Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].CN[C@@H]1CCCC[C@H]1NC>C(O)C.[Cu]I.O>[N:25]([C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1)=[N+:26]=[N-:27]
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(Br)ccc1O2
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: CCO
Solvent: O
Product: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(N=[N+]=[N-])ccc1O2
Temperature: 90 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
To a solution of (S)-7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-2-amine (422 mg, 1.073 mmol) in ethanol (3.5 ml) was added sodium azide (209 mg, 3.22 mmol), copper(I) iodide (41 mg, 0.215 mmol), (+)-sodium L-ascorbate (21 mg, 0.107 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (0.05 ml, 0.322 mmol) and water (1.5 ml) and the mixture was stirred at 90° C. for 4 hrs. The mixture was cooled to RT, additional water (2 ml) was added and stirring continued for additional 30 min. Precipitated material was filtered off, washed with water twice, and dried under a stream of nitrogen overnight to afford (S)-7′-azido-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-2-amine (290 mg, 0.816 mmol, 76% yield) which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]([O:18][CH2:19][C@H:20]4[N:24]([CH2:25][CH2:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:23](=[O:34])[C@H:22]([CH2:35][C:36]([OH:38])=[O:37])[CH2:21]4)=[CH:12][C:13]=3[C:14]2=O)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]([O:18][CH2:19][C@H:20]4[N:24]([CH2:25][CH2:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:23](=[O:34])[C@H:22]([CH2:35][C:36]([OH:38])=[O:37])[CH2:21]4)=[CH:12][C:13]=3[CH2:14]2)=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: [H][H]
Reactant: N=C(N)c1ccc2c(c1)C(=O)c1cc(OC[C@@H]3C[C@@H](CC(=O)O)C(=O)N3CCCc3ccccc3)ccc1-2
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc2c(c1)Cc1cc(OC[C@@H]3C[C@@H](CC(=O)O)C(=O)N3CCCc3ccccc3)ccc1-2

Procedure:
0.3 g of (3S,5S)-5-[(7-amidino-9-keto-2-fluorenyl)oxymethyl]-3-carboxymethyl-1-(3-phenylpropyl)-2-pyrrolidinone are dissolved in 7 ml of glacial acetic acid, 0.05 g of 10% palladium charcoal are added and the mixture is hydrogenated for 6 hours at 70° C. under 3 bar of hydrogen pressure. The catalyst is filtered off, the filtrate is evaporated down and the product is purified by chromatography on silica gel (eluant:tetrahydrofuran/2N acetic acid=10:1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].C([O-])(=O)C.[Na+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:27]([O:26][C:22]([CH:23]=[CH:24][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1)=[O:25])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)C(O)C1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.5 %

