Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:24])[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.[OH-].[Na+].C(O)(=O)C.O>CO>[NH2:1][C:2]1[N:3]=[C:4]([OH:24])[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: COC(=O)c1ccc(CCc2cnc3nc(N)nc(O)c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(O)c2cc(CCc3ccc(C(=O)O)cc3)cnc2n1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 0.46 g of methyl 4-[2-(2-amino-4-hydroxypyrido[2,3,d]pyrimidin-6-yl)ethyl]benzoate and 30 mL of 1N sodium hydroxide is stirred at room temperature for 36 hours and then acidified with glacial acetic acid. The resulting suspension is centrifuged with fresh water several times and then combined with methanol. The water is removed azeotropically under reduced pressure to yield 4-[2-(2-amino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoic acid, m.p. >300° C.; IR (KBr) ν max 3220, 2855, 1680, 1607, 1483, 1398, 1253, 1179, 1016, and 812 cm-1 ; 1H NMR (dTFA, d6DMSO) delta 8.38 (s, 1H (7)-H), 8.02 (s, 1H, (5)-H), 7.62 (d, J=8.0 Hz, 2H, Ar), 6.87 (s, 1H, (3)-H), 6.82 (d, J=8.0 Hz, 2H, Ar), 2.79 (m, 2H, (6)-CH2 --), 2.70 (m, 2H, benzyl).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7](O)=O)=[N:3]1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[F:32][C:33]1[CH:58]=[CH:57][CH:56]=[CH:55][C:34]=1[O:35][C:36]1[CH:37]=[C:38]([NH2:54])[C:39]([NH2:53])=[CH:40][C:41]=1[O:42][C:43]1[CH:44]=[N:45][C:46]([S:49]([CH3:52])(=[O:51])=[O:50])=[CH:47][CH:48]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C.CN(C)C=O>[F:32][C:33]1[CH:58]=[CH:57][CH:56]=[CH:55][C:34]=1[O:35][C:36]1[C:41]([O:42][C:43]2[CH:44]=[N:45][C:46]([S:49]([CH3:52])(=[O:50])=[O:51])=[CH:47][CH:48]=2)=[CH:40][C:39]2[NH:53][C:7]([C:4]3[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=3)=[N:54][C:38]=2[CH:37]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2F)cn1
Reactant: Cn1ccc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1ccc(-c2nc3cc(Oc4ccccc4F)c(Oc4ccc(S(C)(=O)=O)nc4)cc3[nH]2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.3 mg of 1-methyl-1H-pyrazole-3-carboxylic acid, 6.0 mg of hydroxybenzotriazole and 8.5 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added to a dimethylformamide (0.5 ml) solution of 15 mg of 4-(2-fluoro-phenoxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 200, and the reaction liquid was stirred overnight at room temperature. The reaction liquid was diluted with chloroform, washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and 3 mg of p-toluenesulfonic acid was added to the resulting residue, and the reaction liquid was stirred at 120° C. for 2 hours. The reaction liquid was diluted with ethyl acetate, washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=15/1) to obtain the entitled compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:31][CH:30]=[CH:29][C:16]=3[N:17]=[C:18]([C:20]3[CH:25]=[C:24]([F:26])[C:23]([Cl:27])=[CH:22][C:21]=3[F:28])[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32].O1CCOCC1>CCOC(C)=O>[ClH:27].[ClH:32].[Cl:27][C:23]1[C:24]([F:26])=[CH:25][C:20]([C:18]2[N:19]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15]3[S:31][CH:30]=[CH:29][C:16]=3[N:17]=2)=[C:21]([F:28])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1cc(-c2nc(N3CCNCC3)c3sccc3n2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1.16 g of 1-tert-butoxycarbonyl-4-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperazine and 10 ml of 4M HCl-dioxane solution was stirred for two days at room temperature. 10 ml of EtOAc was added to the reaction mixture. After the precipitate was filtered and washed with EtOAc, it was dried under reduced pressure to give 1.17 g of 2-(4-chloro-2,5-difluorophenyl)-4-piperazine-1-ylthieno[3,2-d]pyrimidine dihydrochloride.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1.Cl.[CH2:19]([O:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH3:20]>C(O)C>[CH2:19]([O:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:20]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)Nc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.2 %

