Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[C:31]([O:36][CH3:37])[CH:30]=1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][C:31]=3[O:36][CH3:37])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: COc1cc(F)ccc1N
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: COc1cc(F)ccc1Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and 4-fluoro-2-methoxyphenylamine according to procedure A followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=403.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:6]([CH:8]([CH:12]([C:22]([NH2:24])=[O:23])[C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH3:11])[CH:7]=1.[H][H]>C(O)C.[Pd]>[N:25]1([C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=2[CH:8]([CH:12]([C:22]([NH2:24])=[O:23])[C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH3:11])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCCC(c1cc(Cl)ccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Reaction time: 2 h

Procedure:
One gram (2.33 m mol) of 4-[(1-(5-chloro-2-piperidinophenyl)-1-butyl)-aminocarbonylmethyl]-benzoic acid in 40 ml of absolute ethanol was hydrogenated on 0.5 gm of 10% palladium/charcoal at 50° C. and under 5 bar of hydrogen. After two hours, the catalyst was filtered off over kieselguhr, and the filtrate was concentrated by evaporation in vacuo. The evaporation residue was distributed at pH 6 between water and ethyl acetate. The organic extract was washed with water, dried, filtered, and evaporated in vacuo.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][NH2:8])[C:4]([OH:6])=[O:5].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)=O)=O)=[CH:12][CH:11]=1>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[N:2][C:18]=2[C:20]2[CH:21]=[CH:22][C:23]([Br:26])=[CH:24][CH:25]=2)=[CH:14][CH:15]=1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: NCC(N)C(=O)O
Agent: Cl
Product: O=C(O)c1cnc(-c2ccc(Br)cc2)c(-c2ccc(Br)cc2)n1

Procedure:
The title compound was prepared essentially as described in Preparation A step (a), using monohydrochloride of 2,3-diaminopropionic acid (600 mg, 4.26 mmol) and 4,4′-dibromobenzil (1.745 g, 4.26 mmol, 90%) as starting materials. The reaction mixture was refluxed for 2 hours and air was bubbled through for 1 hour. Hydrochloric acid (aq, 2 M) was added until pH 2. The mixture was evaporated under reduced pressure and the residue was dissolved in water. The solution was extracted with diethyl ether, the combined diethyl ether phases were dried (MgSO4), filtered and evaporated under reduced pressure. The crude product (500 mg, 27%) was used in steps described below without further purification. MS m/z 435, 437, 439 (M+H)+.
Reaction SMILES: CC1C=C(C)C(C)=CC=1NCCC#N.S.[CH2:16]([C:18]1[CH:29]=[C:28]([CH2:30]O)[C:27]([CH2:32]O)=[CH:26][C:19]=1[NH:20][CH2:21][CH2:22][C:23]([NH2:25])=[S:24])O>CN(CCO)C>[CH3:16][C:18]1[CH:29]=[C:28]([CH3:30])[C:27]([CH3:32])=[CH:26][C:19]=1[NH:20][CH2:21][CH2:22][C:23]([NH2:25])=[S:24]
Reactant: NC(=S)CCNc1cc(CO)c(CO)cc1CO
Agent: CN(C)CCO
Agent: Cc1cc(C)c(NCCC#N)cc1C
Agent: S
Product: Cc1cc(C)c(NCCC(N)=S)cc1C
Reaction time: 72 h

Procedure:
To a cold solution of 3-(2,4,5-trimethylanilino)propionitrile (18.9 g.) in dimethylaminoethanol (40 g.) is added hydrogen sulfide (3.5 g.). After three days at room temperature, the mixture is poured on ice and the resulting solid is collected by filtration and recrystallized from benzene to afford 14 g. of 3-(2,4,5-trimethylolanilino)thiopropionamide; m. p. 109.5°-111° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[N:10]1([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=3)[N:21]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:13]2[CH2:12][CH2:11][N:10]([C:16]3[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C:25]([F:26])([F:27])[F:28])=[N:23][N:24]=4)[N:21]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccc(Br)n1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc(Br)n4)CC3)nn12
Yield: 66 %

