Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5]([O:7]CC)=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21].Cl>COCCOC>[F:11][C:4]([F:3])([F:10])[C:5](=[O:7])[CH2:21][C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH3:12])=[O:22]
Reactant: COc1ccccc1C(C)=O
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1C(=O)CC(=O)C(F)(F)F
Temperature: 160 °C

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 202 mg, 8.0 mmol) in 1,2-dimethoxyethane (4 mL) was added drop-wise ethyl trifluoroacetate (954 μL, 8.0 mmol) followed by 1-(2-methoxyphenyl)ethanone (552 μL, 4.0 mmol) and the reaction was heated to 160° C. in a microwave for 15 minutes. Aqueous hydrochloric acid (1 N, 20 mL) was added and the mixture was extracted with tert-butyl methyl ether (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 10% tert-butyl methyl ether in heptanes) afforded the title compound as a red solid. Yield: 933 mg, 3.79 mmol, 95%. GCMS m/z 246 (M+). 1H NMR (400 MHz, CDCl3) δ 3.96 (s, 3H), 6.99 (s, 1H), 7.02 (br d, J=8.5 Hz, 1H), 7.08 (ddd, J=8, 7, 1.0 Hz, 1H), 7.55 (ddd, J=8.4, 7.4, 1.8 Hz, 1H), 7.99 (dd, J=7.9, 1.9 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][C:4]([CH3:10])=[N:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[F:34])[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[N:21]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:28]1([C:26]([NH:25][C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]4[CH:31]=[CH:32][C:33]([F:34])=[C:12]([NH:11][C:7]([CH:6]5[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH2:5]5)=[O:9])[CH:13]=4)=[N:21][N:20]3[CH:22]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: CC1=NN(C)C(C(=O)O)C1
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: CC1=NN(C)C(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)C1
Yield: 63.3 %

Procedure:
In the same manner as in Example 278 and using 1,3-dimethyl-4,5-dihydro-1H-pyrazole-5-carboxylic acid (170 mg, 1.2 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (280 mg, 0.84 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (450 mg, 1.2 mmol), N,N-diisopropylethylamine (330 mg, 2.5 mmol) and N,N-dimethylformamide (7 mL) as starting materials, the title compound (240 mg, 63%) was obtained as a white solid.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=4)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Nc1cccc(O)c1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a solution of the (4-adamantan-1-yl-phenoxy)-acetic acid (85.9 mg, 0.3 mmol) and 3-amino-phenol (65.5 mg, 0.6 mmol) in DMF (5.0 mL) were added benzotriazol-1-yl-N-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (312.2 mg, 0.6 mmol), and N,N-diisopropylethylamine (DIPEA) (0.11 ml, 0.6 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. Purification by silica gel column chromatography (n-Hexane:EtOAc:MeOH=15:3:1) gave 2-(4-Adamantan-1-yl-phenoxy)-N-(3-hydroxyl-phenyl)acetamide as a white solid (67.6 mg, 59.7% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])=[C:8]([C:14]2[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=2)[CH:9]=1)=[O:30]
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccccc1Cl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccccc2Cl)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (51.4 mg, 0.187 mmol) in CH2Cl, (2 mL) was added 2-chlorophenyl isocyanate (0.25 μL, 0.207 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 140 as a colorless solid (76.5 mg, 95%). LCMS m/z (%)=428 (M+H35Cl, 100), 430 (M+H37Cl, 37) 1H NMR (400 MHz, DMSO-d6) δ: 9.36 (bs, 1H), 8.25 (bs, 1H), 8.15 (dd, J=8.33, 1.48 Hz, 1H), 7.48-7.42 (m, 3H), 7.40 (d, J=2.70 Hz, 1H), 7.31-7.26 (m, 1H), 7.11 (d, J=8.92 Hz, 1H), 7.05-6.99 (m, 1H), 6.25 (d, J=1.84 Hz, 1H), 3.98 (t, J=6.36 Hz, 2H), 3.66 (s, 3H), 2.19 (t, J=7.04 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].Cl.[NH2:14][OH:15].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5](=[N:14][OH:15])[NH2:6]
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(C(N)=NO)ccc1[N+](=O)[O-]

Procedure:
To a solution of 3-methyl-4-nitrobenzonitrile (5 g) in ethanol (100 ml) at room temperature was added hydroxylamine hydrochloride (2.25 g) followed by triethylamine (4.5 ml). The mixture was heated under reflux for 2.5 hours. On cooling the mixture was evaporated to a third of its original volume and poured on to water (200 ml). The mixture was filtered to give the title product as a solid, m.p. 127-9° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:15])=[O:14])=[CH:9][C:8]=1[N+:16]([O-])=O>CO>[NH2:16][C:8]1[CH:9]=[C:10]([C:13](=[O:14])[CH3:15])[CH:11]=[CH:12][C:7]=1[CH3:6]
Reactant: CC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: CC(=O)c1ccc(C)c(N)c1
Temperature: 60 °C

