Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:18](O)(=O)[CH3:19].[C:22](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:23].[Na+].[OH-].[Na+]>O1CCCC1>[CH:18]1([CH2:19][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:2][CH2:3]2)[CH2:23][CH2:22]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)O
Reactant: O=C(OCc1ccccc1)N1CCCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.2 %

Procedure:
Benzyl 1-homopiperazinecarboxylate (1.95 g, 8.32 mmol) and cyclopropanecarboxyaldehyde (700 mg, 10.0 mmol) were dissolved in 40 mL of tetrahydrofuran. Acetic acid (600 mg, 10.0 mmol) and sodium triacetoxyborohydride (2.11 g, 10.0 mmol) were added thereto, and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was mixed with 1 N aqueous solution of sodium hydroxide, extracted with ethyl acetate twice, and the combined organic layers were washed with brine once. The mixture was dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Fuji Silysia, NH Silica gel; ethyl acetate:hexane=50:50) to give benzyl 4-(cyclopropylmethyl)homopiperazin-1-carboxylate (2.5 g) as a colorless oil.
Reaction SMILES: NC[CH2:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][CH2:9][NH2:10].C(#[N:14])C=C.[CH2:15]([CH2:17]N)[OH:16]>>[OH:16][CH2:15][CH2:17][N:6]([CH2:5][CH2:4][CH2:3][NH2:14])[CH2:7][CH2:8][CH2:9][NH2:10]
Reactant: NCCCCNCCCN
Reactant: C=CC#N
Reactant: NCCO
Product: NCCCN(CCO)CCCN

Procedure:
An an alternative to obtaining a mixture of Schiff bases VI and VI(a) or VI(b), which upon reduction give a mixture of product I the reaction can be conducted stepwise. For example, 1,4-diaminobutane or 4-(2-aminoethyl)piperazine may be converted to a Schiff base with 1,5-di-(4-chloro-phenyl)-3-pentanone, catalytically reduced, then the resulting amine selectively cyanoethylated with acrylonitrile, followed by catalytic hydrogenation to furnish 1-(3-aminopropyl)-4-[1,5-di-(4-chloro-phenyl)-3-pentyl]diaminobutane, a spermidine derivative, or 1-(3-aminopropyl)-4-[2(1,5-di-(4-chloro-phenyl)-3-pentylamino ethyl]piperazine. A primary amine can be dicyanoethylated with excess acrylonitrile, catalytically reduced to the corresponding 3,3'-substituted iminobis(propylamine) and then converted by condensation with a ketone and reduction to the N-alkylated-3,3'-substituted iminobis(propylamine). For example, dicyanoethylation of monoethanolamine followed by catalytic reduction provides 3,3'-(2-hydroxyethylimino)bis(propylamine). Condensation with 1-(2,4-dimethylphenyl)-6-(3-chlorophenyl)-3-hexanone and subsequent catalytic hydrogenation of the --C=N bond affords 1-[1-(2,4-dimethylphenyl)-6-(3-chlorophenyl)-3-hexyl]-5-(2-hydroxyethyl)-1,5,9-triazanonane.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[N:3]=1.[F:21][C@@H:22]1[CH2:26][NH:25][CH2:24][C@H:23]1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[NH3:3].[CH2:30]([O:29][C:28](=[O:37])[NH:27][C@H:23]1[C@H:22]([F:21])[CH2:26][N:25]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[N:3]=2)[CH2:24]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(F)nc21
Reactant: O=C(N[C@@H]1CNC[C@H]1F)OCc1ccccc1
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(N3C[C@@H](F)[C@H](NC(=O)OCc4ccccc4)C3)nc21
Product: N
Temperature: 100 °C
Reaction time: 14 h
Yield: 82 %

