Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)(=[O:6])=[O:5].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>CO>[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH:20]=1)(=[O:5])=[O:6]
Reactant: CN1CCC(=O)CC1
Reactant: CS(=O)(=O)Nc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(NS(C)(=O)=O)cc23)CC1
Yield: 89.4 %

Procedure:
To a solution of 1.2 gm (21.4 mMol) potassium hydroxide in 12 mL methanol was added 1.0 gm (4.76 mMol) 5-methanesulfonylamino-1H-indole followed by 0.76 mL (6.2 mMol) 1-methyl-4-piperidone. The homogeneous solution was heated to reflux for 18 hours under nitrogen. The reaction mixture was then cooled and concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution adjusted from 14 to 8-9 by the addition of acid. The precipitate that formed was filtered, washed with water and dried under vacuum to give 1.3 gm (89.6%) of the title compound as a tan solid.
Reaction SMILES: [C:1]([C:3]1[CH:34]=[CH:33][C:6]2[NH:7][C:8]([C:10]([C:21]3[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)([O:15][CH2:16][C:17]([O:19]C)=[O:18])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:3]1[CH:34]=[CH:33][C:6]2[NH:7][C:8]([C:10]([C:21]3[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:11]([F:13])([F:14])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)COC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2[nH]ccc12)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C)c2[nH]ccc2c1C(OCC(=O)O)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
(+) or (−)-Methyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate (tr=2.4 min—from Example 35-B) (116 mg, 0.246 mmol) was dissolved in THF (1.2 mL) and MeOH (1.2 mL). A 3N aq. NaOH solution (0.45 mL, 1.35 mmol) was added. The reaction was stirred at 40° C. for 1 hour. At this point the reaction mixture was concentrated. The residue was dissolved in MeOH, and purified with RP-HPLC(HC-A) to provide (−)-2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetic acid.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:3][CH:2]1[N:11]1[CH2:27][CH2:26][C:14]2([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:16][CH:15]2[OH:25])[CH2:13][CH2:12]1.[C:28]([O-:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([O-:33])=[O:32].C(O)(=O)/C=C/C(O)=O>C(OCC)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH2:1]1[CH:10]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:3][CH:2]1[N:11]1[CH2:27][CH2:26][C:14]2([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:16][C:15]2=[O:25])[CH2:13][CH2:12]1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: OC1CCN(c2ccccc2)C12CCN(C1CC3CCCCCC3C1)CC2
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: O=C1CCN(c2ccccc2)C12CCN(C1CC3CCCCCC3C1)CC2

Procedure:
Oxidation of 8-(decahydro-azulen-2-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (mixture of diastereoisomers) according to the general method of example 20 and formation of the fumarate with fumaric acid in diethyl ether yielded the title compound, pale brown solid, m.p. 219° C. and MS: m/e=367.3 (M+H+).
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[NH:29][CH2:30][CH2:31][NH2:32])[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([NH:40][C:41](N1C=CCN1C(=N)NC(OC(C)(C)C)=O)=[NH:42])(OC(C)(C)C)=O.O>C1COCC1>[C:1]1([C:7]2([N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[NH:29][CH2:30][CH2:31][NH:32][C:41]([NH2:42])=[NH:40])[CH2:18][CH2:19]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCNc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Reactant: CC(C)(C)OC(=O)NC(=N)N1C=CCN1C(=N)NC(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: N=C(N)NCCNc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Yield: 71.4 %

Procedure:
A mixture of 2-aminoethylamino-1-[1(1-phenylcycloheptyl)-4-piperidinyl]benzimidazole (Example 27, 85.6 mg, 0.199 mmol) and N, N′-bis Boc guanylpyrazole (117 mg, 0.377 mmol, this was prepared according to the following reported procedure: M. S. Bernatowicz, et al., Tetrahedron Lett., 1993, 34, 3389-3392) in THF (3 ml) was stirred at room temperature for 16 h. Water was added to the reaction mixture and extracted with CH2Cl2. The extracts combined were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel: 30 g, hexane/acetone: 4/1 to 3/1) to give 95.5 mg (71.4%) of colorless amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][NH2:12])=O)[CH2:4][CH2:3]1.[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:17][N:18]=[C:19]=[S:20]>C(O)C>[SH:20][C:19]1[N:18]([CH2:17][C:16]2[CH:21]=[C:22]([F:24])[CH:23]=[C:14]([F:13])[CH:15]=2)[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[N:11][N:12]=1
Reactant: CN1CCN(CC(=O)NN)CC1
Reactant: Fc1cc(F)cc(CN=C=S)c1
Solvent: CCO
Product: CN1CCN(Cc2nnc(S)n2Cc2cc(F)cc(F)c2)CC1

Procedure:
A solution of 2-(4-methyl-1-piperazinyl)acetic acid, hydrazide (3.44 g., 0.020 mole) and 3,5-difluorobenzylisothiocyanate (3.70 g., 0.020 mole) in ethanol (40 ml.) was refluxed for 17 hours and the solvent was removed under vacuum. The residue was triturated with ethyl acetate-ether and the resulting solid was filtered and recrystallized twice from ethanol to give 3-mercapto-4-(3, 5-difluorobenzyl)-5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-triazole as a solid melting at 200°-201° C. (4.60 g., 68%).
Reaction SMILES: O.[OH-].[Li+].[C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([NH2:10])=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:17](Br)(=[O:19])[CH3:18]>C(Cl)Cl>[C:4]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)Br
Reactant: Nc1ccccc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
Lithium hydroxide monohydrate (600 mg, 25.0 mmol) was added to a solution of the amine 3 (1.44 g, 8.53 mmol) dissolved in CH2Cl2 (125 mL) at 0° C. A solution of acetyl bromide (1.97 mL, 25.6 mmol) in CH2Cl2 (10 mL), was added dropwise over 5 minutes at 0° C. to the reaction mixture which was then allowed to warm to ambient temperature and stirred for 2 hours. The reaction crude was filtered, concentrated under reduced pressure, and purified by flash chromatography over silica, eluting with a gradient of 100% CH2Cl2 to 10% MeOH/90% CH2Cl2, yielding product 4 as white solid (1.11 g, 61.5%).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[OH-].[Na+].[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>ClCCl.CN(C=O)C>[C:1]([CH2:3][C:4]([NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:18]2[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=2)=[CH:28][CH:27]=1)=[O:6])#[N:2]
Reactant: Nc1ccc(Cc2ccncc2)cc1
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCC(=O)Nc1ccc(Cc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
Under ice-cooling, to a mixture of 18.0 g of cyanoacetic acid and 25 mL of oxalyl chloride were added 0.07 mL of DMF and 10 mL of dichloromethane, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then to the residue was added toluene, followed by further concentrating under reduced pressure. This procedure was repeated and excess hydrogen chloride and oxalyl chloride were removed. A mixture of the obtained crude product and 50 mL of dichloromethane was added to a mixture of 80 mL of a 1 M aqueous sodium hydroxide solution, 300 mL of dichloromethane, and 14.3 g of 4-(pyridin-4-ylmethyl)aniline under ice-cooling. During mixing the reagent, a 1 M aqueous sodium hydroxide solution was added on time to adjust the reaction solution to be kept alkaline. After stirring at room temperature for 30 minutes, the organic layer was collected by separation and the aqueous layer was extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethanol to obtain 10.2 g of 2-cyano-N-[4-(pyridin-4-ylmethyl)phenyl]acetamide as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][NH2:6].[Cl:8][C:9]1[C:22]2[C:21](=[O:23])[C:20]3[CH:19]=[N:18][CH:17]=[C:16]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[C:15]=3[C:14](=O)[C:13]=2[C:12](F)=[CH:11][CH:10]=1>N1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[N:6]=[C:14]3[C:15]4[C:16]([O:24][CH2:25][C:26]5[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=5)=[CH:17][N:18]=[CH:19][C:20]=4[C:21](=[O:23])[C:22]=1[C:13]=23
Reactant: COc1ccc(COc2cncc3c2C(=O)c2c(F)ccc(Cl)c2C3=O)cc1
Reactant: CN(C)CCNN
Solvent: c1ccncc1
Product: COc1ccc(COc2cncc3c2-c2nn(CCN(C)C)c4ccc(Cl)c(c24)C3=O)cc1
Reaction time: 2 h