Procedure:
Tin(II)dichloride dihydrate (37 g, 168 mmol) was added to 4-methyl-3-nitroacetophenone (10 g, 56 mmol) dissolved in methanol (350 mL). The reaction mixture was heated at 60° C. for 18 h, concentrated, and dried under high vacuum to give to 1-(3-amino-4-methylphenyl)ethanone which contained tin salts. LC (Cond.-J1): 0.73 min; LC/MS: Anal. Calcd. for [M+H]+ C9H11NO: 150.08; found: 150. The material was used without purification. HATU (10.6 g, 28 mmol) was added in one portion to a stirred solution of 1-(3-amino-4-methylphenyl)ethanone (4.1 g, 28 mmol), N-Boc-L-proline (6 g, 28 mmol), and Hunig's base (25 mL) in DMF (225 mL) and the reaction mixture was stirred 18 h. The solvent was removed in vacuo and the residue was taken up in ethyl acetate/methanol (1:1) and applied to a flash SiO2 column. A step elution by gradient 20%; 50%; 75%; 100% B (total elution vol 1500 mL); A=hexanes; B=ethyl acetate; and a final elution with; 10% methanol/ethyl acetate was conducted to give J.38, 4.4 g (46%). 1H NMR (300 MHz, DMSO-d6) δ: 9.51/9.45 (s, 1H), 7.95-7.92 (m, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.37 (d, J=7.7 Hz, 1H), 4.33-4.29 (m, 1H), 3.48-3.29 (m, 2H), 2.50 (s, 3H), 2.26 (s, 3H), 1.98-1.80 (m, 4H), 1.41/1.36 (m, 9H). LC (Cond.-J1): 1.70 min; LRMS: Anal. Calcd. for [M+H]+ C19H27N2O4: 347.20; found 347.41.
Reaction SMILES: [CH3:1][C:2]([CH3:50])([CH3:49])[C:3]([O:5][CH:6]([NH2:48])[O:7][C:8](=[O:47])[N:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[C:13]([S:25](=[O:46])(=[O:45])[NH:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][C:30]=2[O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:12]=1)=[O:4]>O1CCCC1.[Pd]>[CH3:50][C:2]([CH3:1])([CH3:49])[C:3]([O:5][CH:6]([NH2:48])[O:7][C:8](=[O:47])[N:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([S:25](=[O:45])(=[O:46])[NH:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][C:30]=2[O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:12]=1)=[O:4]
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C=NC(=O)OC(N)OC(=O)C(C)(C)C)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C=NC(=O)OC(N)OC(=O)C(C)(C)C)ccc1O
Temperature: 30 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a stirred solution of 99 mg of amino-[4-benzyloxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]ethyl]-sulfamoyl]phenyl]methylenecarbamoyloxymethyl 2,2-dimethyl-propionate in 3 mL of tetrahydrofuran was added 9.2 mg of 10% palladium on carbon under ice-cooling, and the mixture was stirred under a hydrogen atmosphere at 30° C. for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 75 mg of amino-[4-hydroxy-3-[[2-[4-isopropyl-2-(ethoxycarbonylmethoxy)phenyl]ethyl]sulfamoyl]-phenyl]methylenecarbamoyloxymethyl 2,2-dimethylpropionate.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:36])=[CH:29][C:25]=1[C:26]([OH:28])=O.[Br:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:59])[C:50]2[CH:55]=[C:54]([NH2:56])[CH:53]=[CH:52][C:51]=2[O:57][CH3:58])=[CH:44][CH:43]=1>CN(C=O)C>[CH3:58][O:57][C:51]1[CH:52]=[CH:53][C:54]([NH:56][C:26](=[O:28])[C:25]2[CH:29]=[C:30]([CH2:33][NH:34][C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:36])[CH:31]=[CH:32][C:24]=2[Cl:23])=[CH:55][C:50]=1[C:49]([NH:48][C:45]1[CH:46]=[CH:47][C:42]([Br:41])=[CH:43][CH:44]=1)=[O:59]
Reactant: COc1ccc(N)cc1C(=O)Nc1ccc(Br)cc1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cc(CNC(=O)C(C)(C)C)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Reaction time: 0.08 h

