Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:29]([OH:31])=[O:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32](O)[CH3:33].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)O)N3C(=O)c2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CSC2(CCC(Oc3ccc(C(C)C)cc3)CC2)N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 56 ml of methylene chloride was dissolved 2.80 g of (3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid, to which were successively added at 0-5° C. 0.56 ml of ethanol, 0.16 g of N,N-dimethylaminopyridine and 1.98 g of dicyclohexyl carbodiimide. After stirring the mixture at ambient temperature for 24 hours, the insoluble matter was filtered off. The filtrate was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: toluene:ethyl acetate=50:1] gave 0.85 g of ethyl (3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylate as a colorless oily product.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C[O:21][C:22](=[O:35])[CH2:23][O:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([SH:33])=[CH:27][C:26]=1[CH3:34]>>[CH3:32][O:31][C:29]1[C:28]([S:33][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[CH:6][CH:5]=2)=[CH:27][C:26]([CH3:34])=[C:25]([CH:30]=1)[O:24][CH2:23][C:22]([OH:35])=[O:21]
Reactant: FC(F)(F)c1ccc(-c2ccc(CCBr)cc2)cc1
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Product: COc1cc(OCC(=O)O)c(C)cc1SCCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 22C using 4-(2-bromo-ethyl)-4′-trifluoromethyl-biphenyl and 1D. MS m/z 491 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([C:18]([CH3:26])([CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Cl[CH2:28][C:29]([NH:31][C:32]([NH2:34])=[O:33])=[O:30]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:28][C:29]([NH:31][C:32]([NH2:34])=[O:33])=[O:30])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([C:18]([CH3:25])([CH3:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: NC(=O)NC(=O)CCl
Reactant: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,1-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with chloroacetyl-urea according to the method of Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:28])[C:12]=1[O:13][C@H:14]1[C@@H:19]3[O:20]C(=O)[O:22][C@@H:18]3[C@@H:17]([O:24][CH3:25])[C:16]([CH3:27])([CH3:26])[O:15]1)[O:9][C:8](=[O:29])[C:7]([NH:30]C(=O)OCC1C=CC=CC=1)=[CH:6]2.CCN=C=NCCCN(C)C.[NH:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=[C:53]1[C:61]([OH:63])=O.C(=O)([O-])[O-]>[Pd].C1COCC1.N1C=CC=CC=1.C(Cl)Cl.CO.C(Cl)Cl.C(N(CC)CC)C>[OH:20][C@@H:19]1[C@H:18]([OH:22])[C@@H:17]([O:24][CH3:25])[C:16]([CH3:26])([CH3:27])[O:15][C@H:14]1[O:13][C:12]1[C:11]([CH3:28])=[C:10]2[C:5]([CH:6]=[C:7]([NH:30][C:61]([C:53]3[NH:52][C:60]4[C:55]([CH:54]=3)=[CH:56][CH:57]=[CH:58][CH:59]=4)=[O:63])[C:8](=[O:29])[O:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2cc(NC(=O)OCc3ccccc3)c(=O)oc2c(C)c1O[C@@H]1OC(C)(C)[C@H](OC)[C@H]2OC(=O)O[C@@H]12
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc2cc(NC(=O)c3cc4ccccc4[nH]3)c(=O)oc2c(C)c1O[C@@H]1OC(C)(C)[C@H](OC)[C@@H](O)[C@H]1O
Reaction time: 12 h
Yield: 18 %

Procedure:
Palladium on carbon (10%, 15 mg) was added to 25a (74.0 mg, 0.13 mmol) in anhydrous THF (5.00 mL) and the solution was placed under an atmosphere of H2. After 12 hours, the solution was filtered through SiO2 (1:1 CH2Cl2:Acetone) and the eluent was concentrated to afford a yellow solid, which was used without further purification (60.0 mg, 99%). EDCI (69.0 mg, 0.36 mmol) and 1H-indole-2-carboxylic acid (46.4 mg, 0.29 mmol) were added to the amine (60.0 mg, 0.14 mmol) in 30% pyridine/CH2Cl2 (3.50 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 3:1 Hexane:Ether→40:1 CH2Cl2:Acetone) to afford a colorless solid, which was used without further purification (68.0 mg, 85%). Triethylamine (150 μL) was added to the carbonate (68.0 mg, 0.12 mmol) in MeOH (2.5 mL) and CH2Cl2 (2.50 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to afford 26i as a colorless amorphous solid (12.6 mg, 19%, 16% over 3 steps): 1H NMR (CD2Cl2, 400 MHz) 8.29 (s, 1H), 7.63 (s, 1H), 7.45-7.39 (m, 3H), 6.92 (s, 1H), 6.85 (s, 1H), 6.19 (s, 1H), 5.09 (d, J=6.5 Hz, 1H), 4.31-4.28 (m, 1H), 4.01-3.97 (m, 1H), 3.94 (s, 3H), 3.62 (s, 1H), 3.56 (s, 3H), 3.15 (d, J=4.9 Hz, 1H), 2.46 (s, 3H), 2.36 (s, 1H), 1.38 (d, J=11.5 Hz, 3H), 1.32 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 157.6, 152.1, 148.2, 145.4, 142.2, 134.5, 129.9, 127.8, 127.7, 127.5, 127.3, 122.3, 121.2, 120.2, 115.0, 105.3, 105.1, 101.3, 81.7, 69.0, 68.0, 66.5, 59.1, 55.2, 28.7, 24.6, 24.1, 9.1; IR (film) νmax 2926, 1707, 1526, 1464, 1391, 1340, 1296, 1231, 1207, 1086, 1024, 943, 739, 700, 623 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C28H30N2O9, 561.1849; found, 561.1781.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[CH3:16][NH:17][C:18]([C:20]1[C:24]2[C:25]([CH3:37])([CH3:36])[CH:26](CC)[C:27]3[CH:28]=[N:29][C:30](I)=[N:31][C:32]=3[C:23]=2[N:22]([CH3:38])[N:21]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C)C=O>[CH3:16][NH:17][C:18]([C:20]1[C:24]2[C:25]([CH3:36])([CH3:37])[CH2:26][C:27]3[CH:28]=[N:29][C:30]([NH:15][C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[CH:10]=4)=[N:31][C:32]=3[C:23]=2[N:22]([CH3:38])[N:21]=1)=[O:19]
Reactant: CCC1c2cnc(I)nc2-c2c(c(C(=O)NC)nn2C)C1(C)C
Reactant: CN1CCN(Cc2cccc(N)c2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CNC(=O)c1nn(C)c2c1C(C)(C)Cc1cnc(Nc3cccc(CN4CCN(C)CC4)c3)nc1-2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
Pd(OAc)2 (16.34 mg, 0.0728 mmol), (±)-BINAP (45.33 mg, 0.0728 mmol) and dimethylformamide (12 mL) were charged in a round-bottom flask flushed with argon. The mixture was stirred under argon for 30 minutes. Then 3-(4-methyl-piperazin-1-ylmethyl)-phenylamine (448.4 mg, 2.184 mmol), ethyl 8-iodo-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid methylamide (300 mg, 0.728 mmol), K2CO3 (1.508 g, 10.910 mmol) and dimethylformamide (10 mL) were added. The resulting mixture was heated to 80° C. in an oil bath under argon with good stirring for 3 hours. After cooling to room temperature, the reaction mixture was filtered by suction filtration washing with dichloromethane and the filtrate was evaporated to dryness. The crude was purified by flash chromatography on silica gel (eluant; dichloromethane/methanol 95:5) to afford 215 mg (yield 62%) of pure title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[C:3]=1[C:16]([NH2:18])=[O:17].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>CCO.N1CCCCC1>[Cl:15][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:16]([NH2:18])=[O:17])=[C:2]([N:1]=[CH:24][C:23]3[CH:26]=[CH:27][C:20]([OH:19])=[CH:21][CH:22]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1c(Nc2ccc(F)c(Cl)c2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2ccc(F)c(Cl)c2)n[nH]c1N=Cc1ccc(O)cc1
Yield: 53 %

Procedure:
5-amino-3-((3-chloro-4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (45 mg, 1 eq.) and piperidine (4-drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((3-chloro-4-fluorophenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (147 mg, 53% yield).