Procedure:
A solution of N-[2-(dimethylamino)ethyl]hydrazine (8.5 mg) in pyridine (0.5 mL) is added to 9-chloro-6-fluoro-4-(p-methoxybenzyloxy) benzo[g]isoquinoline-5,10-dione of Preparative Example 29 (13 mg) over a period of 2 minutes at 0° C. under a nitrogen blanket and the mixture is stirred for 2 h. The excess pyridine and some excess hydrazine are removed under a nitrogen stream. The residue is placed under vacuum overnight. The product is purified by thick layer chromathography (silica gel, 10 cm by 20 cm) using 4% methanol/96% dicloromethane. The major yellow band is scraped from the plate and the yellow compound extracted into 25% methanol/75% dicloromethane. Removal of the solvent gives 5-chloro-2-[2-(dimethylamino)ethyl]-10-(p-methoxybenzyloxy) isoquino[5,6,7-cd]indazole-6(2H)-one (3 mg) as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=2)=[CH:4][C:3]=1[CH3:9]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Cc1cc(O)ccc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc(N)c(C)c2)ccn1
Temperature: 75 °C
Reaction time: 12 h

Procedure:
To the solution of 4-amino-m-cresol (125 mg, 1.01 mmol, 1.0 eq) in 1 mL of NMP was added 4-chloro-N-methylpicolinamide (189 mg, 1.11 mmol, 1.1 eq) and cesium carbonate (658 mg, 2.02 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred at 75° C. for 12 hours, thereafter the mixture was diluted with water (ca. 50 mL) and aqueous layer extracted with ethyl acetate (ca. 50 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure to give sufficiently pure crude product which was carried to next step without further purification. LC/MS (m/z) [258.1] (MH+).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl.C(O[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44])C>C(#N)C>[N+:43]([C:38]1[CH:39]=[N:40][CH:41]=[CH:42][C:37]=1[NH:23][CH2:22][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)([O-:45])=[O:44]
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CCOc1ccncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cnccc1NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 38.8 %

Procedure:
To a stirred solution of {4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (390 mg, 1.2 mmol) in acetonitrile (˜5 mL), was added Hunig's base (230 μL, 1.35 mmol, 1.1 eq.) and 4-ethoxy-3-nitropyridine hydrogen chloride (250 mg, 1.2 mmol, 1 eq.) and the mixture stirred at reflux for 72 hours. To this a further portion of 4-ethoxy-3-nitropyridine hydrogen chloride (50 mg, 0.24 mmol, 0.2 eq.) was added and the mixture stirred at reflux for a further 24 hours. The reaction mixture was then concentrated in vacuo to give a dark yellow oily residue. This was partitioned between 2M NaOH (30 mL) and DCM (2×30 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give a dark yellow oil. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (98:2:0.2 to 90:10:1, by volume) to provide the title compound (205 mg, 38%). HRMS ESI+ m/z 441.2486 [MH]+.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][NH:6][C:7]([NH:9][CH2:10][C:11]1[CH:29]=[CH:28][C:14]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:13][C:12]=1[CH3:30])=[O:8])C.O.[OH-].[Li+]>C1COCC1.O>[C:4]([CH2:5][NH:6][C:7]([NH:9][CH2:10][C:11]1[CH:29]=[CH:28][C:14]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:13][C:12]=1[CH3:30])=[O:8])([OH:31])=[O:3]
Reactant: CCOC(=O)CNC(=O)NCc1ccc(C(=O)N2CCCCc3ccccc32)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the ethyl ester from Example 32 (0.050 g, 0.10 mmol) in THF (20 ml) and water (5 ml) was added lithium hydroxide monohydrate (0.020 g, 0.45 mmol). The mixture was stirred at room temperature for 4 h. The mixture was concentrated in vaicuo and the residue diluted with water then washed with diethyl ether. The aqueous layer was acidified to pH 1 by addition of 1M HCl and extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a white solid; yield 0.046 g (99%).
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([F:13])=[CH:8][C:7]=1[OH:14].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(O)(=O)C>ClCCl>[F:13][C:9]1[C:10]([CH3:12])=[CH:11][C:6]([NH:5][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[C:7]([OH:14])[CH:8]=1
Reactant: Cc1cc(N)c(O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(O)cc1F
Temperature: 100 °C
Yield: 106.9 %

