Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]([F:32])=[CH:7][C:5]=2[N:6]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1.C(OCC)(=O)C>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:9]2[C:8]([F:32])=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:31])([CH3:28])[CH3:27])#[N:30]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3cc4sc(N)nc4cc3F)c2)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3cc4sc(NC(=O)C5CC5)nc4cc3F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.2 %

Procedure:
To a solution of N-{3-[(2-amino-5-fluoro-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.448 mmol) in pyridine (4.0 mL) was added cyclopropanecarbonyl chloride (61 μL, 0.672 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogencarbonate solution (100 mL) and saturated brine (100 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether/hexane to give the title compound (118 mg, 51%) as a colorless solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH2:25]CCN4CCOCC4)(=[O:24])=[O:23])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:34])([CH3:3])[CH3:2].[O-]O.C1(C(C)C)C=CC=CC=1>C(OCCCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:34])([CH3:3])[CH3:2]
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)CCCN4CCOCC4)cc3)n2)n1C(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Solvent: CCCCOC(C)=O
Product: Cc1ncc(-c2ccnc(Nc3ccc(S(C)(=O)=O)cc3)n2)n1C(C)C
Temperature: 50 °C
Yield: 43.3 %

Procedure:
Titanium isopropoxide (188 μl, 0.62 mmol) was added to a mixture of 4-(1-isopropyl-2-methylimidazol-5-yl)-2-[4-(methylthio)anilino]pyrimidine (Method 86; 700 mg, 2.06 mmol) in butyl acetate (4.9 ml) and the mixture was heated to 50° C. Cumene hydroperoxide (800 μl, 4.32 mmol) was added over 40 minutes and the mixture was allowed to cool to 20° C. The resulting precipitate was collected by filtration, washed with butyl acetate and dried at 50° C. under vacuum to give the title compound (331 mg, 42%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[CH:7]=[C:6]2[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1.[Br:26]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:26][C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]=1[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1
Reactant: CCOc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2c(Br)c(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
To 1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (200 mg, 0.6 mmol) in DMF (2.5 mL) was added a solution of N-bromosuccinimide (107 mg, 0.6 mmol) in DMF (1.5 mL) dropwise. The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted in H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (1:1 CH2Cl2/hexane) to provide 3-bromo-1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (219 mg, 88%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:19][CH3:20])[C:3](=[O:18])[CH2:4][C:5](=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25].Cl.CN>>[CH3:23][N:24]1[CH:26]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=2)[C:5](=[O:17])[C:4]([C:3](=[O:18])[CH:2]([CH3:1])[CH2:19][CH3:20])=[CH:25]1
Reactant: CCC(C)C(=O)CC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Agent: CN
Agent: Cl
Product: CCC(C)C(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
A 1.3 g. portion of impure 5-methyl-1-(3-trifluoromethylphenyl)-2,4-heptanedione was reacted with 50 ml. of N,N-dimethylformamide dimethyl acetal, and then with 2 g. of methylamine hydrochloride as described in Example 12. The impure product was purified as described in Example 12, except that the final product was subjected to an additional step of trituration under hexane to obtain 0.08 g. of the desired product, m.p. 109°-111°, showing the following nmr peaks in CDCl3 : δ7.3-8.1 (m, 6H, aromatic); 3.9-4.2 (m, 1H, COCH); 3.8 (s, 3H, N--CH3); 1.2-2.0 (m, 2H, CH2CH3); 1.1-1.2 (d, 3H, CHCH3); 0.8-1.1 (t, 3H, CH2CH3).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH3:13]O>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1F
Reactant: CO
Product: COC(=O)c1cc(F)c(Br)cc1F
Temperature: 65 °C