Reaction SMILES: [C:1]([C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C1CC=CC=1.[C:15]1([CH3:21])[CH:20]=CC=[CH:17][CH:16]=1>>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:20][CH:15]2[CH2:21][CH:9]1[CH:17]=[CH:16]2)#[N:2]
Reactant: Cc1ccccc1
Reactant: C=C(C#N)C(=O)OCC
Agent: C1=CCC=C1
Product: CCOC(=O)C1(C#N)CC2C=CC1C2
Reaction time: 1 h

Procedure:
Specifically, 50 g (0.33 mol) of ethyl 2-cyanoacrylate (6a) was dissolved in 200 ml of toluene, and 45 g (0.68 mol) of 1,3-cyclopentadiene (5a) was added dropwise to the solution with cooling temperatures of 35° C. or below. Stirring for one hour and subsequent enrichment yielded 72 g of ethyl 5-cyanobicyclo[2.2.1]hept-2-ene-5-carboxylate represented by Formula (7a) (crude product).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:20]=[C:19]4[C:44]3[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=3)=[O:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>CS(C)=O>[C:1]1([N:7]2[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[C:19]4[C:44]3[CH:45]=[CH:46][N:47]=[CH:48][CH:49]=3)=[O:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N[C@@H]1CCCN(c2ccccc2)C1)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: O=C(N[C@@H]1CCCN(c2ccccc2)C1)c1ccc2[nH]nc(-c3ccncc3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Crude N-[(3R)-1-phenylpiperidin-3-yl]-3-(pyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide (129 mg, 0.202 mmol) was stirred with TFA (0.5 ml) at room temperature for 45 minutes. Addition TFA (1 ml) was added and the reaction mixture was stirred at room temperature for 1.5 hours. Triethylsilane (100 μl, 0.626 mmol) was added and then the reaction mixture diluted with DMSO purified by mass-triggered reverse-phase HPLC to provide N-[(3R)-1-phenylpiperidin-3-yl]-3-(pyridin-4-yl)-1H-indazole-5-carboxamide.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[S:14](=[O:22])(=[O:21])[NH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].C[O-].[Na+]>CN(C=O)C.Cl>[CH3:20][O:19][C:17]([C:16]1[NH:15][S:14](=[O:22])(=[O:21])[C:5]2[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:4]=2[C:3]=1[OH:2])=[O:18]
Reactant: COC(=O)CNS(=O)(=O)c1cc(OC)c(OC)cc1C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(O)c2cc(OC)c(OC)cc2S(=O)(=O)N1
Reaction time: 0.75 h

Procedure:
To a solution of 4,5-dimethoxy-2-(methoxycarbonylmethyl-sulfamoyl)-benzoic acid methyl ester (0.555 g, 1.60 mmol) in dry DMF (3 mL) was added dry and freshly prepared sodium methoxide (0.345 g, 6.39 mmol). A red colour was generated upon the addition of the sodium methoxide. The mixture was stirred for 45 minutes, and then diluted with 1N HCl (100 mL). The pale yellow solid that precipitated was collected and washed with water (0.341 g, 68%);
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11](=[S:12]=[O:13])[CH:10]=[C:9]([CH3:14])[CH:8]=[C:4]1[C:5]([OH:7])=O.ClC(OCC(C)C)=O.[CH:23]1([N:26]2[CH2:30][CH2:29][CH2:28][CH:27]2[CH2:31][NH2:32])[CH2:25][CH2:24]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.C(N(CC)CC)C.O.CC(C)=O>[CH:23]1([N:26]2[CH2:30][CH2:29][CH2:28][CH:27]2[CH2:31][NH:32][C:5](=[O:7])[C:4]2[CH:3]([O:2][CH3:1])[C:11](=[S:12]=[O:13])[CH:10]=[C:9]([CH3:14])[CH:8]=2)[CH2:25][CH2:24]1
Reactant: COC1C(C(=O)O)=CC(C)=CC1=S=O
Reactant: NCC1CCCN1C1CC1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: COC1C(C(=O)NCC2CCCN2C2CC2)=CC(C)=CC1=S=O
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
53.5 g of 2-methoxy-5-methyl sulfinyl benzoic acid, 740 ml of acetone, 140 ml of water and 35 ml of triethylamine (density 0.726) are placed in a 2 liter flask fitted with an agitator, a thermometer and a dropping funnel. The solution is cooled to between 0° and +5° C., after which 34.1 g of isobutyl chloroformate is dripped in. The mixture is agitated for 45 minutes at 20° C. then cooled to 0° C., and 42 g of 1-cyclopropyl-2-amino methyl pyrrolidine is poured in drop by drop. The mixture is reacted at room temperature then left to stand. The solvents are evaporated under vacuum. The oily residue is dissolved in 250 ml of water and 50 ml of hydrochloric acid (density 1.18) and extracted twice with 125 ml of methylene chloride. The aqueous phase is then made alkaline with 70 ml of soda lye. A yellow oil is salted out. It is extracted 3 times with 250 ml of methylene chloride and the organic phase is washed 3 times with 100 ml of water and dried over magnesium sulphate. The solution is filtered and the solvent evaporated. An oily residue is obtained. It is dissolved in 500 ml of ethanol and an equimolar quantity of citric acid is added. It is evaporated under vacuum and the residue is dissolved in 1,000 ml of boiling isopropanol then cooled. The supernatant solution is decanted off and the residual paste dissolved in 600 ml of water. The solution is filtered with charcoal then the filtrate is evaporated under vacuum.