Procedure:
To the above solution of crude 2-fluoro-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine was added benzyl [(3R,4R)-4-fluoropyrrolidin-3-yl]carbamate (238 mg, 1 mmol). The resulting solution was heated at 100° C. (block temperature) and stirred for 14 hr. After cooling, the volatiles were removed and the residue was purified via flash chromatography (eluting with a gradient of 100% heptane to 100% ethyl acetate and then to 10% ammonia (7 N in methanol-90% ethyl acetate) to give the title compound as a light yellow solid (402 mg, 82% yield (over 2 steps)). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.62 (s, 1 H) 7.98 (s, 1 H) 7.91 (s, 1 H) 7.80 (d, J=5.75 Hz, 1 H) 7.71 (s, 1 H) 7.27-7.41 (m, 5 H) 4.98-5.30 (m, 3 H) 4.55-4.68 (m, 1 H) 4.16-4.34 (m, 1 H) 3.76-3.96 (m, 6 H) 3.64-3.71 (m, 1 H) 1.50 (d, J=6.72 Hz, 6 H). 19F NMR (376 MHz, DMSO-d6) δ ppm −178.93 (br. s., 1F). m/z (APCI+) for C24H28FN9O2 494.2 (M+H)+. Chiral purity was determined as below (using racemic sample to compare):
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:10]OC(OC)N(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.Br.[CH2:30]([S:32][C:33](=[NH:35])[NH2:34])[CH3:31]>CN(C)C=O>[CH2:8]([O:7][C:1]([C:2]1[C:3]([CH3:5])=[N:35][C:33]([S:32][CH2:30][CH3:31])=[N:34][CH:10]=1)=[O:6])[CH3:9]
Reactant: COC(OC)N(C)C
Reactant: CCSC(=N)N
Reactant: CCOC(=O)CC(C)=O
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(SCC)nc1C
Temperature: 100 °C
Yield: 62.7 %

Procedure:
A mixture of ethyl acetoacetate (6.37 mL, 50.0 mol), dimethylformamide dimethylacetal (8.94 g, 75.0 mmol), and catalytic p-toluenesulfonic acid was heated at 100° C. for 2 h. After cooling to rt, the mixture was diluted with N,N-dimethylformamide (DMF; 50 mL) and 2-ethylisothiourea hydrobromide (9.10 g, 50.0 mmol) was added. After heating the at 100° C. for 18 h, the mixture was cooled to rt and concentrated to give a crude residue, which was purified by FCC (EtOAc/hexanes) to give 7.1 g (61%) of a solid. 1H NMR (CDCl3): 8.97-8.91 (m, 1H), 4.43-4.35 (m, 2H), 3.24-3.15 (m, 2H), 2.81-2.72 (m, 3H), 1.47-1.35 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[O:25]([CH2:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[O:25]([CH2:32][C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C(COc1ccccc1)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 18.3 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.157 mmol) obtained in Example 1, (3), and 2-phenoxyacetyl chloride (27 mg, 0.315 mmol), the title compound (13 mg, yield 18%) was obtained as pale brown crystals in the same manner as that of Example 1, (4).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[CH3:32][C:33]1([CH3:48])[O:38][CH2:37][CH2:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34]1>>[CH3:32][C:33]1([CH3:48])[O:38][CH2:37][CH2:36][C:35]([C:12]2[N:11]=[CH:10][C:9]3[O:8][C:5]4[C:4]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:14]=3[CH:13]=2)=[CH:3][C:2]([C:26]2[CH:27]=[N:28][C:23]([F:22])=[CH:24][CH:25]=2)=[CH:7][CH:6]=4)=[CH:34]1
Reactant: OB(O)c1ccc(F)nc1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CCO1
Product: CC1(C)C=C(c2cc3c(cn2)Oc2ccc(-c4ccc(F)nc4)cc2[C@@]32COC(N)=N2)CCO1