Procedure:
A mixture of 4-bromo-2,5-difluorobenzoic acid (i-7b) (0.48 g, 2 mmol) and methanol (10 mL, saturated with gaseous HCl) was heated at 65° C. for 2 h. The mixture was concentrated. Then MeOH was added and the mixture was concentrated again. The residue was purified by flash chromatography (Pentane/EtOAc=4:1) to give the title compound. LCMS (ESI) calc'd for C8H5BrF2O2 [M+H]+: 251. found: 251.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C(OCC)(=O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:23][C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)=[CH:25][CH:24]=2)[N:10]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(Nc3nc(Cl)ccc3C(N)=O)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A solution of 2,6-dichloronicotinamide (100 mg, 0.524 mmol) and 4-(4-methylpiperazin-1-yl)aniline (300 mg, 1.571 mmol) in THF (5 mL) was cooled to −78° C. and treated with 1 M solution of lithium bis(trimethylsilyl)amide (3.14 mL, 3.14 mmol) in THF. The reaction mixture was stirred at −78° C. for 1 h and then at rt for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water, and concentrated. The residue was purified by MPLC chromatography (ISCO, 5% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 131 mg of 6-chloro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide as a yellow solid. LCMS: (M+H)+=346.09, 348.05 (Cl pattern). 1H NMR (400 MHz, CDCl3-MIX) δ ppm 10.56 (1H, s), 7.59 (1H, d, J=7.91 Hz), 7.56 (2H, d, J=8.79 Hz), 6.93 (2H, d, J=9.23 Hz), 6.61 (1H, d, J=7.91 Hz), 5.76 (2H, br. s.), 3.16-3.21 (4H, m), 2.57-2.62 (4H, m), 2.36 (3 H, s).
Reaction SMILES: F[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][NH2:12].C(Cl)Cl>C(O)CO>[CH3:2][C:3]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:12][N:11]=1
Reactant: NN
Reactant: O=C(CF)c1ccccc1
Solvent: OCCO
Solvent: ClCCl
Product: Cc1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a stirring solution of 36.2 g (0.26 mol) of 2-Fluoroacetophenone in 120 mL of ethylene glycol is added 8.6 mL (0.27 mol, 1.05 equiv.) of hydrazine. The resulting solution is stirred 2 h at RT and then heated at 165° C. for 40 h. The solution is cooled to RT, poured into CH2Cl2 (200 mL) and extracted with H2O (2×200 mL). The organic layers were combined, dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by recrystallization form hexane/CHCl3 afforded 26 g of 3-Methylindazole as a light tan solid: 1H NMR (CDCl3, 300 MHz) δ7.73 (d, 1H, J=8.1), 7.44 (m, 2H), 7.19 (dd, 1H, J=7.0,7.0), 2.67 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1>CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]1([OH:22])[CH2:20][CH2:21][C:16]2([O:23][CH2:13][CH2:14][O:15]2)[CH2:17][CH2:18]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2ccccn2)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 2-bromopyridine (14 g, 88.6 mmol) in anhydrous ether (300 mL) cooled at −78° C. was slowly added a solution of 2.5 M n-butyl lithium (36 mL). After the addition, stirring was continued at −78° C. for 1 hour. To it was slowly added a solution of 1,4-cyclohexanedione mono-ethylene ketal (15 g, 96 mmol) in anhydrous ether (300 mL). When the addition was complete, the mixture was allowed to warm to 0° C. and stirring was continued for 1 hour. The reaction was quenched by the addition of an aqueous solution (100 mL) of ammonium chloride (4.5 g). The organic phase was separated and the aqueous phase was extracted with methylene chloride 4 times. The combined organic phases were dried over MgSO4 and concentrated. Crystallization from EtOAc provided 7 g of the desired product. The mother liquid was purified on silica gel eluting with 10% MeOH/EtOAc to give 3 g of the desired product. MS (M+H)+ 236.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[Cl:31].[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:34]=1[CH:35]=O.[C:42]([OH:45])(=[O:44])[CH3:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:42]([OH:45])(=[O:44])[CH3:43].[Cl:31][C:3]1[CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[NH:1][CH2:35][C:34]1[C:37]([F:41])=[CH:38][CH:39]=[CH:40][C:33]=1[Cl:32]
Reactant: CN1CCN(C2CCC(n3nc(-c4ccc(N)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Reactant: O=Cc1c(F)cccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(NCc5c(F)cccc5Cl)c(Cl)c4)c4c(N)ncnc43)CC2)CC1
Reaction time: 0.08 h

Procedure:
A mixture of 3-(4-amino-3-chlorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.00045 mol) in 1,2-dichloroethane (20 mL) was reacted with 2-chloro-6-fluorobenzaldehyde (0.076 g, 0.00048 mol), acetic acid (0.095 g, 0.00159 mol) and sodium triacetoxyborohydride (0.336 g, 0.00159 mol) at ambient temperature. An additional three equivalents of sodium triacetoxyborohydride (1.008 g, 0.00477 mol) were added in three 24 hour intervals, after which time all the starting material had been consumed. The solvents were removed in vacuo and the residue was partitioned between chloroform (25 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with chloroform (2×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 30% isocratic for five minutes, then 30%-60% acetonitrile—0.1M ammonium acetate over 15 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give to give trans 3-{3-chloro-4-[(2-chloro-6-fluorobenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate as a white solid (0.074 g, 0.00011 mol):
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:13])[C@H:4]1[C:8]([CH3:10])([CH3:9])[O:7][C:6]([CH3:12])([CH3:11])[O:5]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>CCOCC>[CH3:11][C:6]1([CH3:12])[O:5][C@@H:4]([C:3]([Cl:13])=[N:2][O:1][S:15]([CH3:14])(=[O:17])=[O:16])[C:8]([CH3:9])([CH3:10])[O:7]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)O[C@@H](C(Cl)=NO)C(C)(C)O1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1(C)O[C@@H](C(Cl)=NOS(C)(=O)=O)C(C)(C)O1
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
(R)—N-hydroxy-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbimidoyl chloride (12.4 g, 59.7 mmol) was dissolved in Et2O (200 mL) and cooled in an ice bath. Methanesulfonyl chloride (4.6 ml, 59.7 mmol) was added. Triethylamine (8.3 ml, 59.7 mmol) was added slowly and the reaction was stirred in an ice bath for 30 minutes. The reaction was filtered and concentrated. The residue was purified over silica gel (100% CH2Cl2) to afford (R)-2,2,5,5-tetramethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (11.3 g, 39.55 mmol, 66.22% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1)=[O:6]
Reactant: COc1ccccc1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Methoxy-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Methoxy-N-(4-nitro-3-trifluoromethyl-phenyl)-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].C(Cl)(C([Cl:18])=O)=O>C1COCC1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([Cl:18])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1ccccc1C(=O)O
Solvent: C1CCOC1
Product: CC(=O)Oc1ccccc1C(=O)Cl