Procedure:
A mixture of 6-bromopyridine-2-carboxaldehyde and 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 6-[4-[(6-bromopyridin-2-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 66% yield.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:8]=1)=O.[Cl:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34]N)=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([N:34]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=5)[C:17]#[N:18])[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C#N)c2)ccc1=O
Reactant: NNc1ccnc2cc(Cl)ccc12
Product: N#Cc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4cc(Cl)ccc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-benzonitrile (A-19) and (7-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=425.1 (M+H)+
Reaction SMILES: CO[C:3](=[O:15])[NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=2[N:9]=1.[N:16]1([CH2:22][CH2:23][NH2:24])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CN1CCCC1=O>[OH:14][C:12]1[CH:11]=[CH:10][C:8]2[N:9]=[C:5]([NH:4][C:3]([NH:24][CH2:23][CH2:22][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[S:6][C:7]=2[CH:13]=1
Reactant: COC(=O)Nc1nc2ccc(O)cc2s1
Reactant: NCCN1CCOCC1
Solvent: CN1CCCC1=O
Product: O=C(NCCN1CCOCC1)Nc1nc2ccc(O)cc2s1
Reaction time: 0.42 h
Yield: 93.9 %

Procedure:
In a 10 cm3 tube, 200 mg of methyl(6-hydroxy-1,3-benzothiazol-2-yl)carbamate are suspended in 6 cm3 of 1-methyl-pyrrolidin-2-one, and 580 mg of 2-morpholin-4-ylethylamine are added. After closing, the tube is placed in the microwave oven at a temperature in the region of 150° C. for about 25 minutes. After concentrating to dryness under reduced pressure, the residue obtained is purified by flash chromatography on a column of silica [eluent: dichloromethane/methanol (95/5 by volume)]. 270 mg of 1-(6-hydroxy-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea are thus obtained in the form of a resin, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl-].[Al+3].[Cl-].[Cl-].[C:19]1([C:25]([CH:27]=[O:28])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(=S)=S>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH:27]([OH:28])[C:25](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=CC(=O)c1ccccc1
Reactant: CCCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCCCCCc1ccc(C(O)C(=O)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
57.0 g (0.30 mole) of n-octylbenzene are dissolved in 800 ml of carbon disulfide, the solution is cooled to 0° C., 66.5 g (0.50 mole) of aluminum chloride are added, and a solution of 40.0 g (0.30 mole) of phenylglyoxal and 50 ml of carbon disulfide are added dropwise at from 5° to 10° C., while stirring vigorously. The yellow to orange reaction mixture is stirred for a further 15 hours without being cooled, after which it is poured carefully onto 1 l of semiconcentrated ice-cold hydrochloric acid, and the mixture is stirred thoroughly. The phases are separated, the organic phase is extracted by shaking with 300 ml of water, the aqueous phases are extracted with 300 ml of methylene chloride, and the combined organic phases are dried over sodium sulfate. The solution is filtered and the solvent is distilled off to give 75.0 g (=77% of theory) of crude product which has a melting range of 85°-89° C. and is 95% pure according to gas chromatography. Recrystallization from methanol gives analytically pure 4'-n-octylbenzoin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[NH:13][CH3:14].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[S:32](Cl)(=[O:34])=[O:33]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:32]([C:25]1[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=1[O:23][CH3:22])(=[O:34])=[O:33])[C:6](=[O:12])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[NH:13][CH3:14]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CNC1(c2ccccc2Cl)C(=O)Nc2c(F)cc(Cl)cc21
Product: CNC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2c(F)cc(Cl)cc21
Yield: 20.5 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.25 g of 5-chloro-3-(2-chlorophenyl)-7-fluoro-1,3-dihydro-3-(methylamino)indol-2-one and 0.165 g of 2,4-dimethoxybenzenesulfonyl chloride. 0.075 g of the expected product is obtained after crystallization and recrystallization from a DCM/iso ether mixture. M.p.=183°-185° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+:13]([CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])#[C-:14]>>[CH3:1][C:2]1[C:3]2[N:4]([CH:14]=[N:13][C:15]=2[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: [C-]#[N+]CC(=O)OC(C)C
Reactant: Cc1nc2ccccc2nc1O
Product: Cc1nc2ccccc2n2cnc(C(=O)OC(C)C)c12