Procedure:
The titled compound was synthesized by steps analogous to those described in method AA1 above, but using (S)-7-bromo-3-chloro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (prepared as described in Method BB41), 6-fluoropyridin-3-ylboronic acid and 2-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS m/z=459.0 [M+H]+. Calculated for C26H23FN4O3: 458.18 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38 (d, J=2.93 Hz, 6 H) 2.53-2.60 (m, 2 H) 3.96 (t, J=5.38 Hz, 2 H) 4.36 (d, J=6.46 Hz, 2 H) 4.55-4.66 (m, 2 H) 6.56 (s, 1 H) 6.98-7.04 (m, 1 H) 7.28 (d, J=8.61 Hz, 1 H) 7.38 (s, 1 H) 7.45-7.53 (m, 1 H) 7.55 (d, J=2.35 Hz, 1 H) 7.87-8.04 (m, 1 H) 8.41 (d, J=2.35 Hz, 1 H) 8.50 (s, 1 H)
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]1([C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[CH2:31]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:29]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[C:15]([Cl:16])=[CH:14][C:5]=2[N:6]=[C:7]1[CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: BrCc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (521 mg) in DMF (5 mL) was added potassium carbonate powder (802 mg) and 2-phenyl benzyl bromide (1.43 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (5%-40% EtOAc/hexanes), followed by recrystallization with Et2O/hexanes to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC(C)=CC=4)(=O)=O)[C:15]([C:17]4([OH:30])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4([OH:30])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2c1cc(C1(O)CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3(O)CCN(C(=O)OC(C)(C)C)CC3)cc12

Procedure:
A suspension of Example 126B (0.144 g, 0.241 mmol) and 50% sodium hydroxide (0.064 mL, 1.205 mmol)/water (0.064 mL) in dioxane (1 mL) was heated at 80° C. for 4 hours. The mixture was diluted with ethyl acetate and dried over magnesium sulfate, filtered and concentrated. The crude mixture was used in the next step without further purification. LCMS: 442.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[N:12]1([C:18]2[CH:19]=[C:20]([CH2:24]N)[CH:21]=[CH:22][CH:23]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:19]=2)[CH:9]=1
Reactant: NCc1cccc(N2CCOCC2)c1
Reactant: NC(=O)c1cc(Cl)cnc1N
Product: Cl
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cccc(N2CCOCC2)c1

Procedure:
According to the method of Example 179, 2-amino-5-chloronicotinamide was reacted with 1-(3-morpholin-4-ylphenyl)methanamine to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:16][CH2:17][CH2:18][NH2:19].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([NH:19][CH2:18][CH2:17][Cl:16])[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: NCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1CC(NCCCl)C(=O)N1Cc1ccccc1

Procedure:
74.8 g (0.4 mol) of N-benzylmaleimide are reacted with 58 g (0.5 mol) of 2-chloroethylamine hydrochloride and 50.5 g (0.5 mol) of triethylamine in accordance with the working instructions of Example Ia. After working up by chromatography, 81.6 g (77% of theory) of an oil with an RF value of 0.24 (on silica gel using ethyl acetate: petroleum ether=1:1) are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][Cl:22])=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[CH:7][CH:8]=2)[C:3]1=[O:25].[CH3:26][O:27][C:28]1[CH:37]=[CH:36][C:31]([CH2:32][CH2:33][NH:34][CH3:35])=[CH:30][CH:29]=1>>[ClH:22].[CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:34]([CH2:33][CH2:32][C:31]3[CH:36]=[CH:37][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH3:35])=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[CH:7][CH:8]=2)[C:3]1=[O:25]
Reactant: CNCCc1ccc(OC)cc1
Reactant: COc1ccc2cc(-c3ccc(OCCCCl)cc3)n(C)c(=O)c2c1
Product: COc1ccc(CCN(C)CCCOc2ccc(-c3cc4ccc(OC)cc4c(=O)n3C)cc2)cc1
Product: Cl
Yield: 75 %