Procedure:
Under a nitrogen atmosphere, triethylamine (82.1 g, 0.813 mole) was added to a stirred suspension of 2-chloro-3-nitropyridine (51.4 g, 0.325 mole) and (S)-alanine ethyl ester hydrochloride (75 g, 0.488 mole) in absolute ethanol (500 ml). After refluxing for 10.5 hr. and stirring at room temperature overnight, the solvents were evaporated under reduced pressure. The residue was triturated in 500 ml of ethyl acetate, filtered, and the filter cake was rinsed with ethyl acetate. The filtrate was washed three times with water, dried over sodium sulfate, filtered and evaporated to an oil weighing 85.6 g. A 1.25-g sample of the oil was eluted through 20 g of silica gel with isopropyl ether as the eluting solvent to give a pure fraction. The solvent was evaporated and the residual oil was dissolved in methylene chloride, filtered, and evaporated to an oil which was dried under high vacuum at 50° C. overnight to give 0.9 g of title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:9]([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:21][C:22]#[N:23]>CN(C)C=O.O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:9]([CH3:11])[CH3:10])=[C:6]([CH:7]=1)[O:8][CH2:21][C:22]#[N:23]
Reactant: COc1cc(C(C)C)c(O)cc1Br
Reactant: N#CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c(OCC#N)cc1Br
Temperature: 60 °C
Yield: 63.2 %

Procedure:
To a mixture of 5-bromo-2-isopropyl-4-methoxy-phenol from step 4 (0.831 g, 3.4 mmol) and K2CO3 (0.562 g, 4.1 mmol) in 17 mL dimethyl formamide (DMF) was added iodoacetonitrile (0.594 g, 3.6 mmol). The mixture was warmed to 60° C. for 30 minutes and then allowed to cool to room temperature. After cooling to room temperature the mixture was taken up in 50 mL of H2O and extracted with 1:1 toluene/ethyl acetate, washed with H2O and then with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a crude solid. Purification via flash chromatography (1:1 hexane/CH2Cl2) afforded (5-bromo-2-isopropyl-4-methoxy-phenoxy)-acetonitrile (0.611 g, 63%) as a while solid.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15]([O:17]CC)=O)[N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH2:33][CH2:34][NH2:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15]([NH:35][CH2:34][CH2:33][C:27]3[C:26]4[C:30](=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=4)[NH:29][CH:28]=3)=[O:17])[N:11]=2)=[CH:20][CH:21]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1noc(Cc2ccc(C(C)(C)C)cc2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Cc2nc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)no2)cc1
Yield: 22.2 %

Procedure:
This compound was prepared according to method F with ethyl 5-(4-tert-butylbenzyl)-1,2,4-oxadiazole-3-carboxylate (0.125 g; 0.433 mmol) in methanol (2 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol) in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.042 g (22%) of 5-(4-tert-butylbenzyl)-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [OH:1][NH:2][CH:3]([C:5]1[CH:9]=[CH:8][N:7]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH:6]=1)[CH3:4].Cl.[C:19](Cl)(Cl)=[O:20].[OH-].[NH4+:24]>C1(C)C=CC=CC=1.O>[C:19]([N:2]([CH:3]([C:5]1[CH:9]=[CH:8][N:7]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH:6]=1)[CH3:4])[OH:1])(=[O:20])[NH2:24]
Reactant: Cc1cccc(C)c1-n1ccc(C(C)NO)c1
Reactant: O=C(Cl)Cl
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1-n1ccc(C(C)N(O)C(N)=O)c1
Reaction time: 7 h