Procedure:
M.p. 182°-183° C., from 3-methyl-2-quinoxalinol and isopropyl isocyanoacetate. (Compound 5)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3cccnc3)c2)OC1(C)C
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1-c1cccnc1
Yield: 28.3 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (200 mg, 0.86 mmol) was coupled to 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine (349 mg, 1.2 mmol) as described in Example 3 part g), affording 5-(4-fluoro-3-pyridin-3-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (90 mg, 28%). δH (360 MHz, CDCl3) 7.41-7.46 (2H, m), 7.50-7.55 (1H, m), 7.57-7.61 (2H, m), 7.85 (1H, d, J 8.4), 7.91-7.96 (1H, m), 8.55 (1H, d, J 8.8), 8.68 (1H, dd, J 1.4 and 4.9), 8.86 (1H, s), 9.30 (1H, d, J 4.6). m/z (ES+) 370 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(P(CCCC)CCCC)CCC.[C:30]([O:34][CH3:35])(=[O:33])[C:31]#[CH:32]>C1COCC1>[CH3:35][O:34][C:30](=[O:33])[CH:31]=[CH:32][O:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:16])[CH3:8])[CH2:14][CH2:13]1
Reactant: C#CC(=O)OC
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)C=CO[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
27 g (117.7 mmol) of trans-(4-hydroxy-cyclohexyl)-methyl-carbamic acid tert-butyl ester were dissolved in 500 mL of THF and were treated with 6.8 mL of tri-n-butylphosphine and 10.5 mL (117.7 mmol) of methyl propiolate at 0° C. for 2d. Additional 2.1 mL (23 mmol, 0.2 eq) of methyl propiolate and 3.4 mL (11.8 mmol, 0.1 eq) of tri-n-butylphosphine were added. After stirring for 1 h at RT, the solution was evaporated and the crude product was purified by flash chromatography with n-heptane:EtOAc 3:1. Trituration with n-heptane yielded 26.7 g (73%) of trans-3-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyloxy]-acrylic acid methyl ester as white solid, MS: 314 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:10]([OH:12])=O)[S:8][CH:9]=1)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]([NH2:37])=[O:36])[C:30](=[O:38])[CH2:29]2.C(O)(=O)C>CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]([NH2:37])=[O:36])[C:30](=[O:38])[CH:29]2[C:10](=[O:12])[C:7]1[S:8][CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1
Reactant: COC(=O)c1csc(C(=O)O)c1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)c1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1
Yield: 67.9 %

Procedure:
The title compound was prepared according to the procedure of Example 55. To a solution of 1.50 g (8.06 mmoles) of 4-methoxycarbonyl-2-thiophenecarboxylic acid (prepared as described in Example 9) in 15 ml of N,N-dimethylformamide was added 1.57 g (9.67 mmoles) of 1,1′-carbonyldiimidazole. After two hours the reaction contents were slowly added to 1.54 g (7.32 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 2.66 g (21.75 mmoles) of 4-(N,N-dimethylamino)pyridine in N,N-dimethylformamide. Acidic workup of this reaction followed by filtration, drying and trituration with hot acetic acid furnished 1.88 g (4.97 mmoles, 68% yield) of title compound as a yellow solid, m.p. 244-246° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]([NH:16][C:17]2[N:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[C:25](OCC)=[O:26])=[N:21][CH:22]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C[O-].[Na+].Cl>CO>[CH2:1]([O:8][N:9]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]([NH:16][C:17]2[N:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[C:25]([NH:31][OH:32])=[O:26])=[N:21][CH:22]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCC(=O)N(OCc3ccccc3)C2)cn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(/C=C/c1cnc(N[C@@H]2CCC(=O)N(OCc3ccccc3)C2)cn1)NO
Temperature: 0 °C
Reaction time: 4 h
Yield: 7.8 %

Procedure:
To a solution of ethyl (2E)-3-(5-{[(3R)-1-(benzyloxy)-6-oxo-3-piperidinyl]amino}-2-pyrazinyl)acrylate (200 mg, 0.50 mmol) in methanol (5 mL) was added hydroxylamine hydrochloride (175 mg, 2.52 mmol) at ambient temperature under nitrogen. After cooling, 1M sodium methanolate in methanol (5 mL) was added dropwise to the mixture over 1 h, the reaction mixture was stirred at 0° C. for 2 hrs and at ambient temperature for 4 hrs. The reaction mixture was adjusted to PH 6.0 with 1 mol/L hydrochloric acid and evaporated in vacuo. The residue was dissolved in ethanol and the precipitate was removed by filtration. The solvent was evaporated in vacuo. The residue was purified by preparative HPLC (CH3CN, 20% NH4HCO3/30%˜90%, gradient) to give (2E)-3-(5-{[(3R)-1-(benzyloxy)-6-oxo-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide (15 mg, 8%) as a powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][C@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)([O-])=O.CCO>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][C@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccncc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccncc2N)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.3 %