Procedure:
A Schlenk tube was charged under argon with 25.6 mg (0.114 mmol) of Pd(OAc)2, 69.6 mg (0.Z29 mmol) of tri(o-tolyl)phosphine and 20 ml of DMF (distilled under argon) and the reaction mixture was stirred at room temperature for 1 5 minutes. A 200 ml sulphonation flask was charged under argon and while stirring with 8.15 g (22.9 mmol) of tert-butyl (3RS,4RS)-4-(4-bromo-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 25 (c)], 100 ml of DMF, 3.73 ml (34.3 mmol) of ethyl acrylate, 2.25 g (27.5 mmol) of sodium acetate and the yellow catalyst solution. The reaction mixture was stirred at 120° C. for 6 hours. In order to complete the reaction, a solution of 5.1 mg Pd(OAc)2 and 14.3 mg of tri(o-tolyl)phosphine in 5 ml of DMF was added after 5 hours. The dark reaction mixture was evaporated on a rotary evaporator. The grey solid residue was taken up in ether and the turbid solution was washed three times with water, dried over sodium sulphate and evaporated under reduced pressure. The yellow solid residue was chromatographed on 250 g of silica gel using a 2:1 mixture of hexane and ethyl acetate as the eluent. After crystallization from ethyl acetate there were obtained 6.66 g (77% of theory) of tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-vinyl)-phenyl]-3-hydroxy-piperidine-1-carboxylate as colourless crystals; MS: 376 (M+H)+.
Reaction SMILES: [CH3:1]C1(C)[C@@H]2CC[C@@]1(CS(O)(=O)=O)C(=O)C2.C=O.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:30][S:31][S:32][CH2:33][CH3:34])[C:27]([OH:29])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH2:33]([S:32][S:31][CH2:30][C@H:26]1[C:27](=[O:29])[O:28][CH2:1][N:25]1[C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH3:34]
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Reactant: CCSSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: C=O
Solvent: Cc1ccccc1
Product: CCSSC[C@H]1C(=O)OCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
((1S,4R)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid (1.07 g, 4.62 mmol) and paraformaldehyde (847 mg, 2.89 mmol) were added to a solution of dicyclohexylamine (R)-2-((tert-butoxycarbonyl)amino)-3-(ethyldisulfanyl)propanoate (Compound 2d-f) (2.00 g, 4.32 mmol) in toluene (8 ml), and the mixture was stirred at 100° C. overnight. The reaction solution was then returned to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→87/13) to afford (R)-tert-butyl 4-((ethyldisulfanyl)methyl)-5-oxooxazolidine-3-carboxylate (2e-F) (847 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45]O)[CH2:39][CH2:38]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:45][CH2:44][CH2:43][N:40]3[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][F:34])[CH2:42][CH2:41]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: OCCCN1CCN(CCF)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(CCF)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
A suspension of 4-chloro-7-hydroxy-6-methoxyquinazoline (202 mg, 0.96 mmol), (prepared as described for the starting material in Example 4), in methylene chloride (10 ml) was treated with triphenylphosphine (352 mg, 1.35 mmol), 3-[4-(2-fluoroethyl)piperazin-1-yl)propan-1-ol (200 mg, 1.06 mmol), (prepared as described for the starting material in Example 27), and diisopropyl azodicarboxylate (226 mg, 1.15 mmol) and the mixture stirred at ambient temperature for 2 hours. The crude reaction mixture was loaded onto a silica column and eluted using methylene chloride/methanol (95/5). The relevant fractions were combined and evaporated under vacuum to give 4-chloro-7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxyquinazoline (208 mg, 57%) as a white solid.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:27])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.[ClH:28].CO>>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:27])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: Cl
Solvent: CO
Product: N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Intermediate 1a (120 mg) prepared in Step A mentioned above was added with 10% hydrogen chloride/methanol (2 ml, Tokyo Kasei Kogyo), and the mixture was stirred at room temperature for 12 hours. The solvent was concentrated under reduced pressure, and the obtained solid was collected by filtration to obtain the title compound as hydrochloride (84 mg).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:22][C:23](=O)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[C:9]([NH:22][C:23](=[S:41])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc(NC(=O)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cnc(NC(=S)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 127.9 %

Procedure:
Under an argon atmosphere, 3-benzyl-5-(4-methoxyphenyl)-2-(phenylacetylamino)pyrazine (c-16) (539 mg, 1.32 mmol) was suspended in anhydrous toluene (50 mL) and to this was added Lawesson's reagent (320 mg, 790 μmol) while stirring at room temperature, and then heated to reflux for 17 h. After refluxing, it was cooled to room temperature, and concentrated under reduced pressure with a rotary evaporator. The residue was purified by silica gel column chromatography (55 g, n-hexane/ethyl acetate=3/1) to give 3-benzyl-5-(4-methoxyphenyl)-2-(phenylthioacetylamino)pyrazine (c-17) as a yellow amorphous powder (430 mg, 76.6%). Rf=0.33 (n-hexane/ethyl acetate=7/3). Mp. 45-47° C. UV (MeOH) λmax (log ε) 334 (4.23), 295 (4.16), 272 (4.25). UV (pH 7.4 PB) λmax(log ε) 360.5 (4.22), 283.5 (4.16). 1H NMR (400 MHz, DMSO-d6) δ 3.81 (s, 3H), 3.92 (s, 2H), 4.14 (s, 2H), 7.01 (d, J=6.8 Hz, 2H), 7.04-7.10 (AA′BB′, 2H), 7.12-7.24 (m, 3H), 7.29 (t, J=7.3 Hz, 1H), 7.37 (t, J=7.3 Hz, 2H), 7.51 (d, J=7.1 Hz, 2H), 8.05-8.10 (AA′BB′, 2H), 8.99 (s, 1H), 12.20 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 39.3, 51.6, 55.3, 114.5 (2C), 126.3, 127.0, 127.6, 128.2 (2C), 128.3 (2C), 128.4 (2C), 128.9 (2C), 129.0 (2C), 136.9, 137.9, 138.0, 145.0, 149.6, 152.1, 160.9, 204.6. IR (KBr, cm−1) 700, 835, 1028, 1115, 1175, 1252, 1292, 1319, 1369, 1422, 1437, 1493, 1516, 1607, 2961, 3395. HRMS (FAB+) m/z 426.1646 (M+H, C26H24N3OS requires 426.1640).
Reaction SMILES: O.[NH2:2][NH2:3].Br[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1>N1C=CC=CC=1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([NH:2][NH2:3])=[N:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NNc1ccc(Br)cn1