Procedure:
2-Methyl-3-[4-(3-(N-4-methoxyphenethyl-N-methyl-amino)-propoxy)-phenyl]-7-methoxy-isoquinolin-1(2H)-one hydrochloride was prepared analogous to Example 3b from 2-methyl-3-[4-(3-chloropropoxy)-phenyl]-7-methoxy-isoquinoline-1(2H)-one and N-b 4-methoxyphenethyl-N-methyl-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:9])=[O:5].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[C:29]([N+:35]([O-])=O)[CH:28]=1.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][C:29]=2[NH2:35])[CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCl
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)NCC1CCNCC1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Nc1cc(Cl)ccc1CN1CCC(CNC(=O)CNC(=O)c2cc(C(F)(F)F)ccc2N)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 4-chloro-2-nitrobenzyl chloride (0.050 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.7 mL) was stirred overnight at 50° C. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with 50% CHCl3/CH3OH (10 mL) and CH3OH (10 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material was added ethanol (3 mL) and 10% Pd—C (15 mg), and the mixture was stirred under H2 at room temperature for 1.5 h. Filtration, concentration, and preparative TLC afforded 4-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}aminomethyl]-1-(2-amino-4-chlorobenzyl)piperidine (Compound No. 1919) (5.1 mg, 14%): The purity was determined by RPLC/MS (90%); 1H NMR (400 MHz, CDCl3) δ1.09-1.32 (m, 4H), 1.41-1.59 (m, 1 H), 1.66 (d, J=12.5 Hz, 2 H), 1.88 (t, J=11.5 Hz, 2 H), 2.82 (d, J=11.5 Hz, 2 H), 3.17 (t, J=6.5 Hz, 2 H), 3.42 (s, 2 H), 4.05 (d, J=5.5 Hz, 2 H), 4.85 (br s, 1 H), 5.92 (br s, 2 H), 6.25-6.36 (m, 1 H), 6.55-6.66 (m, 1 H), 6.70 (d, J=8.5 Hz, 1 H), 6.85 (d, J=8.5 Hz, 1 H), 7.26 (s, 1 H), 7.42 (d, J=8.5 Hz, 1 H), 7.68 (s, 1 H); ESI/MS m/e 498.2 (M++H, C23H27ClF3N5O2).
Reaction SMILES: C1(CBr)CC1.[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1.[CH3:15][C:16]1[N:17]=[C:18]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])[S:19][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:28]2[CH2:29][CH2:30][N:26]([C:18]3[S:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([CH3:15])[N:17]=3)[C:27]2=[O:31])=[CH:9][CH:8]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(Cl)cc3)C2=O)nc1C
Yield: 84 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with 4-chlorobenzyl chloride to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 84% yield: mp 117-119° C. (ethyl acetate/hexanes): 1H NMR (300 MHZ, DMSO-d6) δ 7.31 (d, J=7.2 Hz, 2H), 7.22 (d, J=7.2 Hz, 2H), 4.51 (s, 2H), 4.27 (q, J=7.8 Hz, 2H), 4.09-4.04 (m, 2H), 3.44-3.41 (m, 2H), 2.59 (s, 3H), 1.25 (t, J=7.8 Hz, 3H): MS (ES+) m/z 380.2 (M+1), 382.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[F:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=1.C(=O)=O.C(O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.O>[F:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](=[O:16])[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][N:5]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(C#N)cn1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(CC(=O)c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 205.4 %

Procedure:
To a solution of 3-cyano-6-methylpyridine (High Force Research Limited) (0.59 g 1,5 mmol) and ethyl 4-fluorobenzoate (0.84 g 5 mmol) (Aldrich) in dry THF (15 ml) stirring under nitrogen at −70° (Dricold/ethanol) was added dropwise lithium bis(trimethylsilyl)amide (10 ml M solution in hexane 10 mmol). The reaction was allowed to warm to room temperature, stirred under nitrogen for 20 hr, poured into water (200 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (50 ml), brine (50 ml) and dried (MgSO4). Removal of solvent gave a solid which was crystallised from ethanol to give the title compound as a yellow solid (0.74 g 62%) which existed as a mixture of keto- and enol-forms by NMR. MH+: 241; mp: 170-1710 (uncorrected)
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35]C(=O)OC(C)(C)C)[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH2:35])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)OC(C)(C)C)C4)n3)c3cc(F)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N)C4)n3)c3cc(F)cnc32)cc1
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-1,3-diamine (44e) tert-Butyl N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamate, 44d, (3.7 g, 6.2 mmol) was dissolved in dichloromethane (105 mL) and treated with trifluoroacetic acid (31 mL). After 5 minutes, the volatiles were evaporated under reduced pressure, and the resulting residue was treated with 1N NaOH (75 mL). The resulting precipitate was collected by filtration, washed with water (3×30 mL) and vacuum dried to provide 2.7 g of (1S,3R)—N1-[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-1,3-diamine as a white solid.
Reaction SMILES: [Br:1][C:2]1C=[C:4]2[C:9](=[O:10])OC(=O)[C:5]2=[CH:11][CH:12]=1.[CH3:13][NH2:14].[CH3:15][CH2:16][OH:17]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:13][N:14]1[C:16](=[O:17])[C:15]2=[C:2]([Br:1])[CH:12]=[CH:11][CH:5]=[C:4]2[C:9]1=[O:10]
Reactant: CCO
Reactant: CN
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CN1C(=O)c2cccc(Br)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromophthalic anhydride (2.0 g) in toluene (20 mL) was treated with 33% methylamine in EtOH (1.65 mL) and a crystal of DMAP. After stirring for 1 h at ambient temperature, the mixture was heated to reflux under a dean-stark trap during 14 h. The reaction mixture was cooled to −20° C., and the resulting white crystals collected and washed with hexanes to give N-methyl-3-bromophthalimide (1.32 g) m.p. 149-151. Concentration of the mother liquor and recrystalization from benzene (3 mL) gave a second crop, 430 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.N1C=CC=[CH:24][CH:23]=1.C(OC(=O)C)(=O)C.Cl>O1CCCC1>[CH2:23]([NH:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[CH2:11]1)[CH3:24]
Reactant: c1ccncc1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (9.3 g) in tetrahydrofuran (100 ml) were sequentially added pyridine (8.0 ml) and acetic anhydride (6.2 ml), and the solution was stirred overnight at room temperature. To the reaction solution was added 1N hydrochloric acid, the solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. To a solution of the resulting N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide (9.1 g) in tetrahydrofuran (100 ml) was added lithium aluminum hydride (2.7 g), and the solution was refluxed for 2 hours. Ammonia solution (1 ml) and anhydrous magnesium sulfate were added on an ice bath, the solution was filtered, and then the solvent was evaporated in vacuo to provide ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (8.8 g). To a solution of 4-benzyloxybenzoic acid (9.1 g) in dichloromethane (80 ml) were sequentially added oxalyl chloride (5.1 ml) and N,N-dimethylformamide (0.05 ml), the solution was stirred overnight at room temperature, then the solvent was evaporated in vacuo. To the total amount of the resulting 4-benzyloxybenzoyl chloride were sequentially added 1,4-dioxane (100 ml), N,N-diisopropylethylamine (15 ml) and ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (8.3 g), and the solution was refluxed for 30 minutes. To the reaction solution was added 1N hydrochloric acid, the solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. Synthesized from the total amount of the resulting 4-benzyloxy-N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (crude product) according to an analogous synthetic method to Example 22, the title compound (13 g) was obtained.
Reaction SMILES: [C:1]([N:4]1[C:9]2[CH:10]=[C:11]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:13][C:8]=2[O:7][C:6]([CH3:22])([CH3:21])[CH2:5]1)(=[O:3])[CH3:2].[N+:23]([O-])([OH:25])=[O:24]>C(O)(=O)C>[C:1]([N:4]1[C:9]2[CH:10]=[C:11]([NH:14][C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[C:12]([N+:23]([O-:25])=[O:24])=[CH:13][C:8]=2[O:7][C:6]([CH3:22])([CH3:21])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(C)(C)Oc2ccc(NC(=O)C(F)(F)F)cc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)N1CC(C)(C)Oc2cc([N+](=O)[O-])c(NC(=O)C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 22.0 g 4-acetyl-3,4-dihydro-2,2-dimethyl-6-trifluoroacetylamino-2H-1,4-benzoxazine in 100 ml acetic acid, was added dropwise a solution of 3.7 ml fuming nitric acid in 50 ml acetic acid, and the resulting solution was stirred at room temperature for two hours. The reaction mixture was poured into 600 ml ice water, the crystals which separated out were collected by filtration, and recrystallized from 100 ml ethanol, giving 21.6 g of 4-acetyl-3,4-dihydro-2,2-dimethyl-7-nitro-6-trifluoroacetylamino-2H-1,4-benzoxazine.