and ethyl 2oxo-4-(2-thienyl)-butyrate (3.18 g) in 25 ml of anhydrous ethyl alcohol. The mixture is stirred for 45 minutes at room temperature, followed by slow addition (3.5 hours) of a solution of sodium cyanoborohydride (0.785 g) in 15 ml of anhydrous ethyl alcohol and stirring overnight at room temperature. The reaction mixture is made just slightly acidic with glacial acetic acid, filtered and the filtrate conc. in vacuo to an orange oil. Extraction of a chloroform solution of this oil with 10% potassium bicarbonate, followed by re-extraction of the acidified (pH 3) bicarbonate extracts with chloroform provide, after drying and evaporation of solvent, 400 mg of the desired substituted dipeptide. The nmr spectrum (CDCl3) shows the thienyl proton as multiplet at 7.0 ppm, two active protons in broad singlet at 6.2 ppm, six methyl protons as broad multiplet 1.22-1.43 ppm range, and a series of ill-defined multiplets ranging 1.8-4.4 ppm.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)#[N:18]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[NH:18])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1ccncc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (10 g, 48.1 mmol) in toluene (250 ml) at 0° C., trimethylaluminum (2M solution in toluene, 36.1 ml, 72.2 mmol) was added over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 4-cyanopyridine (10 g, 96.2 mmol) in toluene (250 ml) was added over 10 minutes and the mixture was heated to 70° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol and later with methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate and filtered. The pale yellow solid (4.8 g, 36%) was used in the next reaction without further purification. Anal. Calc'd. for C13H14N3SClO2H2O: C, 47.34; H, 4.89; N, 12.74; S, 9.72. Found C, 47.69; H, 4.35; N, 12.77; S, 9.74.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])(C)(C)C.CCCCC.[CH2:20]([C:27]1([N:34]([CH3:36])[CH3:35])[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[O:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[C:5]1[C:30]1([OH:33])[CH2:31][CH2:32][C:27]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([N:34]([CH3:36])[CH3:35])[CH2:28][CH2:29]1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Reactant: c1ccc2occc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CN(C)C1(Cc2ccccc2)CCC(O)(c2cc3ccccc3o2)CC1
Temperature: -5 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
A solution of benzo[b]furan (612 mg, 5.12 mmol) in dry THF (40 ml) was cooled to −8° C. under a stream of argon. Thereafter, tert-Butyllithium (6.22 mmol, 4.14 ml of a 1.5 molar pentane solution) was added dropwise such that a reaction temperature of −5° C. was not exceeded during the addition. When the addition had ended the reaction mixture was stirred for two hours at −5° C. Thereafter, a solution of 4-benzyl-4-dimethylaminocyclohexanone (1.20 g, 5.18 mmol) in dry THF (10 ml) was added dropwise at 0° C. The mixture was stirred for one hour at 0° C. and then for four days at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml), the organic phase was separated and the aqueous phase was extracted four times with 30 ml methylene chloride each time. The combined organic phases were dried over sodium sulfate and filtered and the solvent was removed in vacuo. Purification was carried out by means of flash chromatography over silica gel with cyclohexane/ethyl acetate (v/v=8:2). 380 mg 1-benzofuran-2-yl-4-benzyl-4-dimethylaminocyclohexanol with a melting point of 121-124° C. were obtained.
Reaction SMILES: OO.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([C:24]4[NH:28][C:27]5[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:26]=5[N:25]=4)[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][C:6]=1[NH:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([O:41][C:42](=[O:44])[CH3:43])[CH2:37][CH2:36]1)#[N:4].CS(C)=[O:47].[OH-].[Na+]>C(O)C.O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([C:24]4[NH:28][C:27]5[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:26]=5[N:25]=4)[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][C:6]=1[NH:34][C@H:35]1[CH2:36][CH2:37][C@H:38]([O:41][C:42](=[O:44])[CH3:43])[CH2:39][CH2:40]1)(=[O:47])[NH2:4]
Reactant: CC(=O)O[C@H]1CC[C@H](Nc2cc(-n3c4ccccc4c4c(-c5nc6ccc(F)cc6[nH]5)cccc43)ccc2C#N)CC1
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)O[C@H]1CC[C@H](Nc2cc(-n3c4ccccc4c4c(-c5nc6ccc(F)cc6[nH]5)cccc43)ccc2C(N)=O)CC1

Procedure:
In a 50 ml three-necked flask, 1.36 ml of 30% aqueous hydrogen peroxide are added to a mixture of 200 mg of acetic acid 4-{2-cyano-5-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]phenylamino}-trans-cyclohexyl ester, obtained in the preceding stage, in 7.5 ml of ethanol and 3 ml of dimethyl sulphoxide and 0.96 ml of 1M sodium hydroxide, and the mixture is stirred for ¼ hour at ambient temperature. 40 ml of distilled water are added and the mixture is extracted with 3 times 40 ml of ethyl acetate. The combined organic phases are washed with twice 40 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a mixture of dichloromethane and methanol (96/4 by volume). 170 mg of acetic acid 4-{2-carbamoyl-5-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]phenylamino}-trans-cyclohexyl ester are obtained in the form of an off-white solid, the characteristics of which are the following: