Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:12]C[CH2:10][C@H:6]1[C:7]([OH:9])=[O:8])(=[O:4])[CH3:3]>>[Cl:1][CH2:3][C:2]([N:5]([CH3:12])[C@H:6]([C:7]([OH:9])=[O:8])[CH3:10])=[O:4]
Reactant: Cl
Reactant: CC(=O)N1CCC[C@H]1C(=O)O
Product: C[C@@H](C(=O)O)N(C)C(=O)CCl

Procedure:
1 ml of a 30 mM solution of N-choloracetyl-N-methyl-L-alanine in 0.1M tris-HC1, pH 7.0 was introduced into a reaction container thermostatted to 30° C. and mixed with 1.99 ml 0.1M tris --HCl pH 7.0. The reaction was started by adding 0.01 ml N-acyl-L-proline acylase from Comamonas TESTOSTERONI DSM 5416 corresponding to 0.23 units and 0.2 μg protein. 1 unit is defined as the amount of enzyme which converts 1 μmole of N-acetyl-L-proline per minute at 30° C. and pH 7.0. Specimens were taken at various points in time to detect the course of the reaction, compounded with 2N HCl 1:2 and subsequently analyzed by HPLC using an RP 8-column (250×4 mm). After elution with 7% (v/v) acetonitrile in 0.01M heptane sulfonic acid (adjusted to pH 2.2 with 85% H3PO4) at a flow rate of 2.2 ml/min. and a column temperature of 40° C., the decrease of N-chloroacetyl-N-methyl-L-alanine was determined by measuring the UV absorption at 210 nm.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[N:3]=[CH:4][CH2:5][C:6]1[C:11](Cl)=[CH:10][CH:9]=[CH:8][C:7]=1Cl.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1>>[N:15]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[CH:5]=[CH:4][N:3]3[N:2]([CH3:14])[CH3:1])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: CN(C)N=CCc1c(Cl)cccc1Cl
Reactant: c1ccc2[nH]ccc2c1
Product: CN(C)n1ccc2c(-n3ccc4ccccc43)cccc21
Yield: 40 %

Procedure:
4-(1-indolyl)-1-(dimethylamino)indole was prepared in the same manner as in Example 16 except that 2,6-dichlorophenylacetaldehyde N,N-dimethylhydrazone was used in place of 2,4-dichlorophenylacetaldehyde N,N-dimethylhydrazone, and indole (212 mg, 1.81 mmol) was used in place of pyrrole. (Yield: 40%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[S:1]1[C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4](/[CH:6]=[CH:13]\[C:14]([OH:16])=[O:15])=[CH:5]1
Reactant: O=Cc1csc2ccccc12
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C\c1csc2ccccc12
Temperature: 110 °C
Yield: 44.9 %

Procedure:
A suspension of benzo[b]thiophene-3-carbaldehyde (4.9 g, 30 mol), malonic acid (6.6 g, 60 mmol) and piperidine (1 mL) in 100 mL anhydrous pyridine was heated at 110° C. for overnight. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was taken up in 100 mL of water and 1 N hydrochloric acid was added to adjust the pH of this solution to ca. 3. The resulting suspension was filtered and the yellow solid was collected, washed with water (3×30 mL) dried in vacuo to give 329a as a yellow solid (5.5 g, 89%). MS: [M+H]+ 205.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[NH2:21][CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>C(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][NH:21][CH:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: NC1CCc2ccccc21
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Solvent: CCO
Product: O[C@H](CNC1CCc2ccccc21)COc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from a mixture of 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane, 1-aminoindane and ethanol essentially as described above in Example 96. Purity by LC/MS=100%, [M+H]+=416.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH2:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=[CH:17][C:9]=3[O:8]2)[CH2:4][CH2:3]1>C(O)(=O)C.[Ni]>[NH2:18][C:15]1[CH:16]=[CH:17][C:9]2[O:8][C:5]3([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH2:12][C:11](=[O:13])[C:10]=2[CH:14]=1
Reactant: CN1CCC2(CC1)CC(=O)c1cc([N+](=O)[O-])ccc1O2
Agent: [Ni]
Solvent: CC(=O)O
Product: CN1CCC2(CC1)CC(=O)c1cc(N)ccc1O2
Yield: 75.1 %