Procedure:
Polymer supported sodium cyanoborohydride (794 mg, 3.41 mmol) was added to a solution of commercially available 2-amino-5-fluoro-4-methylphenol (241 mg, 1.71 mmol), 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (350 mg, 1.76 mmol) and acetic acid (0.489 mL, 8.53 mmol) in dichloromethane (10 mL). The mixture was heated by microwave at 100° C. for 30 min before being filtered and concentrated by rotary evaporation to give a green oil. The residue was purified via chromatography (silica, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give 1,1-dimethylethyl 4-[(4-fluoro-2-hydroxy-5-methylphenyl)amino]-1-piperidinecarboxylate (593 mg, 73% purity, 78% yield) as a brown oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([NH2:27])=[O:26])[CH2:21][CH2:20]2)=[C:7]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:8]2=[N:9][C:10]=1[CH2:11][CH3:12])=[N+]=[N-]>C(O)C>[NH2:1][CH2:4][C:5]1[C:6]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([NH2:27])=[O:26])[CH2:21][CH2:20]2)=[C:7]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:8]2=[N:9][C:10]=1[CH2:11][CH3:12]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCN(C(N)=O)CC2)c1CN=[N+]=[N-]
Solvent: CCO
Product: CCc1nc2c(cnn2CC)c(NC2CCN(C(N)=O)CC2)c1CN
Reaction time: 21 h
Yield: 100 %

Procedure:
10% Palladium on carbon (0.65 g), in a flask flushed with nitrogen, was treated with water (about 2 ml), ethanol (20 ml) and a suspension of 4-{[5-(azidomethyl)-1,6-diethyl-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}-1-piperidinecarboxamide (4.1 g, 11.0 mmol, e.g. which can be as prepared in Intermediate 16) in ethanol (100 ml). Additional ethanol (200 ml) was used to wash the suspension into the flask. The suspension was stirred under an atmosphere of hydrogen for 21 hours. The mixture was filtered through celite to remove catalyst, and the filtrate was evaporated to dryness to give the title compound as a grey foam (3.8 g). LCMS m/z 346 [MH+]; TRET=about 1.66 min.
Reaction SMILES: O.[N+:2]([C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:14][CH:15]=1
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Nc1ccc(CCC(=O)O)cc1
Reaction time: 2 h

Procedure:
15 g of palladium on carbon (10% and 30 ml of water are added to a mixture of 155 g of 4-nitrocinnamic acid in 1 l of methanol, and hydrogenation is carried out at room temperature under 3 bar until no further hydrogen is taken up, after about 2 hours. After filtration and evaporation of the solvent in a rotary evaporator, residual water is removed by twice adding 300 ml portions of toluene and distilling off the solvent in a rotary evaporator.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[CH:9]2[O:16][CH:10]2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18](O)(C)C.S(=O)(=O)(O)O>C1C=CC=CC=1>[C:1]1([NH:7][C:8](=[O:17])[CH:9]2[O:16][CH:10]2[C:11]([O:13][CH:14]([CH3:18])[CH3:15])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)O
Reactant: CCOC(=O)C1OC1C(=O)Nc1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC(C)OC(=O)C1OC1C(=O)Nc1ccccc1
Yield: 77.4 %