Reaction SMILES: Cl.C[N:3]([CH3:15])[C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[C:16]([O:20][C:21]([NH:23][CH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.O>[CH3:15][NH:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][C:31]([C@H:28]1[CH2:27][CH2:26][C@H:25]([CH2:24][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:30][CH2:29]1)=[O:32]
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To the compound (I) (19.00 g), 4 N hydrogen chloride/1,4-dioxane solution (325 ml) was added under room temperature, and the mixture was stirred at the same temperature for 30 minutes. The mixture was concentrated under a reduced pressure, and L-phenylalanine dimethylamide hydrochloride (II) was obtained quantitatively as a white powder. Subsequently, to a solution of the compound (II), trans-4-(t-butoxycarbonylaminomethyl)cyclohexylcarboxylic acid (16.70 g) and triethylamine (9.75 ml) in dry dichloromethane (200 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13.69 g) was added under ice-cooling, the mixture was stirred for 2 hours, and again stirred at room temperature for 2 hours. To the reaction water was added to obtain an organic layer, which was washed with 10% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate, and water, in this order, followed by drying over anhydrous sodium sulfate. The solids were filtered off, the filtrate concentrated under a reduced pressure and the residue was washed with diethyl ether, followed by filtration to give N-[trans-4-(t-butoxycarbonylaminomethyl)cyclohexylcarbonyl]-L-phenylalanine dimethylamide (III) (21.90 g). The structure was confirmed by NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24](=[O:26])[N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNC1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Product: O=C(O)c1c(CC(=O)N2CCCC2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from Example 68.1.) was ring opened with pyrrolidine at 22° C. to give the title compound as a white solid. MS: 429.3 ([M−H]−).
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][CH:29]([C:34]([O:36][CH3:37])=[O:35])[C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>O1CCCC1>[OH:1][CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][CH:29]([C:30]([O:32][CH3:33])=[O:31])[C:34]([O:36][CH3:37])=[O:35])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)C(CCC1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CCC1(CCO)CCCCC1)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of dimethyl 3-[1-(2-(tert-butyldiphenylsiloxy)ethyl)cyclohexyl]-1,1-propanedicarboxylate (500 mg) in tetrahydrofuran (10 mL) was added a 1M tetrabutylammonium fluoride/tetrahydrofuran solution (1.9 mL) at room teperature. The solution was stirred at room temperature for 3 hours. Water was added to the solution, and it was extracted with ethyl acetate. The organic layer was washed in turn with an aqueous ammonium chloride solution, and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=1:1) to give the title compound (180 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc(F)c(F)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3,4-difluoro-phenylboronic acid to give [1-(3,4-difluoro-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[C:18]([CH2:20][CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=O)[CH3:2].C1(C)C=CC=CC=1.[CH3:29][NH:30][NH2:31]>O>[CH3:29][N:30]1[N:31]=[C:5]([C:4]2[CH:16]=[CH:17][C:18]([CH2:20][CH3:21])=[CH:19][C:3]=2[CH2:1][CH3:2])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:10]
Reactant: CCc1ccc(C(=O)c2ccccc2C(=O)O)c(CC)c1
Reactant: CNN
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc(-c2nn(C)c(=O)c3ccccc23)c(CC)c1
Yield: 55.9 %

Procedure:
A mixture of 2-(2,4-diethylbenzoyl)benzoic acid (40 g, 0.14 mol), toluene (120 mL) and methyl hydrazine (7.5 mL) were refluxed for 3 hours with removal of water via a Dean Stark trap. Additional toluene (100 mL) and methyl hydrazine (4.0 mL) were added and the mixture was refluxed until 2.8 mL of water was collected. The mixture was cooled, extracted with CH2Cl2 /2N NaOH, then 1N HCl and the organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was crystallized from ethanol/water and recrystallized from ethanol/water to afford 22.86 g (55.9%) of 2-methyl-4-(2,4-diethylphenyl)-1-(2H)-phthalazinone, m.p. 94.5°-96.5 ° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[CH:4]=[CH:3][N:2]=1.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](Cl)=[O:15]>>[Cl:12][C:13]([Cl:18])([Cl:17])[C:14]([NH:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:1]=[N:2][CH:3]=[CH:4]2)=[O:15]
Reactant: Nc1cccc2ccncc12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Product: O=C(Nc1cccc2ccncc12)C(Cl)(Cl)Cl

Procedure:
The product from Example 57C and trichloroacetylchloride were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[S:8][C:9]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:10]([OH:13])[C:11]=1[CH3:12])=[O:6])([CH3:3])[CH3:2].[CH2:20]([O:24][C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]=[C:33]=[O:34])=[O:26])[CH2:21][CH2:22][CH3:23]>C(#N)C.C1N2CCN(CC2)C1>[CH:1]([O:4][C:5]([C:7]1[S:8][C:9]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:10]([O:13][C:33]([NH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:25]([O:24][CH2:20][CH2:21][CH2:22][CH3:23])=[O:26])=[O:34])[C:11]=1[CH3:12])=[O:6])([CH3:2])[CH3:3]
Reactant: CCCCOC(=O)CCCCCN=C=O
Reactant: Cc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1O
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CCCCOC(=O)CCCCCNC(=O)Oc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1C
Yield: 93.4 %

Procedure:
10.0 g of 2,5-bis-(isopropoxycarbonyl)-3-methyl-4-hydroxythiophene, 20 ml of anhydrous acetonitrile, 15 g of butoxycarbonylpentyl isocyanate (b.p. 149°-151°/ 13 millibar) and 100 mg of triethylene diamine are maintained at 100° C. for 18 hours. The mixture is diluted with 20 ml of acetonitrile. To remove the excess butoxycarbonylpentyl isocyanate, the reaction mixture is shaken three times with 50 ml of ligroin in each case. The acetonitrile phase is evaporated in vacuo. The evaporation residue is dried at 100° C./0.1 mbar. 16.3 g of 2,5-bis-(isopropoxycarbonyl)-3-methyl-4-[5-(butyloxycarbonyl)pentylaminocarbonyloxy]-thiophene are obtained as a viscous material. 1H--NMR 80 MHz CDCL3 δ-values OCH 2H m 5.0-5.5 ppm; OCH2 2H t 4.13 ppm; N--CH2 2H m 3.1-3.5 ppm; hetar-CH3 s 2.39 ppm.
Reaction SMILES: [CH2:1]([N:7]1[C:14](=[O:15])[CH:13]2[CH:9](N=N[C:12]2([CH:25]([CH3:27])[CH3:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:8]1=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>O1CCOCC1>[CH2:1]([N:7]1[C:14](=[O:15])[CH:13]2[CH:9]([C:12]2([CH:25]([CH3:27])[CH3:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:8]1=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)C2N=NC(c3cccc([N+](=O)[O-])c3)(C(C)C)C2C1=O
Solvent: C1COCCO1
Product: CCCCCCN1C(=O)C2C(C1=O)C2(c1cccc([N+](=O)[O-])c1)C(C)C
Yield: 104.6 %

Procedure:
5-Hexyl-3-isopropyl-3(3-nitrophenyl)-3a,6a-dihydropyrrolo(3,4-c)pyrazole-4,6(3H,5H)-dione (Preparation 58, 0.65 g, 1.6 mmol) was dissolved in dioxan (25 ml) and heated under reflux for 3 h. The solvent was removed in vacuo and the oily residue dried in vacuum for 16 h at room temperature to give the crude product as a yellow solid. The crude product was purified by chromatography on a Biotage Flash 12™ cartridge packed with silica gel (8 g), eluting with hexane:ethyl acetate (9:1) to give the title compound (0.60 g, 100%).