Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]1([C:31](Cl)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[C:21]1([C:31]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1cccc2ccccc12)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2-thienylcarbonyl chloride, there is obtained ethyl N-(2-thienylcarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a solid, mass spectrum m/e:M+ 376 (10), 347 (13), 194 (100), 111 (48); starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 1-naphthoyl chloride, there is obtained ethyl N-(1-naphthylcarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a foam, mass spectrum m/e: M+ 420 (8), 391 (6), 194 (100), 155 (32), 27 (28);
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:10]1[C@@:14]2([CH3:29])[CH2:15][CH2:16][C@@H:17]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:21]4=[CH:20][CH:19]=[C:18]3[C@@H:13]2[CH2:12][CH2:11]1)/[CH:3]=[CH:4]/[C@@H:5]([CH:7]([CH3:9])[CH3:8])[CH3:6].[C:30](OC(=O)C)(=[O:32])[CH3:31].O>N1C=CC=CC=1>[C:30]([O:27][C@H:25]1[CH2:24][CH2:23][C@@:22]2([CH3:28])[C:21](=[CH:20][CH:19]=[C:18]3[C@@H:17]2[CH2:16][CH2:15][C@@:14]2([CH3:29])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[C@H:2]([CH3:1])/[CH:3]=[CH:4]/[C@H:5]([CH3:6])[CH:7]([CH3:8])[CH3:9])[CH2:26]1)(=[O:32])[CH3:31]
Reactant: CC(C)[C@@H](C)/C=C/[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of 50 gm (0.13 mol) of ergosterol (1) in 300 mL of anhydrous pyridine was added 33.3 mL (0.35 mol) of acetic anhydride. The mixture was stirred at room temperature overnight and then 600 mL of water was added. The precipitate was filtered and washed three times with 200 mL portions of acetonitrile and then air dried to yield 42.0 g (74%) of (2).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].O[C:22]1[CH:31]=[CH:30][C:25]([O:26][CH:27]([OH:29])[CH3:28])=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]=[N:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([O:18][C:22]3[CH:31]=[CH:30][C:25]([O:26][CH:27]([OH:29])[CH3:28])=[CH:24][CH:23]=3)=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(O)Oc1ccc(O)cc1
Reactant: O=C(O)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(O)Oc1ccc(OC(=O)c2ccc(N=Nc3ccc([N+](=O)[O-])cc3)cc2)cc1
Yield: 76.1 %

Procedure:
A solution of 0.35 g of 4-(4-nitrophenylazo)benzoic acid, 0.2 g of (4-hydroxyphenoxy)ethanol and 0.04 g of 4-dimethylaminopyridine is reacted with 0.4 g of N,N'-dicyclohexyldicarbodiimide and 50 ml of dichloromethane in an analogous manner to Example 1 to give 0.4 g of (4-[4-(4-nitrophenylazo)benzoyloxy]phenoxy)ethanol.
Reaction SMILES: NC(N)=O.[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([N:15]=[C:16]=[O:17])[CH2:10]2.Cl.[F:19][CH2:20][CH2:21][NH2:22].C(N(C(C)C)CC)(C)C>>[F:19][CH2:20][CH2:21][NH:22][C:16]([NH:15][CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[F:5])[CH2:10]1)=[O:17]
Reactant: O=C=NC1Cc2cccc(F)c2C1
Reactant: NCCF
Agent: Cl
Agent: NC(N)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCF)NC1Cc2cccc(F)c2C1

Procedure:
The title urea was generated from 4-fluoro-2-isocyanato-indan (11.10 mmol), fluoroethyl amine hydrochloride (1.10 g, 90% purity, 9.95 mmol) and diisopropylethyl amine (3.90 mL, 22.39 mmol) according to the protocols as outlined in general procedure G. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ 2.67-2.80 (m, 2H), 3.12-3.28 (m, 3H), 3.31-3.37 (m, 1H), 4.23-4.55 (m, 3H), 6.0 (t, 1H, J=6.7 Hz), 6.4 (d, 1H, J=7.0 Hz), 7.0 (t, 1H, J=9.1 Hz), 7.1 (d, 1H, J=7.3 Hz), 7.15-7.24 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=2)=[C:15]([C:26]([NH2:28])=[O:27])[CH:14]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38].O>CN(C=O)C>[CH3:40][O:39][C:37](=[O:38])[CH2:36][N:21]1[C:22](=[O:25])[CH:23]=[CH:24][C:19]([NH:18][C:16]2[S:17][C:13]([C:3]3[C:2]([F:1])=[CH:7][C:6]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:5][C:4]=3[F:12])=[CH:14][C:15]=2[C:26]([NH2:28])=[O:27])=[N:20]1
Reactant: COC(=O)CBr
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(=O)[nH]n3)s2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1=O
Temperature: 25 °C

