Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:14](=[O:15])[CH2:13][CH2:12][C@H:7]2[C:8]([O:10]C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:6]2[C:14](=[O:15])[CH2:13][CH2:12][C@H:7]2[C:8]([OH:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCC(=O)N1C1CCCC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Methyl 1-cyclopentyl-5-oxoprolinate (0.560 g, 2.65 mmol) was dissolved in ethanol (10 ml) and cooled to 0° C. in an ice-bath. 2M aqueous sodium hydroxide (5 ml) was added and the mixture was stirred at ice temperature for 4 hrs. The ethanol was then evaporated under vacuum and the aqueous residue was acidified to pH1 by the addition of 2N aqueous hydrogen chloride. The volume of resulting aqueous mixture was reduced under vacuum to ˜3 ml and this was then extracted with a 3:1 mixture of chloroform and isopropanol respectively using a phase separator. The aqueous layer was washed with more dichloromethane and then the combined organic fractions were evaporated to give crude 1-cyclopentyl-5-oxoproline which was used in subsequent reactions without further purification.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]1[N:17]=[C:16]([CH2:18][CH2:19][CH3:20])[O:15][N:14]=1)(=O)C.[OH-].[Na+]>C(O)C.C(Cl)Cl>[CH2:18]([C:16]1[O:15][N:14]=[C:13]([CH:5]2[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4]2)[N:17]=1)[CH2:19][CH3:20]
Reactant: CCCc1nc(C2Cc3ccccc3N2C(C)=O)no1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCCc1nc(C2Cc3ccccc3N2)no1
Temperature: 57.5 °C
Yield: 56.1 %

Procedure:
A solution of compound 89 (0.0035 mole) in ethanol (60 ml) was treated with 3M NaOH (60 ml), and the reaction mix was heated to 55-60° C. for 5.5 hours. The reaction was rapidly cooled in an ice bath, diluted with DCM, and treated with cold distilled water. The layers were separated and the aqueous fraction was extracted three times with DCM. The organic fractions were combined, washed once with 1M NaOH, and dried over Na2SO4 and concentrated in vacuo. The residue was purified by prep column chromatography, yielding 0.45 g of 2,3-dihydro-2-(5-propyl-1,2,4-oxadiazol-3-yl)-1H-indole. b) A solution of 2,3-dihydro-2-(5-propyl-1,2,4-oxadiazol-3-yl)-1H-indole (0.0011 mole) in DCM (10 ml) was treated with N-methyl-N-(1-methylethyl)-2-propanamine (0.40 mL) then (2-fluoro-2-oxoethyl)-9H-fluoren-9-yl carbamic acid methyl ester (0.67 g). The reaction was stirred at room temperature for 40 hours and treated with another portion each of N-methyl-N-(1-methylethyl)-2-propanamine then (2-fluoro-2-oxoethyl)-9H-fluoren-9-yl carbamic acid methyl ester and stirred at room temperature for two days. The reaction was diluted with DCM, treated twice with saturated NaHCO3, and dried over Na2SO4. and concentrated. The residue was subjected to reverse phase prep column chromatography, yielding 0.35 g of 9H-fluoren-9-ylmethyl[2-[2,3-dihydro-2-(5-propyl-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]-2-oxoethyl]-carbamate. c) 9H-fluoren-9-ylmethyl[2-[2,3-dihydro-2-(5-propyl-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]-2-oxoethyl]-carbamate (0.35 g) was dissolved in DCM (40 ml), treated with piperidine (0.50 ml), and stirred at room temperature for 18 hours. The completed reaction was concentrated in vacuo and subjected to reverse phase prep column chromatograph, yielding 0.13 g of 2,3-dihydro-β-oxo-2-(5-propyl-1,2,4-oxadiazol-3-yl)-1H-indole-1-ethanamine trifluoroacetate (1:1) (compound 90, mp. 160-162° C.).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[OH:6].[F:16][C:17]([F:23])([F:22])[S:18](Cl)(=[O:20])=[O:19]>CCCCCC.C(OCC)C>[F:15][C:4]([F:3])([F:14])[CH:5]([O:6][S:18]([C:17]([F:23])([F:22])[F:16])(=[O:20])=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1
Reactant: OC(c1ccc(F)cc1)C(F)(F)F
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: O=S(=O)(OC(c1ccc(F)cc1)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
NaH (640 mg, 16 mmol, 60% in mineral oil) was washed twice with hexane (20 mL) and then suspended in dried diethyl ether (20 mL). A solution of 2,2,2-trifluoro-1-(4-fluoro-phenyl)ethanol (1.94 g, 10 mmol) in diethyl ether (10 mL) was added at 0° C. After stirring for 2 h at room temperature, a solution of trifluoromethanesulfonyl chloride (1.68 g, 10 mmol) in diethyl ether (10 mL) was added. After 2 h, the reaction mixture was quenched by adding a solution of NaHCO3 and the product was extracted with diethyl ether. The extracts were washed with brine and dried, and the solvent was removed to yield trifluoromethanesulfonic acid 2,2,2-trifluoro-1-(4-fluorophenyl)ethyl ester (3.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH3:25])[NH:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([F:14])[CH:16]=4)[CH:21]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2cc(F)ccc21
Product: CC1c2ccc(F)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.OS(O)(=O)=O.[CH2:30](O)[CH3:31]>>[N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:30][CH3:31])=[O:22])=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)C(c1ccc(NC(=O)CCCC(=O)O)cc1)n1ccnc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCC(=O)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Yield: 18 %