Procedure:
To a solution of compound 2-acetoxybenzoic acid (1.0 g, 5.5 mmol) in THF (30 mL) was added (COCl)2 (0.8 ml, 9.1 mmol) at 0° C. The mixture was heated (reflux, 1.5 h) and concentrated under reduced pressure to afford 2-(chlorocarbonyl)phenyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]([CH2:19][CH2:20][CH3:21])[C:10]=2[CH3:22])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:31])[C:27]([O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:19][CH2:20][CH3:21])[C:10]([CH3:22])=[C:9]2[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:29])[CH3:28])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(C)c(-c2ccc(OC)cc2)c2cc(O)ccc21
Product: CCCn1c(C)c(-c2ccc(OC)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
In accordance with the procedure of Example 10, the above compound was prepared from 3-(4-methoxy-phenyl)-2-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C>[F:1][C:2]1[C:3]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: O=C(O)c1ncccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ncccc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
To 3-fluoro-2-pyridinecarboxylic acid (available from Fluorochem, 63 mg, 0.44 mmol) was added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (172 mg, 0.45 mmol), DIPEA (0.106 ml) and DMF (1 ml). The reaction was stirred for 20 mins at 25° C. 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol) was added and the reaction was stirred for a further 20 h at 25° C. The solvent was dried under a stream of nitrogen to give the crude product. This sample in DMF was loaded onto an aminopropyl cartridge (5 g) and after standing for 3 h, the column was washed with 10% methanol in dichloromethane. The appropriate fractions were combined and dried under a stream of nitrogen to give the crude product which was purified by Mass Directed Automated Preparative HPLC (Method B). The solvent was dried under a stream of nitrogen to give the title compound (23 mg).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](O)(=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29].O>ClCCl>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCC(=O)O
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCC(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(2-Phenylchroman-6-yloxy)pyridin-3-ylamine (example 35) (270 mg) and succinic acid (151 mg) were dissolved in dichloromethane (16 ml). 1-(3-Dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (245 mg) was added into a reaction mixture and it was stirred at room temperature for 3 hours. Water was added and the mixture was filtered. The precipitate was collected and treated with methanol and filtered again. The methanol-filtrate was evaborated to dryness to yield N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]succinamic acid. 1H NMR (400 MHz, d6-DMSO) δ: 12.0 (bs, 1H), 10.08 (s, 1H), 8.29 (d, 1H, J 2.4 Hz), 8.01 (dd, 1H, J 8.8, 2.4 Hz), 7.46-7.32 (m, 5H), 6.93 (d, 1H, J 8.8 Hz), 6.86-6.84 (m, 3H), 5.11 (d, 1H, J 8.6 Hz), 2.96 (m, 1H), 2.70 (m, 1H), 2.56-2.52 (m, 4H), 2.16 (m, 1H), 2.00 (m, 1H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([CH2:12]O)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:16][CH2:12][C:10]1[CH:9]=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=1
Reactant: OCc1cnn(-c2ccccc2)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1cnn(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
(1-Phenyl-1H-pyrazol-4-yl)methanol (6.3 g) synthesized in Reference Example 17 was dissolved in dichloromethane (100 mL) and, after ice-cooling, thionyl chloride (5.59 g) was added thereto, and the mixture was stirred at 0° C. for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (7.4 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[CH:12][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C=Cc1c(Cl)cccc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.6 %

Procedure:
(31) (Canadian Journal of Chemistry. 1968 46, 1952-6). To a solution of 2,6-dichlorobenzaldehyde (1.75 g, 10.0 mmol) and acetophenone (1.20 g, 10.0 mmol) in 30.0 ml of methanol was added 4.4 ml of 40% sodium hydroxide in water at 10° C. After stirring for 3 hours at room temperature, a solid appeared and was filtered. The precipitate was recrystallized from methanol to afford 1.68 g (60.6%) of yellow needles: mp 84.5-85.3° C. (lit. mp 83° C. Kuck and Grutzmacher, Org. Mass. Spect. 1978, 13, 90-102). 1H NMR (250 MHz) δ 8.05-8.01 (m, 2 H), 7.90-7.84 (d, 1 H), 7.70-7.64 (d, 1 H), 7.62-7.48 (m, 3 H), 7.41-7.37 (d, 2 H), 7.24-7.18 (dd, 1 H); 13C NMR (62.7 MHz) 190.3, 139.0, 135.3, 133.3 132.8, 130.7, 130.0, 129.0, 128.9 ppm.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([F:30])[CH:36]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(F)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3-fluorobenzeneboronic acid. The title compound was obtained in 97% yield as yellow foam. MS (m/e): 500.1 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccc(Br)cc1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 4-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.