Procedure:
5-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-[(6-oxo-1,6-dihydropyridazin-3-yl)amino]thiophene-3-carboxamide (Example 578 Step 3) (50 mg, 0.12 mmol), K2CO3 (18.70 mg, 0.14 mmol) and methyl bromoacetate (0.012 mL, 0.13 mmol) were stirred in DMF (1 mL) at 80° C. overnight. The reaction mixture was cooled to room temperature, water was added and the reaction mixture was extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (0-15% MeOH—CHCl3) gave the title compound as a yellow solid after triturating in DCM.
Reaction SMILES: [CH3:1][C@@H:2]1[C:6]2[NH:7][C:8]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)=[CH:9][C:5]=2[C:4](=[O:19])[NH:3]1.N1C=CC2C(=O)NC3(CC3)[C:21]1=2>>[CH3:17][C:12]1([CH3:18])[C:13]([CH3:16])([CH3:15])[O:14][B:10]([C:8]2[NH:7][C:6]3[C:2]4([CH2:21][CH2:1]4)[NH:3][C:4](=[O:19])[C:5]=3[CH:9]=2)[O:11]1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: O=C1NC2(CC2)c2[nH]ccc21
Product: CC1(C)OB(c2cc3c([nH]2)C2(CC2)NC3=O)OC1(C)C

Procedure:
This compound as a brown solid was prepared according to the procedure described for intermediate 705, using 1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (704) as the starting material. m/z (ESI, +ve) 275.0 (M+H)+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].ClCCl>O>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:6][CH2:5]1
Reactant: OCCN1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(CCO)CC1

Procedure:
A mechanically-stirred solution of 1-(2-hydroxyethyl)piperazine (10.0 g, 9.4 mL, 0.07 mol) in 30 mL of deionized water is cooled to 0 C. Then portions of 4N sodium hydroxide (total 28 mL) and portions of benzyl chloroformate (18.8 g, 15.7 mL, 0.11 mol) are added over 15 minute periods, keeping the temperature at 0 C. to 5 C. At the end of the additions, 4N sodium hydroxide solution is added to bring the pH of the reaction mixture to 10. After 1 hour dichloromethane (200 mL) is added and the layers are separated. The organic solution is dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 1-(2-hydroxyethyl)-4-carbobenzyloxypiperazine.
Reaction SMILES: [CH2:1]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=2)[NH:16]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+].[CH3:29]I>O.CO>[CH3:29][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=2)[CH2:23][CH:15]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCC1Cc2ccc(C(=O)O)cc2N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCC1Cc2ccc(C(=O)O)cc2N1C