Procedure:
To a solution of ethyl N-phenyl-2,3-epoxysuccinamate (Compound No. 1) (0.5 g) and isopropanol (1.0 g) in benzene (30 ml), a catalystic amount of a concentrated sulfuric acid was added, the mixture was refluxed for 5 hours. The reaction mixture was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. The residue thus obtained was treated by silica gel column chromatography using benzene as a developer and the resulting crude crystals were recrystallized from a mixture of n-hexane-acetone to give 0.41 g of isopropyl N-phenyl-2,3-epoxysuccinamate (Compound No. 93) as colorless needles melting at 113°-114.5° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[N+:10]([O-])=O.C([O-])=O.[NH4+]>C1COCC1.CO.[Pd]>[CH3:9][C:7]1[CH:8]=[C:3]([NH:2][CH3:1])[C:4]([NH2:10])=[CH:5][CH:6]=1
Reactant: CNc1cc(C)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(C)ccc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl-(5-methyl-2-nitro-phenyl)-amine (2.47 g, 14.9 mmol), ammonium formate (15 g, 237.9 mmol) in THF (7 mL) and MeOH (35 mL) at room temperature was added 10% Pd/C (650 mg) and the resuitng mixture was stirred at room temperature for 10 min. The resulting mixture was then filtered over CELITE® and concentrated in vacuo. The resulting residue was diluted with CH2Cl2, washed with H2O and the organic layer dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield 4,N2-dimethyl-benzene-1,2-diamine
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20](O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>O1CCCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
3-Hydroxybenzaldehyde (0.98 g), 1-t-butoxycarbonyl-4-hydroxypiperidine (2.41 g) and triphenylphosphine (3.15 g) were suspended in tetrahydrofuran (10 mL). To the mixture was added dropwise 40% azodicarboxylic acid diisopropyl ester-toluene solution (6.1 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/3) to give the title compound (0.74 g).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1>C(OCC)(=O)C.[Pd]>[CH3:2][C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)o1
Yield: 94 %

Procedure:
A solution of methyl 5-chloromethyl-2-furoate (5.0 g, 28.7 mmol) in ethyl acetate (40 ml) was hydrogenated over 10% palladium on charcoal (50 mg) for 3 h. The catalyst was filtered off and washed with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to yield the title compound as a colourless oil (3.78 g, 94%); νmax (CH2Cl2) 1725, 1534, 1522, 1437 and 1311 cm-1 ; δHCDCl3, 90 MHz) 2.38 (3H, s), 3.86 (3H, s), 6.12 (1H, br d, J 4 Hz) and 7.07 (1H, d, J 4 Hz). [Mass spectrum: M+ (140)].
Reaction SMILES: [Al].[CH2:2](Br)[C:3]#[CH:4].[O:6]1[CH2:11][CH2:10][CH2:9][O:8][CH:7]1[C:12]1[CH:13]=[C:14]([C:18]([CH3:27])([CH3:26])[CH2:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:15]=[CH:16][CH:17]=1>C1COCC1.C(OCC)C>[O:6]1[CH2:11][CH2:10][CH2:9][O:8][CH:7]1[C:12]1[CH:13]=[C:14]([C:18]([CH3:27])([CH3:26])[CH2:19][C:20]([C:21]([F:23])([F:24])[F:22])([OH:25])[CH2:4][C:3]#[CH:2])[CH:15]=[CH:16][CH:17]=1
Reactant: C#CCBr
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cccc(C2OCCCO2)c1
Agent: [Al]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCC(O)(CC(C)(C)c1cccc(C2OCCCO2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
Aluminum amalgam was prepared from aluminum foil (1.16 g, 14.4 mmol) and mercuric chloride (12 mg, catalytic amount) in 20 mL of anhydrous THF by vigorously stirring the mixture at room temperature for 1 hour under an argon atmosphere. A solution of propargyl bromide (4.80 mL, 80 wt. % in toluene, 43.1 mmol) in 25 mL of anhydrous THF was slowly added to a stirred suspension maintaining a temperature of 30° C.-40° C., and after addition, stirring at 40° C. was continued until a dark gray solution was obtained (ca. 1 hour). The propargyl aluminum sesquibromide solution was added to a solution of 4-(3-[1,3]dioxan-2-ylphenyl)-1,1,1-trifluoro-4-methylpentan-2-one (5.6 g, 14.2 mmol) in 100 mL of anhydrous diethyl ether at −78° C. The reaction mixture was stirred at this temperature for 3 hours, and then was allowed to warm to room temperature, at which time it was stirred for 12 hours. The reaction mixture was then poured into 20 mL of ice-water and extracted with four 30 mL portions of diethyl ether. The combined extracts were washed with 20 mL of brine, dried over magnesium sulfate, and concentrated in vacuo. Chromatography on silica gel (100% hexanes to 40% ethyl acetate in hexanes, gradient) afforded 2.5 g of the title compound as an oil (50% yield).