Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:23]=2[C:24]([NH2:26])=[O:25])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:33][CH:34]([N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[C:44]([O:49][CH3:50])[CH:43]=2)[CH2:38][CH2:37]1)[CH3:35].[I-].[K+].S(=O)(=O)(O)O>C(O)C(F)(F)F.C1COCC1>[F:32][C:27]1[CH:28]=[C:29]([F:31])[CH:30]=[C:22]([NH:21][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([NH:46][C:45]3[CH:47]=[CH:48][C:42]([N:39]4[CH2:40][CH2:41][N:36]([CH:34]([CH3:33])[CH3:35])[CH2:37][CH2:38]4)=[CH:43][C:44]=3[O:49][CH3:50])[N:3]=2)[C:23]=1[C:24]([NH2:26])=[O:25]
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(F)cc(F)c4C(N)=O)nc(Cl)nc32)cc1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: OCC(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2cc(F)cc(F)c2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A suspension of 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluorobenzamide (2.71 g, 5.68 mmol), 4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)aniline (2.12 g, 8.52 mmol), potassium iodide (catalytic), and sulfuric acid (2.72 ml, 51 mmols) in trifluoroethanol (150 ml) was heated at 90C for 4 hrs. The reaction was diluted with 1:1 THF:ethyl acetate (300 ml) and washed with saturated NaHCO3 (300 ml). The organic layer was removed and concentrated by rotary evaporation. The solids were then added to THF (300 ml) followed by ammonium hydroxide (300 ml) and the resulting mixture was stirred at rt overnight. Next, the crude reaction was adsorbed to silica gel and purified by LC (DCM to 5% MeOH/DCM) to afford 2,4-difluoro-6-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (1.5 g, 38% over two steps). ESIMS (M+H)+=691.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:40][CH2:39][CH2:38][O:37][CH3:36])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: COCCN
Product: COCCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Yield: 91.7 %

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and 2-methoxyethylamine (225 mg, 2.97 mmol) as starting materials to afford the title compound as a colourless oil (372 mg).
Reaction SMILES: [CH:1]1([N:4]2[CH2:16][C@@H:7]3[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]3[C:5]2=[O:17])[CH2:3][CH2:2]1.C(N)(C)C>>[CH:1]([N:4]1[CH2:16][CH:7]2[CH:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1NCCN2C(=O)N(C3CC3)C[C@H]12
Solvent: CC(C)N
Product: COC(=O)C1NCCN2C(=O)N(C(C)C)CC12

Procedure:
Compound 84-C was prepared in analogy to compound 82-C by using isopropylamine instead of cyclopropylamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH3:29]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][CH3:29])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: CCI
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 70 °C
Yield: 39.6 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (25 mg, 0.095 mmol), potassium carbonate (26 mg, 0.19 mmol) and iodoethane (11 μL, 0.14 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 70° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography of the residue using hexanes/ethyl acetate/dichlrormethane (3.5:0.5:4) followed by trituration with diethyl ether afforded 11 mg (39%) of 3-(2-pyridyl)-5-(3-cyano-5-ethoxyphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.91 (m, 1H), 7.49 (m, 1H), 7.38 (s, 1H), 4.17 (q, 2H), 1.49 (t, 3H).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([O-:34])=[O:33]>C(Cl)Cl>[N+:32]([C:35]1[CH:36]=[CH:37][C:38]([S:41]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:43])=[O:42])=[CH:39][CH:40]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 0 °C
Yield: 56.5 %