Procedure:
(RS)-2-(n-Tetradecyl)indoline-6-carboxylic acid (10.5 g) and sodium hydroxide (5.0 g) were refluxed together in a mixture of water (30 ml) and methanol (70 ml) for 1.5 hours, then methyl iodide (5 ml) was added. Water (30 ml) was added and the mixture was refluxed for 1 hour. The mixture was filtered, and the filtrate was diluted with water and acidified with acetic acid. The product was collected and recrystallised from a mixture of methanol and ethanol to give (RS)-1-methyl-2-(n-tetradecyl)indoline-6-carboxylic acid (7.0 g) in the form of off-white crystals, m.p. 115°-118° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5]([C:19]2[C:20]([CH3:27])=[N:21][N:22]([CH:24]([F:26])[F:25])[CH:23]=2)=[CH:4][N:3]=1.[Li+].[OH-].Cl>C1COCC1.CO>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5]([C:19]2[C:20]([CH3:27])=[N:21][N:22]([CH:24]([F:26])[F:25])[CH:23]=2)=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3cn(C(F)F)nc3C)cnc2N)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(C(F)F)cc1-c1cnc(N)c(-c2ccc(C(=O)O)c(F)c2)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of methyl 4-(2-amino-5-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-fluorobenzoate (352 mg, 0.935 mmol) in THF (6236 μL) and MeOH (3118 μL) was added LiOH (1 M solution) (1684 μL, 1.684 mmol). The reaction mixture was stirred at room temperature. To the reaction mixture, 1 N HCl was added up to pH 5. The reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo to provide crude 4-(2-amino-5-(1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-fluorobenzoic acid (88%). LCMS (m/z): 363.3 (MH+), 0.51 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:14]([C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=1[O:24][CH3:25])([CH3:16])[CH3:15]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:23][C:21]2[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([CH:14]([CH3:16])[CH3:15])[N:22]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: COc1ccc(N)nc1C(C)C
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(OC)c(C(C)C)n1
Temperature: 80 °C
Yield: 37 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (747 mg, 3.38 mmol) in acetonitrile (11.3 mL) was added 6-isopropyl-5-methoxypyridin-2-amine (562 mg, 3.38 mmol) and heated to 80° C. for 20 h. The mixture was cooled and concentrated in vacuo. Purification by chromatography (silica, 10 to 50% ethyl acetate in hexanes) gave ethyl 6-chloro-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxylate (438 mg, 1.25 mmol, 37%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 10.61 (s, 1H), 9.15 (s, 1H), 7.22 (d, J=8.7 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 4.57 (q, J=7.6 Hz, 2H), 3.88 (s, 3H), 3.53 (m, 1H), 1.53 (t, J=7.0 Hz, 3H), 1.31 (d, J=6.7 Hz, 6H); MS (EI/CI) m/z: 351.0 [M+H].
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]([C:25]([O:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[CH2:22]3)=[CH:17][CH:16]=2)[CH:12]=[C:11]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)[N:10]=1>>[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]([C:25]([O:27][CH:28]4[CH2:33][CH2:32][N:31]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:30][CH2:29]4)=[O:26])[CH2:22]3)=[CH:17][CH:16]=2)[CH:12]=[C:11]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)[N:10]=1
Reactant: CCOC(=O)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Agent: Cl
Product: CCOC(=O)N1CCC(OC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 4 starting from ethyl chloroformate and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=524.3.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:5][CH3:6].[CH3:16]I.Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([C:7]1[N:8]([CH3:16])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1cc2ccccc2[nH]1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 105.3 %

Procedure:
Sodium hydride (60% oil disperson; 1.52 g, 38.0 mmol) was added under nitrogen in portions over 5 minutes to a solution of 2-butyl-1H-indole (5.00 g, 28.9 mmol) in 150 mL of anhydrous DMF at room temperature. After the addition the reaction was stirred at room temperature for 1.25 h. Methyl iodide (3.60 mL, 57.8 mmol) was then added and the reaction stirred at room temperature for 3.5 h. 1 N HCl was added to the reaction until the evolution of gas ceased. The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-1-methyl-1H-indole (5.70 g, 100%) as a yellow oil, MS m/z: 188 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][C:7](=[O:23])[C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:22])[CH2:4]1.N1C=CC=CC=1[CH2:30][C:31](OC(=O)CC1C=CC=CN=1)=[O:32]>>[CH3:1][O:2][C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][C:7](=[O:23])[C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:22][C:31](=[O:32])[CH3:30])[CH2:4]1
Reactant: CO[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]32)C1
Reactant: O=C(Cc1ccccn1)OC(=O)Cc1ccccn1
Product: CO[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
3β-methoxy-17β-hydroxyandrost-5-ene-7-one (28) was acetylated in pyridine-acetic anhydride mixture at room temperature to obtain product 29, m.p. 168-70° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH:26]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH3:27])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[OH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH3:27])=[CH:19][CH:20]=2)=[N:13][CH:14]=1
Reactant: CC(CCCC#Cc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1)OC1CCCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(CCCCCc1ccc(-c2ncc(O)cn2)cc1)OC1CCCCO1