Procedure:
TBTU (40 mg, 0.125 mmol) in 0.25 mL DMF was added to 2-chloro-5-(tert-butylcarbonylamino)methyl-benzoic acid (34 mg, 0.125 mmol), followed by 50 μL TEA and the mixture was stirred for 5 min. Then N-(4-bromophenyl)-2-methoxy-5-amino-benzoic acid amide in 0.25 mL DMF was added and it was stirred overnight. The crude mixture was filtered through aluminium oxide and the solid phase was washed 4× with 1 mL DMF/MeOH 9:1. The combined organic phase was concentrated i.vac. dissolved in Acetonitrile/HCOOH, filtered and dried via lyophilisation to furnish the title compound.
Reaction SMILES: [N:1]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]=12.[F:13][C:14]1[CH:36]=[CH:35][C:17]([C:18]([C:20]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24][N:23]([CH2:26][CH2:27]O)[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([C:20]2([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:5]3[C:4](=[O:8])[N:3]4[CH2:9][CH2:10][CH2:11][CH2:12][C:2]4=[N:1][C:6]3=[O:7])[CH2:22][CH2:21]2)=[O:19])=[CH:35][CH:36]=1
Reactant: O=C(c1ccc(F)cc1)C1(c2ccccc2)CCN(CCO)CC1
Reactant: O=c1nc2n(c(=O)[nH]1)CCCC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1(c2ccccc2)CCN(CCn2c(=O)nc3n(c2=O)CCCC3)CC1

Procedure:
In the manner described in Example 1-2), 6,7,8,9-tetrahydro-2H-pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione obtained in Example 1-1) and 4-(4-fluorobenzoyl)-4-phenyl-1-(2-hydroxyethyl)piperidine were condensed in N,N-dimethylformamide in the presence of triphenylphosphine and diethyl azodicarboxylate to obtain the entitled compound as an oily substance.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]4[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][C:32]=4[F:41])=[C:24]3[CH:23]=[N:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C.CO.ClCCl>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:41][C:32]1[CH:33]=[C:34]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=[CH:36][C:31]=1[O:30][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:21]([CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)[N:22]=[CH:23][C:24]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)c(F)c1
Yield: 90 %