Procedure:
The 3,4-dihydro-1'-methyl-6-nitro-spiro[2H -1-benzopyran-2,4'-piperdin]-4-one (11.2 g, 0.04 mol) was dissolved in acetic acid (200 ml) and was hydrogenated using two "lab spoon" spatulas of Raney nickel catalyst in a Parr shaker. The theoretical amount of hydrogen was absorbed in 4 hours. The reaction mixture was filtered under nitrogen and the acetic acid was removed in vacuo. The residual oil was taken up in 3N HCl (150 ml), washed with ethyl acetate and neutralized with solid sodium bicarbonate. The product was extracted into ethyl acetate (3×100 ml), washed with sat'd. NaCl, dried, filtered and concentrated in vacuo to yield 7.4 g (75%) of product.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])=O.Cl.[NH2:18][C:19]([NH2:21])=[NH:20].[OH-].[Na+]>C(O)C>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[CH:4]=[CH:3][N:18]=[C:19]([NH2:21])[N:20]=1)([O-:15])=[O:14]
Reactant: N=C(N)N
Reactant: CN(C)C=CC(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nccc(-c2ccccc2[N+](=O)[O-])n1
Yield: 40.8 %

Procedure:
3-(dimethylamino)2′-nitroacrylophenone (1.0 g, 4.54 mmol) in absolute ethanol (25 mL) was treated with guanidine hydrochloride (540 mg, 5.68 mmol), and 10N sodium hydroxide (200 μL). The reaction was heated to reflux for 18 hours. Upon cooling a white precipitate was collected by filtration and rinsed with diethyl ether to give 4-(2-nitrophenyl)-2-pyrimidineamine (400 mg). Additional material was obtained by concentration and chromatography on silica, eluting with 1;1 hexane:ethyl acetate.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][O:16][CH2:17][CH2:18][NH2:19].[BH4-].[Na+]>CO.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH2:18][CH2:17][O:16][CH3:15])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COCCNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 16 h

Procedure:
Amine preparation: 1-BOC-4-piperidone (500 mg) and 2-methoxyethylamine (218 μL) were stirred in MeOH at room temperature. After 16 h, sodium borohydride was added (190 mg) carefully. After a further 3 h, the reaction mixture was diluted with DCM, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (560 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:35])[CH3:34])=[N:9]2)=[CH:4][CH:3]=1.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:36])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:40]3[CH2:41][CH2:42][NH:37][C:38](=[O:43])[CH2:39]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:34])[CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CNCCN1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(C)(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2C(=O)N2CCNC(=O)C2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazinone (Avocado Organics) to give the title compound. HR-MS (ES, m/z) calculated for C32H35N4O4Cl2 [(M+H)+] 609.2030, observed 609.2025.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCCC[C@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 19 h
Yield: 81.2 %