Procedure:
A solution of 1.0 g of N-hydroxy-1-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-ethylamine in 60 ml of toluene is stirred and treated first with one mole equivalent of 4.0M ethanolic HCl, followed by 10 ml of 2.0M phosgene in toluene. The solution is stirred for 7 hours, 50 ml of concentrated ammonium hydroxide is added and the mixture is stirred overnight. Excess water is then added and the mixture is again stirred for 2 hours. The organic layer is separated, washed with brine, dried over magnesium sulfate, treated with charcoal and evaporated to dryness to yield N-carbamoyl-N-hydroxy-1-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-ethylamine.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]([CH3:19])[C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]2[C:17]=1[CH3:18])=[O:4].[F:22][C:23]([F:40])([F:39])[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36](O)=[O:37])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>>[CH3:18][C:17]1[N:9]2[CH:10]=[C:11]([NH:14][C:36]([C:33]3[CH:32]=[CH:31][C:30]([C:27]4[CH:28]=[CH:29][C:24]([C:23]([F:22])([F:39])[F:40])=[CH:25][CH:26]=4)=[CH:35][CH:34]=3)=[O:37])[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[N:5]([CH3:19])[C:3](=[O:4])[C:2]([F:21])([F:20])[F:1]
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: Cc1c(N(C)C(=O)C(F)(F)F)nc2ccc([N+](=O)[O-])cn12
Product: Cc1c(N(C)C(=O)C(F)(F)F)nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cn12
Yield: 61.2 %

Procedure:
Operations similar to Example 1 were conducted using 2,2,2-trifluoro-N-methyl-N-(3-methyl-6-nitroimidazo[1,2-a]pyridin-2-yl)acetamide (580 mg) and 4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid (510 mg), to provide N-{3-methyl-2-[methyl(2,2,2-trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl}-4′(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamide (610 mg) as white solid.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(NC(C)C)(C)C.[Li].[Sn:21](Cl)([CH3:24])([CH3:23])[CH3:22]>C1COCC1.CCCCCC.C1COCC1>[Br:1][C:2]1[S:3][C:4]([Sn:21]([CH3:24])([CH3:23])[CH3:22])=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCc1ccsc1Br
Reactant: C[Sn](C)(C)Cl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCc1cc([Sn](C)(C)C)sc1Br
Yield: 78 %

Procedure:
3-hexylthiophene and N-bromosuccinimide (hereinafter, referred to as ‘NBS’) in the same amount were reacted in DMF at room temperature for 15 hours to obtain 2-bromo-3-hexylthiophene (d). 12.4 g (50 mmol) of the 2-bromo-3-hexylthiophene (d) was added to a solution of 28 mL (56 mmol) of lithium diisopropylamine (hereinafter, referred to as ‘LDA’, 2.0M in THF/Hexane) in 40 mL of anhydrous THF at about −80˜−90° C. with stirring. At this temperature, the reaction was allowed to proceed for 20˜30 minutes. A solution of 10.0 g (50 mmol) of Me3SnCl in THF was added to the mixture, and was then stirred at −50° C. for 1 hour. After completion of the reaction, the reaction mixture was extracted with ether and water. The obtained organic layer was concentrated, and distilled to afford the title compound (yield: 78%) as a colorless oil. The 1H-NMR spectrum (CDCl3) of the monomer (3) is shown in FIG. 2.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>O=S(Cl)Cl>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:6]([C:5]2[CH:4]=[CH:3][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:10][CH:9]=2)=[O:8])=[CH:23][CH:24]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
mono-Methyl terephthalate (1.02 g, 5.67 mmol) was refluxed in SOCl2 (10 mL) for 1 hour, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was taken up in tetrahydrofuran (30 mL) and treated with 4tert-butylaniline (0.9 mL, 5.65 mmol) and DIEA (5 mL, 28.8 mmol) at room temperature. After stirring overnight, the mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate. The ethyl acetate was washed with H2O and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with 3:2 hexanes:ethyl acetate and the solid air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.08 (m, 4H), 7.69 (m, 2H), 7.39 (m, 2H), 3.90 (s, 3H), 1.29 (s, 9H); MS (ESI—) m/z 312 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH:29]=[CH:28][S:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:10][CH:9]=1)(=[O:7])=[O:6].CCN(S(F)(F)[F:36])CC>C(Cl)Cl.C1COCC1>[F:36][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH:29]=[CH:28][S:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCO)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCF)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a solution of N-(2-hydroxyethyl)-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzenesulfonamide (120 mg, 0.28 mmol) in methylene chloride (10 mL) and THF (6 mL) under nitrogen at −78° C. was added DAST (89 mg, 0.56 mmol) and the reaction mixture was stirred at −78° C. for 2 h and warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, ethyl acetate/hexanes gradient). The resulting crude residue was triturated in methylene chloride and filtered to afford the desired product (90 mg, 75%) as a off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.10 (t, J=5.9 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.76 (d, J=5.4 Hz, 1H), 7.56 (d, J=9.1 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.43 (d, J=9.2 Hz, 1H), 5.75 (d, J=5.4 Hz, 1H), 4.51 (t, J=4.9 Hz, 1H), 4.42 (t, J=4.9 Hz, 1H), 3.71 (s, 3H), 3.24 (q, J=5.2 Hz, 1H), 3.19 (q, J=5.2 Hz, 1H); ESI MS m/z 433 [C20H17FN2O4S2+H]+; HPLC 93.4% (AUC), tR=15.64 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:24][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(Br)ccc3o2)c1
Reactant: CCCN
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-5-bromobenzoxazole (576 mg, 2.0 mmol) and propylamine (492 μL, 6.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]N)=[O:10])[CH:6]=[CH:5][N:4]=1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH:15]=[CH:14]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C:13](=[O:19])/[CH:14]=[CH:15]\[C:16]([OH:18])=[O:17])=[O:10])[CH:6]=[CH:5][N:4]=1
Reactant: O=C1C=CC(=O)O1
Reactant: COc1cc(C(=O)NN)ccn1
Solvent: C1CCOC1
Product: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxypyridine-4-carbohydrazide 8 (167 mg, 1.0 mmol) in 10 mL of THF was added maleic anhydride (110 mg, 1.1 mmol 1). The mixture was stirred at ambient temperature for 2 h. After removal of the solvent, the residue was diluted with 10 mL of dichloromethane. The solid was collected by filtration to give (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 9 as a solid. Yield: 190 mg, 71%.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:32])[N:4](CC2C=CC(OC)=CC=2OC)[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[CH:9][C:8]([O:19][CH3:20])=[CH:7][CH:6]=2.CSC>FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:3](=[O:32])[NH:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[CH:9][C:8]([O:19][CH3:20])=[CH:7][CH:6]=2
Reactant: COc1ccc(Cn2c(=O)c(N)c(-c3cccc(F)c3)c3cc(OC)ccc32)c(OC)c1
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]c(=O)c(N)c(-c3cccc(F)c3)c2c1
Reaction time: 48 h