Procedure:
A 20% solution of trifluoroacetic acid in dichloromethane (12 mL) was added to a solution of 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 60; 520 mg, 1.06 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature until TLC (6% methanol/dichloromethane) showed that all of the starting material had reacted. Volatiles were evaporated. Ether (5 mL) was added, and the solvents were evaporated again. The resulting white semi-solid was held under vacuum, then triturated with ether and held under vacuum again to give 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine trifluoroacetate salt (479 mg, 90%) as a white powder. A portion of this material (200 mg, 0.4 mmol) was taken up in anhydrous dichloromethane (5 mL) with diisopropylethylamine (210 μL, 1.2 mmol) and the resulting suspension was cooled to about 0° C. Ethyl chloroformate (57 μL, 0.6 mmol) was added, and the reaction mixture was stirred at 0° C. for 2 min and then at room temperature for 30 min. Water (5 mL) was added, and the layers were separated. The organic layer was washed with brine, dried (sodium sulfate), filtered, evaporated, and purified on a 4 g Isco column, eluting with 0-10% methanol/dichloromethane, to give 4-[4-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid ethyl ester (140 mg, 77%). 1H NMR (300 MHz, DMSO-d6) δ 1.19 (t, 3H, J=7.1 Hz), 1.95-2.06 (m, 4H), 3.05-3.14 (m, 2H), 4.02-4.16 (m, 4H), 4.98-5.07 (m, 1H), 7.82 (dd, 1H, J=7.1, 8.5 Hz), 7.89 (dd, 1H, J=1.8, 8.8 Hz), 8.06 (dd, 1H, J=2.0, 9.5 Hz), 8.50 (s, 1H), 8.56 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH2:25][CH2:26][CH2:27][O:28]CC2C=CC=CC=2)=[C:23]([C:36]([NH:38][CH:39]2[CH2:41][CH2:40]2)=[O:37])[N:22]=[N:21]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH:39]1([NH:38][C:36]([C:23]2[N:22]=[N:21][N:20]([C:10]3[CH:11]=[CH:12][C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=3[OH:8])[C:24]=2[CH2:25][CH2:26][CH2:27][OH:28])=[O:37])[CH2:41][CH2:40]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCO)c(O)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
To a solution of 1-{2-(benzyloxy)-4-[(ethylamino)carbonyl]phenyl}-5-[3-(benzyloxy)propyl]-N-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (1.17 g) obtained in Example 335b) in ethanol (50 ml) was added 10% Pd(OH)2/C (120 mg), and the mixture was stirred under 5 atm at 80° C. for 2 hr. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column (ethyl acetate to ethyl acetate/methanol=5/1) to give the title compound as a white powder (520 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4([C:31]#[N:32])[CH2:30][CH2:29]4)[CH:23]=3)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[N:5]=2.Cl.Cl.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44](O)=[O:45])[CH2:39][CH2:38]1.Cl.C(N=C=NCCCN(C)C)C.CO>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:31]([C:28]1([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:6]3[N:5]=[C:4]4[S:3][C:2]([NH:1][C:44](=[O:45])[CH2:43][N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)=[N:10][C:9]4=[CH:8][CH:7]=3)[CH:13]=2)=[O:33])[CH2:30][CH2:29]1)#[N:32]
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)CN3CCN(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (457 mg, 998 μmol) produced in Example C1(vii) in pyridine (10 mL) were added (4-methylpiperazin-1-yl)acetic acid dihydrochloride (474 mg, 2.05 mmol), N,N-dimethylpyridine-4-amine (51.3 mg, 420 μmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (403 mg, 2.10 mmol), and the mixture was stirred at room temperature for 2 hr. Methanol (10 mL) was added to the reaction solution, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and tetrahydrofuran (10 mL), and the solution was washed with 0.1N hydrochloric acid (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL). The earlier 0.1N hydrochloric acid washing solution was neutralized (pH 7.0) with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate (50 mL×2). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give the title compound (419 mg, 70%) as colorless crystals.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH:12]([CH2:17][CH3:18])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6].C([BH3-])#N.[Na+]>CO>[C:5]([N:10]1[CH2:15][CH2:14][CH:13]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:12]([CH2:17][CH3:18])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6]
Reactant: NC1CC1
Reactant: CCOC(=O)N1CCC(=O)C(CC)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(NC2CC2)C(CC)C1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Cyclopropylamine (14.25 g, 250 mmol) was added to the stirred solution of 1-carbethoxy-3-ethyl-4-piperidone (10 g, 50 mmol) in methanol (100 ml) and stirring was continued for 12 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (3.9 g, 62 mmol) was added to it. Cooling was removed after 10 min. and stirring was continued for 12 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to afford crude 1-carbethoxy-4-cyclopropylamino-3-ethyl piperidine. The obtained crude 1-carbethoxy-4-cyclopropylamino-3-ethylpiperidine was suspended in 7 M NaOH solution (30 ml), stirred at 130° C. for 160 hr, cooled and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to afford 4-cyclopropylamino-3-ethyl-piperidine. Yield 5.7 g (67%), C10H20N2, m/z 169, (M+1).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:11]O>C(O)(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:11]
Reactant: FC(F)(F)c1ccccn1
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1ccccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 2-trifluoromethyl pyridine (5 g, 34 mmol) in acetic acid (25 mL) is added 33% of aqueous H2O2 (20 mL) at room temperature. The reaction mixture is allowed to stir for 12 h at 70° C. After complete consumption of starting material the reaction mixture is concentrated under reduced pressure. The residue is dissolved in chloroform (250 mL) and pH is adjusted to 7 with K2CO3 (20 g approx). Resulting solid is filtered through glass sintered funnel and washed with chloroform. Filtrate is concentrated under reduced pressure to give 2-trifluoromethyl-pyridine 1-oxide as syrupy liquid (4.3 g).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:21][NH2:22]>C(O)CCC>[C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:21][NH2:22])=[O:2])[CH2:6][CH2:7]1)#[N:19]
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cccc(C#N)c2)CC1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: N#Cc1cccc(O[C@H]2CC[C@H](C(=O)NN)CC2)c1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(3-cyano-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.277 g, 1.07 mmol) and hydrazine hydrate (0.104 ml, 2.14 mmol) in n-butanol (0.5 ml) was heated at 120° C. for 18 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The layers were separated and the aqueous layer was extracted with a 50-ml portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated in methanol (7 ml). The solids were removed by filtration and the filtrate was concentrated in vacuo to give the crude title compound (0.15 g, 55%) as light red solid, which was used in the next step without further purification. MS m/e: 260 (M+H+)
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH2:24]([N:13]1[CH2:14][CH2:15][CH:10]([C:8](=[O:9])[C:7]2[CH:16]=[CH:17][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)c1ccc(C(=O)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(C(=O)C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66 %

Procedure:
To a solution of 4-(4-isopropylbenzoyl)piperidine in N,N-dimethylformamide (100 mL), potassium carbonate (9.60 g, 69.5 mmol) and benzyl bromide (8.50 g, 71.5 mmol) were added, and the resulting mixture was stirred for 20 hours at room temperature. The mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from hexane to obtain the title compound (13.53 g, yield 66%).