Procedure:
To a stirred solution of 37.2 (0.077 g, 0.15 mmol) in THF (2 mL, 0.2 mmol) and EtOH (2 mL, 0.2 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). The resulting reaction mixture was stirred for 19 hours. The resulting reaction was concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted EtOAc, dried over MgSO4, filtered, and concentrated. The product thus obtained was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 37 (60 mg, 80% yield) as a colorless oil. MS ESI (neg.) m/e: 983.5 (2M−H)+, 491.3 (M−H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:36]([Cl:37])=[CH:35][C:29]([C:30]([O:32]CC)=[O:31])=[CH:28][N:27]=2)[CH2:22][CH:21]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:36]([Cl:37])=[CH:35][C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=2)[CH2:22][CH:21]1[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cnc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc(OC)c3)C(c3ccccc3)C2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc([C@@H](C)N(CC2CCN(c3ncc(C(=O)O)cc3Cl)CC2c2ccccc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 131 mg of ethyl 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(3-methoxyphenyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-5-chloronicotinate were added 2.0 mL of THF, 1.0 mL of methanol, and 1.0 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 2 days. It was neutralized by addition of 1.1 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and dried to obtain 143 mg of a colorless foamy substance of 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(3-methoxyphenyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-5-chloronicotinic acid as a crude product. ESI+: 580
Reaction SMILES: [CH:1]([C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[CH:16]=[CH:17]/[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[CH:16]=[CH:17]/[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:8])=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2/C=C/c2n[nH]c3ccccc23)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
(E)-4-formyl-N-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}benzamide (100 mg, 0.27 mmol) was dissolved in methanol (1.1 mL) and the solution was added with sodium borohydride (120 mg, 2.72 mmol), stirred at room temperature for 1 hour, added with water and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethanol to obtain Compound 79 (10 mg, 10%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH2:10]([Mg]Cl)[CH:11]=[CH2:12]>CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH2:12][CH:11]=[CH2:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C=CC[Mg]Cl
Solvent: CCOCC
Product: C=CCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A 250 ml two-necked round-bottom flask, equipped with an additional funnel and condenser, was charged with 4-bromo-benzyl bromide (20.0 g, 80 mmol) in 50 ml dry ether at 0° C. ice bath for 10 min. The allylmagnesium chloride (48.0 ml of a 2.0 M solution in ether, 96 mmol) was added dropwisely via an additional funnel over a period of 30 min at 0° C. Subsequently, the mixture was stirred at room temperature for 2 h and refluxed for another 3 h. The reaction was monitored by TLC analysis. After the starting material disappeared, the reaction was quenched by water and transferred to a separation funnel. The organic layer was washed with brine, dried over anhydrous MgSO4, and then concentrated under vacuum to yield a yellow crude liquid. The product was purified by Kugelrhor distillation to obtain the final product as a transparent liquid (14.10 g, 83%), whose 1H and 13C NMR spectra matched with the earlier reported literature data [7].
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.I[CH:9]([CH2:11][CH2:12][CH2:13][CH3:14])[CH3:10]>CC(CC)=O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:10][CH2:9][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][CH2:3]1
Reactant: CCCCC(C)I
Reactant: OC1CCNCC1
Solvent: CCC(C)=O
Product: CCCCCCN1CCC(O)CC1
Yield: 63.9 %

Procedure:
4-Hydroxypiperidine (2.02 g, 20 mmol) was dissolved in 100 mL of methyl ethylketone. To this stirred mixture was added 2-iodohexane (1.5 mL, 10 mmol) and the resulting solution was heated at reflux for 1.5 hours. The mixture was allowed to cool and was then washed with saturated aqueous sodium bicarbonate (3×75 mL). The organic layer was dried over magnesium sulfate, filtered, and evaporated, and the residue was dried overnight under house vacuum to yield 1.184 g (64%) of the title compound which was used without further purification. 1H NMR consistent with desired product. MS(FD) 186(M+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]#[N:26])=[CH:22][CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[O:33][C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[CH3:41])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:40][C:38]1[CH:37]=[CH:36][C:35]([CH3:41])=[C:34]([CH:39]=1)[O:33][C:17]1[N:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:19]2[C:24]([C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2
Reactant: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(C#N)cc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCNCC2)c2ccc(C#N)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
The compound of step 3 (20 mg, 36 μmol) was dissolved in DCM (6 ml), TFA (2 ml) was added, and the mixture was stirred at room temperature for 1 h. The solvents were evaporated. The residue was dissolved in a small quantity of MOH, mixed with hydrochloric acid (0.1 M) and lyophilized overnight. 11 mg of the title compound were obtained in the form of the 2-(5-fluoro-2-methyl-phenoxy)-1-phenyl-3-(piperazine-1-carbonyl)-1H-indole-6-carbonitrile hydrochloride.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12](Cl)[C:11]=2[C:10]([I:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][OH:20].C[O-].[Na+].O>CO>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([O:20][CH3:19])[C:11]=2[C:10]([I:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccc2c1c(I)nn2Cc1ccccc1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1nccc2c1c(I)nn2Cc1ccccc1

Procedure:
To a mixture of 1-benzyl-4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (3.7 g) in methanol (40 mL) was added sodium methoxide methanol solution (1.5 M, 27 mL) at room temperature, and the reaction mixture was refluxed overnight. The reaction mixture was added to water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with petroleum ether to give the title compound (3.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:12](Cl)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][NH:35][C:36](=[O:38])[CH3:37].O1CCCC1>O>[C:36]([N:35]([CH2:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=1)[C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:10]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)NCc1ccccn1
Reactant: CCCCCCCOc1ccc(C(=O)Cl)cc1OCCCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(C)=O)cc1OCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 5.0 g of product from Example 111, 0.683 g of washed 50% sodium hydride, 2.14 g of product from Example 12 and 100 ml of dry tetrahydrofuran. The reaction is stirred at room temperature for 1 hour, heated at reflux temperature for 18 hours and cooled to room temperature. The mixture is poured into water, extracted with chloroform and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 15-30% ethyl acetate/hexane) to give 2.93 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1>O1CCOCC1.O.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>[S:18]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:19]1
Reactant: OB(O)c1ccsc1
Reactant: COC(=O)c1cccc(Br)c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2ccsc2)c1
Temperature: 100 °C
Yield: 98.3 %