Procedure:
To a solution of 3-amino-1-(2,4-dimethoxybenzyl)-4-(3-fluorophenyl)-6-methoxyquinolin-2-(1H)-one (62 mg, 0.143 mmol) in 3 mL of trifluoroacetic acid was added dimethyl sulfide (0.30 mL). After stirring for 2 days, the reaction was heated to reflux for 3 hours, then concentrated in vacuo. The crude residue was purified by flash chromatography through SiO2 (1-3% MeOH/CH2Cl2) to provide the titled product as a yellow solid. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C16H13FN2O2 (M+H+): 285.1034. Found 285.1029.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[Cl-].[NH4+:11].[C-:12]#[N:13].[Na+].N>CO.O>[NH2:11][C:6]1([C:12]#[N:13])[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]1
Reactant: [NH4+]
Reactant: [C-]#N
Reactant: CCN1CCC(=O)CC1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN1CCC(N)(C#N)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-ethyl-4-piperidone (13.2 ml, 100 mmol), ammonium chloride (21.4 g, 400 mmol), sodium cyanide (19.6 g, 400 (mmol) and water (550 ml) was stirred at room temperature for 48 h. The pH of the reaction mixture was adjusted to 10.1 and the product was extracted with ethyl acetate. The organic extracts were washed with brine and dried over magnesium sulfate. Rotary evaporation of the solvent gave a mixture of 4-amino-4-cyano-1-ethyl piperazine and 4-hydroxy-4-cyano-1-ethyl piperazine (7.67 g). This mixture of products was treated with 7 M ammonia in methanol (20 ml) and allowed to stand at room temperature for 24 h. The methanol and excess ammonia were removed in vacuo and the residue was cooled to give 4-amino-4-cyano-1-ethylpiperidine as a crystalline solid (7.762 g).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([NH:19][C:20]2[C:21]3[CH:38]=[CH:37][NH:36][C:22]=3[N:23]=[C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=3)[N:25]=2)[CH2:14]1.O>C(Cl)Cl.CN(C=O)C>[C:1]([CH2:3][C:4]([N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([NH:19][C:20]2[C:21]3[CH:38]=[CH:37][NH:36][C:22]=3[N:23]=[C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=3)[N:25]=2)[CH2:14]1)=[O:6])#[N:2]
Reactant: NC(=O)c1ccc(Nc2nc(NC3CCCNC3)c3cc[nH]c3n2)cc1
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCCC(Nc2nc(Nc3ccc(C(N)=O)cc3)nc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 46.9 %

