Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4](C)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.[Br:14][C:15]1[CH:16]=[C:17]([C:21](=[CH:27]O)[C:22](OCC)=[O:23])[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[CH:16]=[C:17]([C:21]2[C:22](=[O:23])[N:2]([CH3:1])[C:3]3[NH:4][C:5]4[C:10]([C:11]=3[CH:27]=2)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=4)[CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(=CO)c1cccc(Br)c1
Reactant: CNc1cc2cc(C)ccc2n1C
Product: Cc1ccc2[nH]c3c(cc(-c4cccc(Br)c4)c(=O)n3C)c2c1

Procedure:
This compound is prepared according to the usual methods by reaction of N,1,5-trimethyl-1H-indole-2-amine with ethyl 2-(3-bromophenyl)-3-hydroxy-2-propenoate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:12][F:13])[C:8]2[C:4](=[CH:5][N:6](COCC[Si](C)(C)C)[N:7]=2)[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:14][CH2:15][C:16]3([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:12][F:13])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CF)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(COC(CF)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-fluoroethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (40 mg, 0.063 mmol) was dissolved in tetrabutylammonium fluoride (1M in tetrahydrofuran, 0.8 mL, 0.8 mmol). The flask was sealed and placed in a 55° C. bath. After 1.5 h, the reaction was cooled to room temperature, diluted with diethyl ether, washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (50%→60% ethyl acetate/n-hexane) gave 29 mg (91%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 9.82 (bs, 1H), 7.91 (s, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.27 (dd, J=89., 5.5 Hz, 2H), 7.07 (dd, J=8.9, 8.5 Hz, 2H), 7.03 (d, J=1.5 Hz, 1H), 4.61 (ddd, J=18.0, 5.2, 4.6 Hz, 1H), 4.53 (d, J=4.6 Hz, 1H), 4.44 (d, J=4.9 Hz, 1H), 3.74 (m, 2H), 3.49 (d, J=9.2 Hz, 1H), 3.39 (d, J=9.2 Hz, 1H), 3.06 (m, 1H), 2.97 (m, 1H), 2.30 (m, 1H), 2.06 (m, 1H), 1.87 (m, 1H), 1.75 (m, 1H), 1.43 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.7 (d, J=247 Hz), 155.0, 137.7, 136.4, 133.8, 128.8 (d, J=7.7 Hz), 126.2, 125.6, 124.9, 121.0, 120.9, 120.2, 115.8 (d, J=21 Hz), 85.8, 84.4, 81.3, 81.1, 79.8, 79.7, 41.4, 40.3, 39.6, 32.4, 32.1, 28.5. Mass spec.: 506.23 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=O)[CH2:4][NH:5][C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15].C(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[S:15][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][CH:4]=1
Reactant: CCOC(=O)C(=O)NCC(=O)OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ncc(OC)s1
Temperature: 60 °C
Reaction time: 7 h
Yield: 7.4 %

Procedure:
A mixture of ethyl 2-(2-methoxy-2-oxoethylamino)-2-oxoacetate (1.00 g, 5.29 mmol) and phosphorus pentasulfide (1.29 g, 5.82 mmol) in chloroform (20 ml) was stirred at 60° C. for 7 h. To the cooled reaction mixture DCM (100 ml) was added and the mixture was washed with water (50 ml) and brine (50 ml). Organic phase was dried over Na2SO4 and evaporated. Evaporation residual was dissolved in dry MeCN (10 ml) and phosphorus pentoxide (0.75 g, 5.29 mml) was added and the mixture was heated to reflux for 4.5 h. To the cooled reaction mixture water (35 ml) was added and the mixture was extracted with EtOAc (3×50 ml). Combined organic fractions were dried over Na2SO4 and evaporated to give crude product, which was purified twice by CombiFlash (1st column: silica, eluent: 0-100% EtOAc in heptane; 2nd column: C-18, eluent: 0-100% MeCN in water) to yield 73 mg (7%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.42 (t, 3H), 4.01 (s, 3H), 4.43 (q, 2H), 7.30 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][N:28]3[CH3:31])=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1.C[Si](Cl)(C)C>C(O)CCC>[CH3:31][N:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=[C:2]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([N:39]5[CH2:40][CH2:41][N:42]([C:45](=[O:47])[CH3:46])[CH2:43][CH2:44]5)=[CH:37][CH:38]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cnn(C)c5c4)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cnn(C)c5c4)c4cc[nH]c4n3)cc2)CC1
Yield: 26.1 %