Procedure:
A mixture of (compound 218) (0.023 mol) in ethanol (200 ml) and H2SO4 (3 ml) was stirred and refluxed for 12 hours. When the reaction was complete, the solvent was evaporated, the residue was taken up in water and extracted with CH2Cl2. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1). The pure fractions were collected and evaporated. The residue was crystallized from 2-butanone and DIPE, yielding 1.45 g (18%) of (±)-ethyl 5-[[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]amino]-5-oxopentanoate (compound 219).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[H-].[Na+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1COCC1.[NH4+].[Cl-]>[CH2:9]([O:8][C:6]([C:4]1[CH:5]=[N:1][N:2]([S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:3]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(S(=O)(=O)c2ccc(C)cc2)c1
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 1H-pyrazole-4-carboxylate (4.50 g, 32.11 mmol) in THF was added 60% NaH (1.60 g, 40.00 mmol) in mineral oil. After 20 minutes, p-toluenesulfonyl chloride was added. After 3 hours, the mixture was diluted with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 30-50% ethyl acetate in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford 1-(toluene-4-sulfonyl)-1H-pyrazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=3)=[O:14])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+].C(OC(=O)C)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13]([NH:15][C:16]3[CH:17]=[C:18]([C:26]4[CH:27]=[CH:28][C:23]([CH3:32])=[CH:24][CH:25]=4)[CH:19]=[CH:20][CH:21]=3)=[O:14])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(Nc1cccc(I)c1)Nc1cccc2c1CC(O)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cccc(NC(=O)Nc3cccc4c3CC(O)CC4)c2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
Next, to a solution of N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(3-iodophenyl)urea (9.0 mg, 0.02 mmol) and 4-tolylboronic acid (3.60 mg, 0.03 mmol) in THF was added tetrakis(triphenylphosphine)palladium(0) (2.55 mg) followed by 0.1 mL of saturated sodium bicarbonate solution. The mixture was stirred for 3 hours at 90° C., then ethylacetate was added. The mixture was passed through a short pad of silica gel and was concentrated under reduced pressure to afford N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(4′-methylbiphenyl-3-yl)urea (2.80 mg, 34% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:10]([O:17][C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([O:9][C:3]1[C:2]([Cl:1])=[CH:7][NH:6][C:5](=[O:8])[CH:4]=1)=[O:24])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1cccc(C(=O)OCc2ccccc2)c1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Product: O=C(OCc1ccccc1)c1cccc(C(=O)Oc2cc(=O)[nH]cc2Cl)c1
Yield: 29.8 %