Procedure:
To a suspension of cyanoacetic acid (46 mg, 0.54 mmol) in CH2Cl2 (1 mL) (containing 2 drops of DMF), oxalyl chloride (0.047 mL, 0.54 mmol) was added. The mixture was stirred at room temperature for 40 min. To the above solution cooled in an ice bath, a solution of 4-(4-(piperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (18 mg, 0.051 mmol) and TEA (0.250 mL, 1.80 mmol) in DMF (2 mL) was added. The mixture was stirred for 2 h. Water was added. CH2Cl2 was removed in vacuo. The residue was purified by HPLC to give the titled compound (10 mg). MS 419.3 (M+H); UV 201.6, 311.9 nm.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[O:37][CH3:38])[C:21]([Cl:39])=[CH:20][N:19]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>COC(O)C>[Cl:39][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][C:26]=2[O:37][CH3:38])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: COC(C)O
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)ccc2C1
Temperature: 95 °C

Procedure:
To a solution of 8-Amino-1,4-diethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5one (22.0 g, 0.0944 mol) in dioxane (400 mL) was added borane dimethyl sulfide complex solution (2 M in THF, 118 mL, 0.236 mol) and heated at 75° C. for 4 hr. The reaction was quenched with ethanol (100 mL) and stirred at room temperature for 18 hr., then evaporated. To the residue was added hydrazine hydrate (100 mL) and heated at 95° C. for 4 hr. After evaporation, toluene (50 mL) and ethanol (50 mL) were added, distilled and the reaction evaporated. The residue was extracted with DCM, evaporated, dissolved in ether, filtered and evaporated to give 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine as an oil (16.0 g, 84%). LCMS (m/e) 220 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.79-6.71 (d, 1H, J=7.83 Hz), 6.49 (br, 1H), 6.01-5.99 (d, 1H, J=7.83 Hz), 4.79 (s, 2H), 3.07-3.02 (q, 2H, J=6.82 Hz), 2.85-2.83 (t, 2H, J=8.08 Hz), 2.70-2.68 (t, 2H, J=8.09 Hz), 1.13-1.10 (t, 3H, J=7.07 Hz), 1.00-0.97 (t, 3H, J=7.32 Hz), 712d) 5-Chloro-N*2*-(1,4-diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl)-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidin-2,4-diamine was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine (0.068 g, 0.00023 mol) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (0.081 g, 0.00023 mol), camphorsulfonic acid (0.0187 g, 0.0008 mol) and methoxyethanol (10 mL). The mixture was heated at 95° C. for 18 hr. The reaction was evaporated and the residue treated with a 10% sodium carbonate solution and DCM, separated, washed, dried and evaporated to give a solid. This material was chromatographed on a silica gel prep plate with THF/methanol (10-1) giving the product as a tan solid (0.053 g, 43%). Mp 165-166° C. LCMS (m/e) 538 (M); 1H-NMR (DMSO, 400 MHz) δ 9.07 (s, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.65 (d, 1H), 7.15-7.13 (d, 1H, J=8.33 Hz), 7.01 (s, 1H), 6.84-6.82 (d, 1H, J=8.08 Hz), 6.69 (s, 1H), 6.49-6.47 (d, 1H, J=8.59 Hz), 3.80 (s, 3H), 3.76 (t, 2H, J=4.05), 3.54 (s, 2H), 3.14 (t, 3H), 3.01-2.99 (q, 2H, J=7.07 Hz), 2.90-2.84 (m, 2H), 2.78-2.69 (m, 2H), 2.40-2.30 (m, 2H), 1.11-1.08 (t, 3H, J=6.57 Hz), 1.03-1.00 (t, 3H, J=7.33).