Procedure:
A mixture of 2-chloro-N-(1-methyl-1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (108 mg, 0.239 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (78 mg, 0.356 mmol) and TMSCl (0.100 mL, 0.791 mmol) in nBuOH (2 mL) was stirred at 135° C. for 20 h. nBuOH was removed in vacuo. The residue was purified by HPLC to give 1-(4-(4-(4-(1-methyl-1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (30 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19].[CH2:26]=[O:27].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:1]([C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:17])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[O:27])[CH3:19]
Reactant: CCc1ccccc1
Reactant: C=O
Agent: O=C(O)c1cc(Cc2ccccc2)ccc1O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1ccccc1C=O

Procedure:
To a mixture of 22.8 parts of 5-benzylsalicylic acid, 21.2 parts of ethylbenzene, 3.8 parts of 87% paraformaldehyde and 25 parts of acetic acid was added 1.0 part of 95% sulfuric acid (catalyst). After being heated under reflux for 4 hours, the reaction mixture was washed with water, and unreacted ethylbenzene and water were removed by vacuum distillation to give 33 parts of 5-benzylsalicylic acid-ethylbenzene-formaldehyde co-condensation product. 10 parts of the co-condensation product was converted into its zinc salt in a similar manner as in Synthesis Example 1. There was obtained 11 parts of zinc salt of 5-benzylsalicylic acid-ethylbenzene-formaldehyde co-condensation product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)[C:8]1=[O:28].[F:36][C:37]1[CH:59]=[CH:58][C:40]([CH2:41][N:42]2[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=[C:43]2[NH:51][CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:39][CH:38]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][N:55]2[CH2:54][CH2:53][CH:52]([NH:51][C:43]3[N:42]([CH2:41][C:40]4[CH:39]=[CH:38][C:37]([F:36])=[CH:59][CH:58]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)[CH2:57][CH2:56]2)([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:8]1=[O:28]
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: COc1cc(CN2CCC(CCCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Product: COc1cc(CN2CCC(CCCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 23.4 using 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonyloxypropyl)-2-oxopyrrolidine and (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]([F:42])([F:41])[C:10]1[CH:11]=[C:12]([C:20]([CH3:40])([CH3:39])[C:21]([N:23]([C:25]2[CH:26]=[N:27][C:28](Cl)=[CH:29][C:30]=2[C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[CH3:24])=[O:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>CN(C1C=CN=CC=1)C.COC(C)(C)C>[F:8][C:9]([F:42])([F:41])[C:10]1[CH:11]=[C:12]([C:20]([CH3:40])([CH3:39])[C:21]([N:23]([CH3:24])[C:25]2[CH:26]=[N:27][C:28]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:29][C:30]=2[C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1
Reactant: Cc1ncccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Product: Cc1ncccc1-c1cc(N2CCN(C)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 140 °C

Procedure:
Process variant b) describes the reaction of a compound of formula II-2 with 1-methylpiperazine to produce a compound of formula I-2. A mixture of 2-(3,5-bis-trifluoromethyl-phenyl)-N-(6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-N-methyl-isobutyramide, 1-methylpiperazine and 4-(N,N-dimethylamino)pyridine is heated at about 140° C. over night. After cooling to room temperature, the mixture is diluted with tert-butyl methyl ether and washed with water. The aqueous layer is extracted with tert-butyl methyl ether. The combined organic layers are dried and concentrated to give the compound 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-methyl-6′-(4-methyl-piperazin-1-yl)-[3,4′]bipyridinyl-3′-yl]-isobutyramide of formula I-2.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:31])[CH2:16][N:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O:32]([C@H:40]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:41][CH:42]=[O:43])[Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].S([O-])(O)(=O)=O.[K+]>C1COCC1.CCCCCC>[CH2:24]([N:17]([CH:16]([CH:42]([OH:43])[CH2:41][C@H:40]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:15]([O:14][CH3:13])=[O:31])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCCCCCCCCC[C@H](CC=O)O[Si](C)(C)C(C)(C)C
Reactant: COC(=O)CN(Cc1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCCCCCCCCCC[C@H](CC(O)C(C(=O)OC)N(Cc1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: -75 °C
Yield: 7.9 %

Procedure:
A solution of 0.5 ml of diisopropylamine in 15 ml of THF was treated at 0° C. with 2.0 ml of a solution of 1.6M n-butyllithium in hexane and, after stirring, cooled to -75° C. Then, a solution of 765 mg of N-benzyl-N-phenylglycine methyl ester in 3 ml of THF was added. After stirring a solution of 700 mg of (R)-3-(t-butyl-dimethylsiloxy)tetradecanal (Example Bb)) in 5 ml of THF was added dropwise. After stirring at -75° C. the reaction mixture was poured into aqueous potassium hydrogen sulphate and extracted with ether. The ether phase was dried, concentrated, partitioned between hexane and methanol/water (7:3), the hexane phase was dried and concentrated and the residue was chromatographed on silica gel with pentane/ether (5:1). There were obtained 96.3 mg of methyl (5R)-2-(N-benzylanilino)-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoate, diastereomer A, MS: 540 (M+ ·-C4H9 ·), and 142.8 mg of methyl (5R)-2-(N-benzylanilino)-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoate, diastereomer B, MS: 540 (M+ ·-C4H9 ·), and 313.4 g of a mixture of the above two diastereomers.
Reaction SMILES: Br([O-])(=O)=O.[Na+].[CH3:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1.CC[O:17]CC>C(#N)C.O>[CH3:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:17])=[O:12])=[CH:9][CH:8]=1
Reactant: Cc1ccc(CO)cc1
Reactant: CCOCC
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 40 h
Yield: 96 %