Procedure:
The general procedure of Example 1 was followed using 2.20 g of 5-chloro-4-hydroxy-2-pyridone and 5.31 g of 3-benzyloxycarbonylbenzoyl chloride, thereby giving 1.73 g of the title compound in a yield of 29%.
Reaction SMILES: C[C@@H](PC)[C]1[C](P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)[CH][CH][CH]1.[F:31][C:32]1[CH:33]=[C:34]([CH:53]=[CH:54][CH:55]=1)[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=2)[CH2:39][CH2:38][C:37]=1[NH:48][C:49](=[O:52])[CH2:50][CH3:51].[H][H]>[Rh+].ClC1CCCCC=CC=1.CO>[F:31][C:32]1[CH:33]=[C:34]([CH:53]=[CH:54][CH:55]=1)[CH2:35][C@@H:36]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=2)[CH2:39][CH2:38][C@@H:37]1[NH:48][C:49](=[O:52])[CH2:50][CH3:51]
Reactant: CCC(=O)NC1=C(Cc2cccc(F)c2)c2cc(OC)ccc2CC1
Reactant: [H][H]
Agent: [Rh+]
Agent: CP[C@H](C)[C]1[CH][CH][CH][C]1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: ClC1=CC=CCCCC1
Solvent: CO
Product: CCC(=O)N[C@H]1CCc2ccc(OC)cc2[C@H]1Cc1cccc(F)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 86.6 %

Procedure:
Chlorocyclooctadiene rhodium(I) dimer (0.165 g, 0.669 mmol of Rh), Josiphos SL-J216-2 (0.451 g, 0.702 mmol), and N-(1-(3-fluorobenzyl)-7-methoxy-3,4-dihydronaphthalen-2-yl)propionamide (45.4 g, 134 mmol) were combined in a metal reactor, and the vessel was inerted with argon. Degassed methanol (223 ml) was added, and the reactor was agitated under argon for 20 min at 50° C. The reactor was pressurized with 60 psig of hydrogen and stirred at 60° C. for 30 hrs. HPLC analysis indicated complete conversion and 95.2% ee. The mixture was concentrated, filtered in EtOAc through silica gel, concentrated, slurried in hot heptane, filtered, and dried to yield 39.6 g (yield: 87%) of the title compound.
Reaction SMILES: [CH:1]1([NH:9][C@H:10]([C:20]([OH:22])=O)[CH2:11][CH:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:15])=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:36][CH2:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[C:45]([NH:49][C:50]([O:52][CH2:53][CH:54]=[CH2:55])=[O:51])=[N:44][CH:43]=[CH:42]2)=O)(C)(C)C>>[CH:1]1([NH:9][C@H:10]([C:20]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]2[CH2:36][CH2:37][O:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([NH:49][C:50]([O:52][CH2:53][CH:54]=[CH2:55])=[O:51])=[N:44][CH:43]=[CH:42]3)=[O:22])[CH2:11][CH:12]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:13](=[O:14])[OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)C(C[C@H](NC1CCCCCCC1)C(=O)O)C(=O)O
Reactant: C=CCOC(=O)Nc1nccc2cc(OCC[C@@H]3CCCCN3C(=O)OC(C)(C)C)ccc12
Product: C=CCOC(=O)Nc1nccc2cc(OCCC3CCCCN3C(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC3CCCCCCC3)ccc12
Yield: 53.1 %

Procedure:
N-Cyclooctyl-γ-tert-butyl-L-glutamic acid (8a, 344 mg, 1.1 mmol) and 2-(2-(1-allyloxycarbonylamino-isoquinolin-6-oxy)-ethyl)-piperidine (1g, 391 mg, 1.1 mmol) were coupled, using the methodology described in Example 1i, providing 380 mg (58%) of the title compound as a colourless oil. ESI-MS: 651.3 (M+H)+. Rf (silica gel; dichloromethane/methanol, 9:1, v/v): 0.23.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)=[N:12][CH:11]=[N:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[NH2:24][CH2:25][C:26]#[N:27].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>CN(C=O)C.C(OCC)(=O)C>[C:25]([CH2:26][NH:27][C:18]([C:17]1[CH:16]=[C:15]([C:13]2[C:14]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][NH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:23]=[CH:22][CH:21]=1)=[O:20])#[N:24]
Reactant: N#CCN
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(C(=O)O)c3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(C(=O)NCC#N)c3)c12
Temperature: 45 °C