Procedure:
A 25-mL round-bottomed flask was cooled to 0° C. and charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (250 mg, 0.62 mmol, Example 91, Step 1), CH2Cl2 (5 mL) and triethylamine (0.26 mL, 1.87 mmol). 4-Nitrobenzenesulfonyl chloride (166 mg, 0.75 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. After 10 min at 0° C. the reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(4-(4-((4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (180 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[BH4-].[Na+].[O-][Mn](=O)(=O)=O.[K+].Cl.[CH3:18]COCC>CO.CO.C(Cl)Cl>[CH3:18][O:7][C:6]([C@H:4]1[CH2:5][C@@H:2]([OH:1])[CH2:3]1)=[O:8]
Reactant: O=C1CC(C(=O)O)C1
Reactant: CCOCC
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](O)C1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A methanolic solution (210 mL) of 3-oxocyclobutanecarboxylic acid, cooled in an ice bath, was charged portionwise with sodium borohydride (4.66 g, 123 mmol). After stirring for 2 h, the reaction was deemed complete by TLC analysis (10% MeOH/CH2Cl2, KMnO4 stain). The reaction was charged with 2N HCl in ether until the pH of the solution became acidic (pH=2). The reaction mixture was diluted with 400 mL of methanol and heated to 75° C. for 16 h. The reaction was concentrated in vacuo, resuspended in CH2Cl2 (100 mL), washed with water (2×50 mL), saturated bicarbonate (1×50 mL), water (1×50 mL), and brine (1×50 mL), then dried over Na2SO4, filtered and concentrated to afford the desired product as an oil (predominantly cis). IR (film) 3406, 2989, 2949, 1727, 1720 cm−1. 1H NMR (400 MHz, CDCl3) δ 1.97 (d, 1H, J=7.2 Hz), 2.13-2.21 (m, 2H), 2.56-2.64 (m, 3H), 3.67-3.70 (m, 3H), 4.17-4.20 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.CC(=O)CC.[I-:21].[Na+]>C(OC(=O)C)C>[I:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: [I-]
Reactant: N#Cc1ccc(OCCCCCCl)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OCCCCCI)cc1
Reaction time: 6 h
Yield: 98.9 %

Procedure:
While 50 g of 4-(5-chloro-pentoxy)-benzonitrile (8) prepared in Example 5 were added to 500 ml of 2-butanone and stirred, 167 g of sodium iodide were added. Subsequently, the reaction temperature was gradually increased and stirring was continued at 70-80° C. for 6 hr. After the reaction was completed, the reaction temperature was decreased to room temperature, and the resultant reaction mixture was added with 1 L of ethylacetate, and then washed with water and brine. The ethylacetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residual solution was crystallized with methylalcohol, thus obtaining 69.7 g (yield: 99%) of a title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27]I>>[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1ccc(Cl)cc1Cl
Yield: 60.2 %

Procedure:
Step AF (1): 2-(2,4-Dichlorophenyl)acetic acid (2.5 g, 12.19 mmol) was deprotonated with NaHMDS (1.0 M in THF, 24.0 mL, 24.4 mmol) and reacted with 1-chloro-4-iodobutane (1.49 mL, 12.2 mmol) using a procedure analogous to Step AC (1) to afford, after purification by silica gel column chromatography, 6-chloro-2-(2,4-dichlorophenyl)hexanoic acid (2.17 g, 7.34 mmol, 60% yield) as a colorless oil. LC-MS (M−H)− 295.1.
Reaction SMILES: N[C@@H](CC1C=CC=CC=1)C(N[C@H:6]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[N:8]([CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[C:7]1=[O:29])=O.C(N(CC)CC)C.C1(N=C=S)C=CC=CC=1>O1CCCC1>[C:13]1([C:11]2[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=3[N:8]([CH2:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[C:7](=[O:29])[CH2:6][N:12]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O
Solvent: CCN(CC)CC
Solvent: S=C=Nc1ccccc1
Solvent: C1CCOC1
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1Cc1nnn[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 179.4 %