Procedure:
A mixture of Ceiv catalyst from Example 47 (0.08 g), sodium bromate (0.3 g) and 4-methylbenzyl alcohol (0.24 g, 2 mmol) in acetonitrile:water (1:1, 10 ml) was stirred at 80° C. for 40 h under an atmosphere of nitrogen. On cooling ether (70 ml) was added and the catalyst was filtered off. The organic layer was separated and the aqueous phase was extracted with ether (2×50 ml). The combined organic extracts were washed with water (25 ml), dried with anhydrous magnesium sulphate and concentrated to give 4-methylbenzoic acid as a white solid (0.26 g, 96%). M.p. 178° C., lit. 180-182° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Si:58]([O:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]([CH2:73]O)=[N:71][CH:72]=1)([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59]>O1CCCC1>[Si:58]([O:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]([CH2:73][N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])=[N:71][CH:72]=1)([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:59])[CH3:60]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CO)nc1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCc1nc(C)n(Cc2ccc(CO[Si](C)(C)C(C)(C)C)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.4 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.6 g), 1,1′-(azodicarbonyl)dipiperidine (0.48 g), tributylphosphine (0.95 g), [5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]methanol (0.48 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.54 g, 49%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.Cl.Cl.[CH3:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH2:23][CH2:22]2)[CH:18]=[CH:17][N:16]=1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:31]2[CH2:30][CH2:29][N:28]([CH2:27][CH:24]3[CH2:25][CH2:26][N:21]([C:19]4[CH:18]=[CH:17][N:16]=[C:15]([CH3:14])[N:20]=4)[CH2:22][CH2:23]3)[CH2:33][CH2:32]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1nccc(N2CCC(CN3CCNCC3)CC2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nccc(N2CCC(CN3CCN(C(=O)c4ccc(F)cc4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-fluorobenzoyl chloride(238 mg) in methylene chloride (5 ml) was added dropwise over 5 minutes to a mixture of 4-[-1-(2-methylpyrimidin-4-yl)-4-piperidylmethyl]piperazine trihydrochloride (625 mg) and triethylamine (1.04 ml) in dichloromethane (20 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 1-2% methanol in dichloromethane. Filtration from ether gave 1-(4-fluorobenzoyl)-4-[1-(2-methyl-4-pyrimidinyl)-4-piperidylmethyl]piperazine, as a solid (244 mg), mp 127-128° C.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>>[O-:33][N+:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[N:1]([CH2:14][CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[CH:2]=[N:3][C:4]=2[CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(CCCn1cnc2cnc3ccccc3c21)c1ccccc1
Product: O=C(CCCn1cnc2c[n+]([O-])c3ccccc3c21)c1ccccc1

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 4-(1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one (4.08 g, 12.9 mmol) by reaction with m-CPBA (3.20 g, 14.2 mmol) to provide 4-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one followed by reaction with p-toluenesulfonyl chloride (2.71 g, 14.2 mmol) and ammonium hydroxide solution (22 mL) to provide 4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-one) as white needles, mp 209-211° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[C@H:20]12[NH:27][CH2:26][C@H:25]1[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:21]2.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:3]=1[C:4]([N:27]1[C@H:20]2[C@H:25]([CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:21]2)[CH2:26]1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN[C@@H]2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)c3c(F)cccc3-n3nccn3)[C@@H]2C1
Temperature: 50 °C
Reaction time: 15 h
Yield: 64.2 %