Procedure:
Pd on C, (10%, wet, Degussa) (1 g, 0.9397 mmol) was added to a stirred solution of tert-butyl (3S)-3-[(3-nitro-4-pyridyl)oxy]piperidine-1-carboxylate (2.65 g, 8.196 mmol) in EtOAc (30 mL)/EtOH (15 mL). The reaction was placed under an atmosphere of hydrogen and stirred at ambient temperature for 16 hours. The catalyst was removed by filtration through a pad of celite and the filtrate concentrated in vacuo to give the sub-title compound as an off-white solid (2.46 g, >100% Yield). MS (2ES+) 587.3.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1>[C:33]([CH2:35][C:36]([N:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)=[O:37])#[N:34]
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Reactant: N#CCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
The mixture of 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (90 mg, 0.19 mmol), cyanoacetic acid (81 mg, 0.95 mmol), DIEA (330 μL, 1.9 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (360 mg, 0.95 mmol). The mixture was stirred at RT for overnight. To it was added TFA (0.5 mL). The mixture was subjected to reverse phase preparative HPLC to isolate the title compound (81 mg). MS found for C27H26F2N6O2 as (M+H)+ 505.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.05 (1H, s), 7.24 (2H, d, J=8.4 Hz), 7.15 (1H, m), 7.06 (1H, m), 7.04-6.97 (3H, m), 5.71 (1H, s), 4.56 (1H, m), 4.46 (2H, s), 3.91-3.77 (3H, m), 3.16 (1H, m), 2.83-2.69 (2H, m), 1.84 (2H, m), 1.60 (2H, m) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:16][S:15][C:14](=[O:17])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]>>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][CH2:19][N:13]1[N:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:16][S:15][C:14]1=[O:17]
Reactant: CN(C)CCCCl
Reactant: COc1ccc(C2=NNC(=O)SC2)cc1OC
Product: COc1ccc(C2=NN(CCCN(C)C)C(=O)SC2)cc1OC

Procedure:
In analogy to Example 1, by reacting 5-(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one with 3-chloropropyldimethylamine, 3-dimethylaminopropyl-5(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one is obtained; m.p. 195°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14]COC)[C@H:10]([CH2:18][O:19][C:20]2[N:21]=[N:22][C:23]([CH2:39][CH2:40][CH2:41][CH3:42])=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:28][CH:27]=3)[CH:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.C(Cl)Cl.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:18][O:19][C:20]2[N:21]=[N:22][C:23]([CH2:39][CH2:40][CH2:41][CH3:42])=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:30][CH:31]=3)[CH:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2OCOC)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (1.59 mmol, 0.93 g) in a mixture of methanol (2 mL) and DCM (0.5 mL) was added 4 N HCl in dioxane (5 mL) at room temperature and continued stirring for 1 h. The progress of the reaction was monitored by LCMS analysis of an aliquot of the reaction mixture. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL) and added 2 N sodium hydroxide solution (2 mL) followed by di-t-butyl dicarbonate (1 g) and the resultant reaction mixture was stirred at room temperature for 2 h. The organic layer was separated and the aqueous layer was extracted with DCM (5 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography by eluting with 50% ethyl acetate in hexanes to afford (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-])=O)=[C:9]([CH:13]=1)[C:10]([NH2:12])=[O:11]>CCO.[Pd]>[NH2:14][C:8]1[CH:7]=[CH:6][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=2[F:1])=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11]
Reactant: NC(=O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1cc(Oc2ccc(F)cc2F)ccc1N
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To compound (1C) (27 g, 0.09 mol) in EtOH was added palladium on activated carbon (2.7 g), and the mixture was stirred under hydrogen for 18 h. The suspension was filtered through celite and the filtrate concentrated and dried in vacuo to yield 23 g of 2-amino-5-(2,4-difluoro-phenoxy)-benzamide (1D).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1.[CH:35]1(I)[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH:35]1([O:1][C:2]2[CH:10]=[C:9]3[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]4[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=4)=[O:22])=[C:7]([CH:18]([CH3:19])[CH3:20])[N:8]3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:4][CH:3]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)c1c(C(=O)NCc2ccc(C(F)(F)F)nc2)c2ccc(O)cc2n1Cc1ccccn1
Reactant: IC1CCCC1
Product: CC(C)c1c(C(=O)NCc2ccc(C(F)(F)F)nc2)c2ccc(OC3CCCC3)cc2n1Cc1ccccn1

Procedure:
The title compound was prepared from 6-hydroxy-2-isopropyl-1-(pyridin-2-ylmethyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-indole-3-carboxamide (Compound 141) and cyclopentyl iodide by General Procedure N.