Procedure:
In a reactor equipped with a stirrer and a thermometer, 5-benzyloxy-2-[4-(6-tetrahydropyranyloxy-1-heptynyl)phenyl]pyrimidine, 5% Pd/C and THF are charged. After replacing an internal atmosphere of the reactor by hydrogen gas under atmospheric pressure, the mixture is reacted at room temperature for 10 hours in a hydrogen atmosphere under ordinary pressure. After filtrating the catalyst off, the reaction mixture is evaporated under reduced pressure. A resulting residue is purified by silica gel column chromatography to obtain 5-hydroxy-2-[4-(6-tetrahydropyranyloxy1-heptyl)phenyl]pyrimidine.
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[F:16][C:17]1([F:33])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:18]1=[O:32]>>[CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:29]2[CH2:30][CH2:31][CH:26]([N:19]3[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:17]([F:16])([F:33])[C:18]3=[O:32])[CH2:27][CH2:28]2)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C1N(C2CCNCC2)c2ccccc2C1(F)F
Reactant: CCCCCNC(=O)c1ccc(Cl)nn1
Product: CCCCCNC(=O)c1ccc(N2CCC(N3C(=O)C(F)(F)c4ccccc43)CC2)nn1
Yield: 65 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 6-chloropyridazine-3-carboxylic acid pentylamide in place of 6-chloropyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide to react with 3,3-difluoro-1-piperidin-4-yl-1,3-dihydroindol-2-one, the title compound was obtained as a white powder in 65% yield (0.063 g). m.p. 100-102° C. 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J=9.6 Hz, 2H), 7.92 (br, 1H), 7.54 (m, 1H), 7.41 (t, J=8.1 Hz, 1H), 7.14 (t, J=7.5 Hz, 1H), 7.04 (d, J=9.3 Hz), 6.95 (d, J=7.8 Hz, 1H), 4.70 (m, 2H), 4.41 (m, 1H), 3.50 (m, 2H), 3.12 (t, J=12.3 Hz, 2H), 2.45 (m, 2H), 1.94 (m, 2H), 1.60 (m, 2H), 1.34 (m, 4H), 0.88 (t, J=6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.2, 164.8, 163.1, 159.8, 145.0, 142.5 142.4, 133.5, 127.1, 125.2, 123.8, 120.7, 120.4, 120.1, 113.6, 112.4, 110.8, 110.3, 107.0, 50.9, 44.7, 39.4, 29.3, 29.1, 27.8, 22.4, 14.0. MS (ES+) m/z 444.1 (M+1).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.[CH2:30]([C:32]1[C:33]([OH:55])=[CH:34][C:35]([OH:54])=[C:36]([C:38]2[C:39]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)=[C:40]([C:43]([OH:45])=O)[NH:41][N:42]=2)[CH:37]=1)[CH3:31].[C:56]([NH:63][CH2:64][CH2:65][CH2:66][NH2:67])([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57]>C(Cl)Cl>[CH2:30]([C:32]1[C:33]([OH:55])=[CH:34][C:35]([OH:54])=[C:36]([C:38]2[C:39]([C:46]3[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=3)=[C:40]([C:43]([NH:67][CH2:66][CH2:65][CH2:64][NH:63][C:56](=[O:57])[O:58][C:59]([CH3:61])([CH3:60])[CH3:62])=[O:45])[NH:41][N:42]=2)[CH:37]=1)[CH3:31]
Reactant: CCc1cc(-c2n[nH]c(C(=O)O)c2-c2ccc(OC)cc2)c(O)cc1O
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCc1cc(-c2n[nH]c(C(=O)NCCCNC(=O)OC(C)(C)C)c2-c2ccc(OC)cc2)c(O)cc1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
HOBT (572 mg, 4.2 mmol), NMM (1.55 ml, 14.1 mmol) and EDAC.HCl (820 mg, 4.3 mmol) were added at 0° C. consecutively to a solution of 5-(5-ethyl-2,4-dihydroxy-phenyl)-4-(4-methoxyphenyl)-2H-pyrazole-3-carboxylic acid (500 mg, 1.4 mmol) in 40 ml of dry DCM. The resulting mixture was stirred at 0° C. for 15 minutes. Then a solution of N—BOC-1,3-diaminopropane (740 mg, 4.3 mmol) in 5 ml of dry DCM was added. The resulting mixture was stirred at 0° C. for one our and at room temperature for 2.5 hours. The reaction mixture was washed with 50 ml of 10% w/v aqueous citric acid solution, 50 ml 20% aqueous KHCO3 solution and 50 ml of distilled water. The organic extracts were dried over MgSO4 and evaporated under reduced pressure. The crude material was purified by automated column chromatography on a 40 g RediSep™ normal phase silica cartridge using an ISCO Companion™ eluting with a mixture of 5% methanol in DCM was used. The fractions containing the desired product were combined and evaporated under reduced pressure go give the title compound as a white solid (450 mg, 63%); 1H NMR Spectrum: δH (400 MHz, DMSO-d6) 0.90 (3H t, J=7.5 Hz), 1.38 (9H, s), 1.56 (2H t, J=6.9 Hz), 2.28 (2H q, J=7.4 Hz), 2.95 (2H d, J=6.1 Hz), 3.15-3.20 (2H, m), 3.72 (3H, s), 6.41 (1H, s), 6.57 (2H, s), 6.72 (1H, s br), 6.78 (2H d, J=7.3 Hz), 7.12-7.14 (2H, m), 7.92-8.02 (1H, m br), 9.28-9.35 (2H, m), 12.89 (1H, s, br);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: Oc1ccc(C2COC(c3c(F)cccc3F)=N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(F)c1C1=NC(c2ccc(OCc3ccc4ccccc4c3)cc2)CO1
Yield: 50 %