Procedure:
To 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (406 mg, 1.5 mmol) in PhCH3 (5 mL) was added SOCl2 (117 μL, 1.6 mmol). The flask was heated with an oil bath to 50° C. for 1 h. To (1S,6R)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate (260 mg, 1.3 mmol) and Na2CO3 (519 mg, 4.9 mmol) in PhCH3 (5 mL) and H2O (5 mL) at 0° C. was added the above solution dropwise. The reaction was allowed to warm slowly to rt and stir for 15 h and extracted with DCM (2×). The combined organics were dried (Na2SO4). Purification via silica gel chromatography (1-7% 2M NH3/MeOH in CH2Cl2) gave 335 mg (68%) of the title compound. MS (ESI) mass calcd. C20H24FN5O3, 401.44; m/z found 346.1 [M−C(CH3)3]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]([O:21]C)=[O:20])[C:5]2[C:6]([CH3:18])=[C:7]([CH2:14][N:15]([CH3:17])[CH3:16])[N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:19]([OH:21])=[O:20])[C:5]2[C:6]([CH3:18])=[C:7]([CH2:14][N:15]([CH3:16])[CH3:17])[N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Cl)cc2c1c(C)c(CN(C)C)n2C(C)C
Agent: Cl
Product: Cc1c(CN(C)C)n(C(C)C)c2cc(Cl)cc(C(=O)O)c12
Temperature: 80 °C
Reaction time: 18 h
Yield: 178.4 %

Procedure:
To methyl 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.44 g, 1.363 mmol) was added 6 N HCl (20 ml, 120 mmol). The reaction was purged with N2, attached a reflux condenser, heated to 80° C., and stirred for 18 hr. LCMS showed that the reaction was complete. The reaction was cooled to RT, diluted with an equal volume of water, washed with EtOAc, and evaporated to dryness under vacuum to give the product 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid hydrochloride salt (0.42 g, 1.216 mmol, 89% yield) as a beige solid. (86% pure by LCMS, contains ˜10% of the des-chloro side product from the previous reaction.) Used as is in the next step. 1H NMR (400 MHz, DMSO-d6) δ=13.19 (br. s., 1H), 10.45 (br. s., 1H), 7.90 (d, J=1.8 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 4.91 (quin, J=6.9 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 2.79 (d, J=4.8 Hz, 6H), 2.34 (s, 3H), 1.58 (d, J=6.8 Hz, 6H). MS(ES)+ m/e 309.2 [M+H]+, 264.1 [M+H]+ −45 (HNMe2).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccc3c(N)nccc3c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2cc(NC3CCCNC3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a degassed solution of 1-amino-6-bromoisoquinolin (554 mg), prepared as described in WO 98/47876 (Akzo Nobel N.V.), 3-aminopiperidine-1-carboxylic acid tert-butyl ester (823 mg), 2-(di-tert-butylphosphino)biphenyl and sodium tert-butoxide (367 mg) in dioxane (10 ml) under argon, was added tris(dibenzylidene-acetone)dipalladium(0). The mixture was further degassed with argon then heated at 120° C. for 90 minutes. The mixture was cooled to room temperature then diluted with methanol. The crude mixture was loaded onto a pre-acidified SCX column and the basic products eluted with 2M ammonia in methanol to give a crude residue (700 mg). The residue was purified by preparative HPLC to give 3-(1-aminoisoquinolin-6-ylamino)piperidin-1-carboxylic acid tert-butyl ester. A mixture of the 3-(1-aminoisoquinolin-6-ylamino)-piperidin-1-carboxylic acid tert-butyl ester in dichloromethane (6 ml) and trifluoroacetic acid (3 ml) were stirred at ambient temperature for 3 h. The mixture was concentrated then purified by preparative HPLC followed by loading onto a pre-acidified SCX column and the free base eluted with 2M ammonia in methanol to give 6-(piperidin-3-ylamino)-isoquinolin-1-ylamine, El-MS: m/z=243.7 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:17]=[CH:16][C:10]([CH2:11][C:12](=[CH2:15])[CH2:13]Cl)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[OH-].[Na+]>CC1C=CC(C)=CC=1>[C:1]1([C:7]2[CH:17]=[CH:16][C:10]([CH2:11][C:12](=[CH2:15])[CH2:13][N:22]3[CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1CCNCC1
Reactant: C=C(CCl)Cc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccc(C)cc1
Product: C=C(Cc1ccc(-c2ccccc2)cc1)CN1CCC(C)CC1

Procedure:
A mixture of 2-[(4-phenyl)benzyl]-2-propenyl chloride (4 g.), formed in a manner analogous to that used in Example 1, and 4-methylpiperidine (3.3 g.) in p-xylene (15 ml.) was refluxed for five hours, cooled and neutralized with 25% aqueous sodium hydroxide (15 ml.). The mixture was extracted with toluene, dried over sodium sulfate and evaporated under reduced pressure to give an oil. The oil was distilled under vacuum and the fraction boiling at 195° C. to 200° C. at a pressure of 0.7 mm Hg. was collected and identified as 1-[2-[(4-phenyl)benzyl]-2-propenyl]-4-methylpiperidine. The compound, obtained in a yield of 3.5 g., solidified after being left at room temperature for a few hours. The solid was characterized by a melting point of 53° C.