Procedure:
To a mixture of (3S)-3-[((2S)-2-amino-3phenylpropanoyl)amino]-1,3-dihydro-5-phenyl-1 -[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (12 g) and triethylamine (3.83 ml) in tetrahydrofuran (240 ml) was added phenyl isothiocyanate (2.99 ml) at room temperature. After stirring for 4 hours at room temperature, the solvent of the reaction mixture was evaporated under reduced pressure. Hydrochloric acid was added to the residue, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from ether to give (3S)-3-[[(2S)-2-[N'-phenyl)thioureido]-3-phenylpropanoyl]amino ]1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (14.26 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(=O)([O-])[O-].[K+].[K+].I[C:50]1[C:55]([O:56][CH3:57])=[CH:54][CH:53]=[C:52]([CH3:58])[N:51]=1>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:57][O:56][C:55]1[C:50]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:51][C:52]([CH3:58])=[CH:53][CH:54]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C)nc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC#N
Solvent: O
Product: COc1ccc(C)nc1-c1ccc(C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-(trifluoromethyl)phenylboronic acid (0.97 g, 5.1 mmol), S—PHOS (0.20 g, 0.47 mmol), potassium carbonate (2.0 g, 15 mmol), and Pd(OAc)2 (0.061 g, 0.27 mmol) was added a solution of 2-iodo-3-methoxy-6-methylpyridine (prepared in the previous step) in acetonitrile (6 mL) followed by water (4 mL). The reaction mixture was degassed by bubbling nitrogen through the solution for 10 min, and the reaction mixture was heated to 75° C. After 4 h, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (5% to 20% EtOAc in hexanes) gave 3-methoxy-6-methyl-2-(4-(trifluoromethyl)phenyl)pyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@H:4]([OH:6])[CH3:5].C1COCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1>>[N+:30]([C:29]1[C:24]([O:6][C@H:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:7])=[N:25][CH:26]=[CH:27][CH:28]=1)([O-:32])=[O:31]
Reactant: COC(=O)[C@@H](C)O
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C)Oc1ncccc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of 5.3 g (50.5 mmol) (R)-2-Hydroxy-propionic acid methyl ester in THF 50.5 mL (1 M in THF; 50.5 mmol) LiHMDS is added drop wise. After 10 minutes of stirring 4.0 g (25.2 mmol) 2-choro-3-nitro-pyridine is added. The mixture is stirred at 60° C. over night. The solvent is evaporated and the residue take up EtOAc washed with water, dried and evaporated to give rise to methyl (2R)-2-[(3-nitro-2-pyridyl)oxy]propanoate
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][NH:23][C:24](=[O:25])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1.C(N(CC)CC)C.[CH3:33][C:34]([OH:38])([C:36]#[CH:37])[CH3:35]>CN(C=O)C.[Cu]I.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>[Cl:1][C:2]1[CH:7]=[C:6]([C:37]#[C:36][C:34]([OH:38])([CH3:35])[CH3:33])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][NH:23][C:24](=[O:25])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1
Reactant: C#CC(C)(C)O
Reactant: O=c1[nH]ccc2c(Nc3c(Cl)cc(I)cc3Cl)nc3ccncc3c12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 6-[(2,6-dichloro-4-iodophenyl)amino]pyrido[4,3-c]-1,6-naphthyridin-10(9H)-one (50 mg, 0.10 mmol) in DMF (4 mL) were added CuI (3.94 mg, 0.02 mmol), triethylamine (30 uL, 0.20 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg, 10.4 umol), and 2-methylbut-3-yn-2-ol (17.4 mg, 0.21 mmol). The mixture was degassed by bubbling nitrogen gas and heated to 80° C. overnight. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layers were combined, dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (100% CH2Cl2 to 70% CH2Cl2/30% MeOH) afforded the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C3CCCCO3)[CH:8]=2)[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])O.[Na+]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=3)[N:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Clc1ccc2cc(OC3CCCCO3)ccc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(O)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Chloro-6-(tetrahydropyran-2-yloxy)quinoline (1.00 g) and piperazine-1-carboxylic acid tert-butyl ester (0.76 g) were heated to 140° C. in the absence of solvent under an argon atmosphere and stirred for 2 hours. After cooling the reaction mixture to room temperature, a sodium hydrogen carbonate aqueous solution was added thereto, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The result was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25→67:33). The result was concentrated to dryness under reduced pressure to afford the title compound as a pale yellow amorphous compound (0.55 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:16][CH2:15]2)=O)[CH2:3][CH2:2]1.N1C2C(=CC=CC=2)C(=O)CC1.CP(OC(OC(CC)(CC)C)=O)(=O)[O-].COC1C=C(C2CCNCC2)C=CC=1OC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>[H][H].[Pd]>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][CH2:12][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C2CCN(C(=O)CC3CCNc4ccccc43)CC2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: CCC(C)(CC)OC(=O)OP(C)(=O)[O-]
Agent: COc1ccc(C2CCNCC2)cc1OC
Product: COc1ccc(C2CCN(CCC3CCNc4ccccc43)CC2)cc1OC

Procedure:
Analogously to Example 2, reduction of 1-(1,2,3,4-tetrahydroquinolin-4-yl-acetyl)-4-(3,4-dimethoxyphenyl)piperidine [obtainable by reaction of 1,2,3,4-tetrahydroquinolin-4-one with diethylethoxycarbonyl methanephosphonate, subsequent hydrogenation with H2 /Pd-C, hydrolysis of the ester present and subsequent amide formation with 4-(3,4-dimethoxyphenyl)piperidine] using lithium aluminium hydride gives 1-(2-(1,2,3,4-tetrahydroquinolin-4-yl)ethyl)-4-(3,4-dimethoxyphenyl)piperidine, m.p. 235°-236° (dihydrochloride).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[C:7]1([CH2:13][CH2:14][OH:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:15][CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCc1ccccc1
Reactant: BrCCCCBr
Product: BrCCCCOCCc1ccccc1