Procedure:
To a mixture of crude 3-(5-(ethoxycarbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzoic acid 113 mg (theoretical mass 55 mg, 0.18 mmol), 2-aminoacetonitrile (49.5 mg, 0.883 mmol), HATU (101 mg, 0.265 mmol) in DMF (1.0 mL) was added DIPEA (62 μL, 0.35 mmol). The reaction mixture was heated to 45° C. for 2 hours and then diluted with ethyl acetate (5 mL). The reaction mixture was washed with 2 M aqueous sodium bicarbonate (5 mL) and brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier to give ethyl 4-(3-(cyanomethylcarbamoyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C18H16N5O3[M+H]+: 350, found 350. 1H NMR (600 MHz, DMSO-D6) δ 9.19 (t, J=5.28 Hz 1H), 8.55 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.86 (d, J=8.21 Hz, 1H), 7.75 (d, J=7.63 Hz, 1H), 7.48 (t, J=7.63 Hz, 1H), 6.86 (bs, 1H), 4.30 (q, J=5.28 Hz, 2H), 3.76 (q, J=7.04 Hz, 2H), 0.83 (t, J=7.04 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([S:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([S:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[CH2:2][CH2:3]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC3CC3)c(SC)nn12
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CCOCC3)CC3CC3)c(SC)nn12
Reaction time: 1 h
Yield: 55.2 %

Procedure:
After dissolving N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (100 mg) in tetrahydrofuran (2 mL), tetrahydro-2H-4-pyrancarbaldehyde (78 mg) [CAS No. 50675-18-8] and sodium triacetoxyborohydride (87 mg) were added, and the mixture was stirred for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (70 mg) was obtained from the n-hexane:ethyl acetate (7:1) fraction as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[NH:8][CH:7]=[C:6]([C:9]([OH:11])=[O:10])[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)(=[O:3])[NH2:2].[H][H].[ClH:23]>CO.O1CCOCC1.[Pd]>[ClH:23].[C:1]([C:4]1[NH:8][CH:7]=[C:6]([C:9]([OH:11])=[O:10])[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)(=[O:3])[NH2:2]
Reactant: [H][H]
Reactant: NC(=O)c1[nH]cc(C(=O)O)c1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)c1[nH]cc(C(=O)O)c1-c1ccc(N)cc1

Procedure:
To a suspension of 0.135 g (0.126 mmol) of 10% palladium-on-charcoal in 20 cm3 of methanol is added, at a temperature in the region of 20° C., 0.15 g (0.545 mmol) of 5-carbamoyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylic acid. After hydrogenating for 3 hours in an autoclave under 3 bar of hydrogen, at a temperature in the region of 30° C., the reaction mixture is taken up in 5 cm3 of a 4N solution of hydrogen chloride in dioxane, and then filtered. The catalyst is rinsed with twice 2 cm3 of a 4N solution of hydrogen chloride in dioxane, and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.141 g of 5-carbamoyl-4-(4-aminophenyl)-1H-pyrrole-3-carboxylic acid hydrochloride in the form of a yellow solid; ES+: m/z=246: [M+H]+
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:7][CH:8]=2)[N:3]=1.[N:24]12CCN(CC1)C[CH2:25]2.[C-]#N.[Na+]>CS(C)=O>[N:18]1([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:25]#[N:24])=[N:3]3)=[CH:8][CH:7]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: C1CN2CCN1CC2
Reactant: Clc1nc(N2CCCCC2)c2ccc(N3CCOCC3)cc2n1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1nc(N2CCCCC2)c2ccc(N3CCOCC3)cc2n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
0.20 g (0.60 mmol) of 2-chloro-7-morpholin-4-yl-4-piperidin-1-ylquinazoline and 0.067 g (0.60 mmol) of 1,4-diazabicyclo[2.2.2]octane were dissolved in 3.0 ml of dimethyl sulfoxide. After 1.0 h, 0.03 g (0.60 mmol) of sodium cyanide were added, and the reaction mixture was subsequently stirred at 80° C. for 24 h. Conventional work-up gave 0.17 g of 7-morpholin-4-yl-4-piperidin-1-ylquinazoline-2-carbonitrile (No. 58).
Reaction SMILES: [NH2:1][C:2]1[C:3](I)=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C1COCC1>[NH2:1][C:2]1[C:3]([C:12]2[O:11][CH:15]=[CH:14][CH:13]=2)=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(Cl)nc(I)c1N
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)nc(-c2ccco2)c1N
Temperature: 90 °C
Reaction time: 12 h
Yield: 86.6 %