Procedure:
The compound of Example 6 (0.36 g, 1.3 mmol) and 2-bromomethyl naphthalene (0.4 g, 1.7 mmol) were stirred at 23° C. for 18 h with potassium carbonate (0.6 g, 4 mmol) in dimethylformamide (10 mL). The mixture was poured into water (50 mL) and extracted with diethylether (50 mL). The diethylether was washed with water (50 mL) twice, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel chromatography using hexanes/ethyl acetate (6:1) as eluent to give the title compound as a solid (0.27 g): m.p. 148°-150° C. 1H NMR (CDCl3, 200 MHz) δ 7.8-7.0 (m,14H), 5.4 (m,1H), 5.2 (m,2H), 4.8 (m,1H), 4.3 (m,1H).
Reaction SMILES: O.O.O.O.O.O.O.O.[OH-].[Ba+2:10].[OH-].[CH3:12][C:13]([CH3:24])([C:15](=[O:23])[CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14]>C1(C)C(C)=CC=CC=1>[CH3:12][C:13]([CH3:24])([CH3:14])/[C:15](/[O-:23])=[CH:16]/[C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22].[CH3:12][C:13]([CH3:24])([CH3:14])/[C:15](/[O-:23])=[CH:16]/[C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22].[Ba+2:10]
Reactant: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(C)C(=O)/C=C(\[O-])C(C)(C)C
Temperature: 50 °C
Reaction time: 10 h

Procedure:
37.8 g of barium hydroxide octahydrate (0.12 mole) were placed in a 250 ml round-bottomed flask. 50 ml of 2,2,6,6-tetramethyl-3,5-heptane dione (0.24 mole) were added in drops via a dropping funnel. Then 70 ml of xylene were added. The reaction mixture was then heated to 50° C. by means of an oil bath and stirred at this temperature for 10 hours. Then the oil bath temperature was adjusted to 60° C. and volatile constituents were distilled off under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl.[NH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH:14]=1
Reactant: O=C1CCNCC1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reaction time: 8 h

Procedure:
A mixture of 15.1 g of 5-chloro-1H-indole, 30.7 g of the hydrate of 4-piperidone hydrochloride and 150 ml of 2 N methanolic potassium hydroxide solution was refluxed under an inert atmosphere for 71/2 hours and was allowed to stand overnight at room temperature. The mixture was poured into 1.5 liters of water and the mixture was extracted with ethyl acetate. The organic phase was washed with water, aqueous sodium chloride solution, was dried over magnesium sulfate and evaporated to dryness. The 20.5 g of residue were dissolved in 1 liter of refluxing benzene and the solution was filtered hot. The solution was cooled to induce crystallization and after 3 hours, the mixture was vacuum filtered. The recovered product was rinsed with benzene to obtain 10.2 g of 5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 177° C. The mother liquors were concentrated and crystallization induced to obtain 2.49 g of the said product melting at 175°-177° C. for a total yield of 12.69 g. For analysis, the product was purified by salification with an acid and then return to the basis.