Procedure:
Nitrogen (gas) was bubbled through the solution of methyl 3-bromobenzoate (50 mg, 0.233 mmol), potassium carbonate (96 mg, 0.698 mmol) and 3-thiopheneboronic acid (59.5 mg, 0.465 mmol) in dioxane (2 mL) and Water (0.2 mL) for 5 minutes. tetrakis(triphenylphosphine)palladium(0) (26.9 mg, 0.023 mmol) was added and again nitrogen was bubbled through the solution for 5 minutes. The reaction mixture was heated overnight at 100° C. and concentrated to dryness. Purified by chromatography (20% EtOAc in heptane) gave compound methyl 3-(thiophen-3-yl)benzoate 82 (50 mg, 99%). (m/z)=219 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[C:26]([F:29])([F:28])[F:27].Cl.N1C=CC=CC=1.C(OCCO)C>>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[CH:21][C:20]=1[C:26]([F:27])([F:28])[F:29]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(Cl)c(C(F)(F)F)c3)c2cc1OC
Temperature: 139 °C
Yield: 65.2 %

Procedure:
A mixture of 0.248 g (1 mmol) of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.215 g of 4-chloro-3-trifluoromethylaniline, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 1.5 hours; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.266 g (65.5%) of the desired product as cream crystals. MP 265-267° C.; mass spectrum (electrospray, m/e,): 408.2(M+H)+.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:16])[CH2:9]1.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>C(N(CC)CC)C>[C:26]([O:16][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][CH:8]([CH3:7])[CH2:9]1)(=[O:27])[CH2:25][C:24]([CH3:23])=[O:28]
Reactant: C=C1CC(=O)O1
Reactant: CC1CCCN(CC(O)c2ccccc2)C1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OC(CN1CCCC(C)C1)c1ccccc1
Yield: 106.5 %

Procedure:
To 100 ml of benzene are added 9.5 g of 2-(3-methyl piperidino)-1-phenylethanol having a melting point of 70° C., 5 g of diketene and 0.1 ml of triethylamine, and the mixture is refluxed under heating for two hours. The reaction mixture is concentrated under reduced pressure to give 14 g of 2-(3-methylpiperidino)-1-phenylethyl acetoacetate as oily substance. To 150 ml of isopropanol are added 14 g of 2-(3-methylpiperidino)-1-phenylethyl acetoacetate, 6.5 g of m-nitrobenzaldehyde and 5 g of methyl β-aminocrotonate, and the mixture is refluxed under heating for 15 hours. The reaction mixture is concentrated under reduced pressure and the oily residue is dissolved in ethyl acetate. The ethyl acetate layer is washed with 1N-hydrochlroic acid, potassium carbonate and water, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue (25 g) is purified by column chromatography. The eluate is concentrated and the residue is dissolved in acetone, whereupon an ethanol solution of hydrogen chloride is added to crystallize. The precipitated crystals are collected by filtration and recrystallized from ethanol to give 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methylester-5-[2-(3-methylpiperidino)-1-phenyl]ester in the form of hydrochloride as crystals melting at 225° C.-226° C. (decomposition).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12](=[NH:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:3])[CH3:2].C([Li])CCC.Cl[P:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12](=[N:20][P:27]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=N)Nc2c(C)cccc2C(C)C)cc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Product: Cc1ccc(C(=NP(c2ccccc2)c2ccccc2)Nc2c(C)cccc2C(C)C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.33 g of N1-(2-isopropyl-6-methylphenyl)-4-methylbenzamidine (Amidine V, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.93 mL chlorodiphenylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, the residue was treated with 20 mL of pentane. Prolonged stirring deposited a beige solid which was collected and dried (1.62 g, 72%).