Procedure:
3-Amino-6-chloro-2-iodo-4-methylpyridine (1.38 g), 2-furanboronic acid (861 mg), and sodium carbonate (815 mg) were suspended in a solvent mixture consistent of toluene (19 mL), THF (19 mL) and water (6 mL). The mixture was degassed using subsequent evaporation and flushing with nitrogen (5×) and tetrakis(triphenylphosphine)palladium(0) (658 mg) was added. The reaction mixture was stirred at 90° C. for 5 hours and 12 hours at room temperature. After addition of another portion of 2-furanboronic acid (430 mg) and tetrakis(triphenyl phosphine)palladium(0) (132 mg), the mixture was stirred again for 12 hours at 90° C. After 12 hours stirring at room temperature, the reaction mixture was quenched with water and extracted 2× with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=4:1, Rf=0.25) to afford 929 mg of the title compound of the formula
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:17])[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.N>[Zn]>[Cl:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[C:12]([Cl:17])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21
Agent: N
Agent: [Zn]
Product: Clc1cccc2cc3cccc(Cl)c3cc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
A suspension of 1,8-dichloroanthraquinone 1 (10.0 g, 36.1 mmol) and Zinc dust (50.0 g, 765 mmol) in 200 ml of aqueous 28% NH3 was stirred for 3 h at 100° C. After cooling to room temperature, the resulting solid was separated by suction filtration. A CH2Cl2 solution of the resulting crude solid was combined with the CH2Cl2 extract of the supernatant liquid, and the mixture was dried over MgSO4 and concentrated under vacuo. The residual crude solid was dissolved in a mixture of 500 ml of isopropanol and 50 ml of 12 M HCl. After the resulting solution had been refluxed for 3 h, it was concentrated and partitioned between CH2Cl2 and 5% NaHCO3. The organic layer was collected and dried over MgSO4. The solvent was evaporated, and the crude solid product was recrystallized from a CH2Cl2-hexane mixture. The collected product was allowed to dry in the air for 24 h to provide 5.5 g (62%) of 1,8-dichloroanthracene 2 as yellow needles: mp 153° C. IR (KBr): ν=1617, 1547, 1438, 1300, 1210, 953, 872, 775, 720, 678; 1H NMR (CDCl3, 400 MHz) δ=7.25-7.88 (m; 6H, ArH), 8.36 (s; 1H, ArH-10), 9.16 (s; 1H, ArH-9); 13C NMR (CDCl3, 400 MHz) δ=120.99, 125.68, 126.04, 127.33, 127.61, 132.63; MS (EI) m/z (%)=246 (100) [M+], 248 (65); HRMS (EI) Calcd. For C14H8Cl2 [M+] 246.0003, Found 246.0001.
Reaction SMILES: [OH:1][CH2:2][N:3]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:4]1.CN(C1C=CC=CN=1)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:1][CH2:2][N:3]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:4]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cn(CO)cc1-c1ccccc1Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(=O)OCn1cc(C#N)c(-c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
41.4 g of N-hydroxymethyl-3-(2-chlorophenyl)-4-cyanopyrrole are dissolved in 350 ml of pyridine and 1.8 g of dimethylaminopyridine are added. Then 21.4 ml of acetic anhydride are slowly added dropwise at 0° to 7° C. and the mixture is stirred for 12 hours. The reaction mixture is then poured into ice-water and extracted twice with ethyl acetate. The extracts are washed twice with dilute ice-cold hydrochloric acid and twice with a semi-saturated aqueous solution of sodium chloride, dried over sodium sulfate and filtered. The filtrate is concentrated and the residue is recrystallised from diethyl ether/hexane to give the title compound in the form of colourless crystals with a melting point of 91°-95° C.