Procedure:
(2.85 g), T.l.c. [K] Rf 0.41, from 1,4-dibromobutane (10.6 g) and benzeneethanol (2 g).
Reaction SMILES: O=[C:2]1O[C:6]2[C:8]3[C:13]([CH2:14][C:5]=2[C:4]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]1[C:21]#[N:22])=[CH:12][CH:11]=[CH:10][CH:9]=3.[H-].[Na+]>C1COCC1>[N:15]1([C:4]2[C:5]3[CH2:14][C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:6]=3[C:6]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[CH2:14][C:2]=3[C:3]=2[C:21]#[N:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#Cc1c(N2CCCCC2)c2c(oc1=O)-c1ccccc1C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c2c(c3c(c1N1CCCCC1)Cc1ccccc1-3)-c1ccccc1C2

Procedure:
A mixture of 2-oxo-4-(piperidin-1-yl)-2,5-dihydroindeno[1,2-b]pyran-3-carbonitrile (292 mg), indanone-2 (132 mg) and NaH. (40 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 200-202° C.; IR (KBr) 2215 cm−1 (CN); MS (ESI) 363 (M++1) HRMS Calculated for C26H22N2 362.1783 measured 362.1792.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:4]([F:15])[C:3]=1[C:16]1[N:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][C:17]=1[F:26].C1COCC1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:4]([F:15])[C:3]=1[C:16]1[N:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][C:17]=1[F:26]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(OC3CCCOC3)cc2F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)c(-c2c(F)cc(OC3CCCOC3)cc2F)n1

Procedure:
The methyl 6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxylate was treated with THF (2 mL), MeOH (2 mL) and 1.0 M aq. NaOH (2 mL, 2 mmol) at room temperature for 1 h. The volatile organic solvents were removed and the residue was neutralized to pH-5-6 with 1 M HCl. The solid that precipitated was filtered, rinsed with water, and dried to give sub-title compound as a white solid. LCMS calc. for C17H15F3NO4 (M+H)+ m/z=354.1. found: 353.9.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:24](O)=[O:25])[C:11]3[C:16]([CH3:17])=[N:15][N:14]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C[O-].[Na+].Cl>C(Cl)Cl.CCOC(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[N:15]=[C:16]([CH3:17])[C:11]3=[C:10]([CH:24]=[O:25])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)O)c12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a suspension of 3.80 g of 6-(4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid in 100 ml of DCM were added 5.5 ml of Hünig's base, 6.48 g of BEP and 2.41 g of (2R,5S)-dimethyl-1-benzylpiperazine. The reaction was stirred overnight at r.t. Then 3 ml of sodium methanolate (30% in methanol) were added, and the reation was stirred for 30 min. The pH was then brought to 5 by the addition of 2 M aqueous hydrochloric acid. The mixture was then diluted with EtOAc and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc gradient) to obtain 2.10 g (36%) of the title compound.
Reaction SMILES: [C:1](/[CH:3]=[C:4](\[O-])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:2].[Na+].Cl.[NH:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH2:14]>C(Cl)(Cl)Cl.C(OCC)C>[NH2:2][C:1]1[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:14]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)/C([O-])=C/C#N
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(N)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.5 %

Procedure:
To a suspension of sodium (Z)-1-cyano-3-ethoxy-3-oxoprop-1-en-2-olate (1.44 g, 8.78 mmol) in CHCl3 (80 mL) was added HCl (5 mL) in ethyl ether. t-butyl hydrazinecarboxylate (1.16 g, 8.78 mmol) was added, the mixture was stirred for 24 h at rt, the precipitate was removed by filtration, and the filtrate was concentrated to give 1-tert-butyl 5-ethyl 3-amino-1H-pyrazole-1,5-dicarboxylate (1.2 g, 37%), which was purified by preparative TLC. 1H NMR: δ 1.34 (m, 3H), 1.66 (s, 9H), 4.36 (m, 2H), 5.84 (s, 1H),