Procedure:
Hydrazine monohydrate (10 mL) was added to 2,5-dibromopyridine (10.0 g) in pyridine (100 mL) at room temperature, and the resultant mixture was refluxed under heat for 13 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was partitioned by use of aqueous 0.5N sodium hydroxide and chloroform. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give 5-bromo-2-hydrazinopyridine as a solid (7.61 g, 96%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26](C(OC(C)(C)C)=O)[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[CH:29][CH:28]=3)=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][N:9]=[C:10]2[C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([O:34][CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[CH:29][CH:28]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCN(CC)CCOc1ccc2c(c1)cc(-c1nn(C(=O)OC(C)(C)C)c3ccc(OCc4ccccc4)cc13)n2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCOc1ccc2[nH]c(-c3n[nH]c4ccc(OCc5ccccc5)cc34)cc2c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
A solution containing 1.15 g of 5-benzyloxy-3-[1-tert-butoxycarbonyl-5-(2-diethylaminoethoxy)-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester and 4 ml of trifluoroacetic acid in 5 ml of dichloromethane is stirred at 20° C. for 2 hours. The reaction mixture is evaporated under reduced pressure and the crude compound thus obtained is purified by chromatography (Nucleodur C18 column, 100-10, 250 mm×40 mm, reference No. 762020, series No. 3051181, Batch No. 2023; eluent A: water/0.07% trifluoroacetic acid, eluent B: acetonitrile/0.07% trifluoroacetic acid, gradient of composition A/B of 95%//5% to 5%/95% over 52 minutes at 75 ml/min, detection 300 nm). The fractions containing the expected compound are combined and evaporated under reduced pressure. The compound is taken up in ethyl acetate (20 ml), dried over magnesium sulfate and then evaporated under reduced pressure to obtain 320 mg of {2-[2-(5-benzyloxy-1H-indazol-3-yl)-1H-indol-5-yloxy]ethyl}diethyl-amine, which is characterized.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[N:14][CH:15]=4)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:37][CH:36]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cnc(NCCN3CCOCC3)nc21
Reactant: NCc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccc(Cl)cc3)n2)c2cnc(NCCN3CCOCC3)nc21
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A sealed tube was charged with [3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 32 supra) (200 mg, 0.37 mmol), 4-chlorobenzylamine (74 mg, 0.52 mmol), Pd2(dba)3 (21 mg, 10% mmol), DavePhos (29 mg, 20% mmol), t-BuONa (50 mg, 0.52 mmol) and dioxane (10 mL). The mixture was stirred at 130° C. under an atmosphere of N2 for 6 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane:MeOH, 100:1) to give [3-[6-(4-chloro-benzylamino)-pyridin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 100 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:26](OC)(OC)OC.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[N:12]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:26]1
Reactant: COC(OC)OC
Reactant: Nc1cnc2ccccc2c1NCCCCCC(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CCCCCn1cnc2cnc3ccccc3c21)c1ccccc1

Procedure:
By the general method described in Step 6 of Example 4, a solution of 6-(3-aminoquinolin-4-ylamino)-1-phenylhexan-1-one (2.76 g, 8.25 mmol), trimethyl orthoformate (1.5 g, 9.9 mmol), and pyridine hydrochloride (95 mg, 0.83 mmol) in toluene (26 mL) was heated at reflux under a Dean-Stark trap for 2 hours, then concentrated under reduced pressure to provide 6-(1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1.C(N(CC)CC)C.[CH:22]([N:25]([CH:29]([CH3:31])[CH3:30])[C:26](Cl)=[O:27])([CH3:24])[CH3:23]>C1C=CC=CC=1>[CH:22]([N:25]([CH:29]([CH3:31])[CH3:30])[C:26]([N:5]([CH2:4][CH2:3][N:2]([CH3:14])[CH3:1])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:27])([CH3:24])[CH3:23]
Reactant: Cc1cc(C)nc(NCCN(C)C)c1
Reactant: CC(C)N(C(=O)Cl)C(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(N(CCN(C)C)C(=O)N(C(C)C)C(C)C)c1
Yield: 24.1 %

Procedure:
A solution of 5.80 g (30.0 mmoles) of 2-(2-dimethylaminoethylamino)-4,6-dimethylpyridine (from Example 1, B) and 2.20 ml (30.0 mmoles) of triethylamine in 50 ml of benzene is dried by azeotropic distillation. After adding 4.91 g (30.0 mmoles) of diisopropylcarbamoyl chloride, the reaction mixture is heated at reflux for 24 hours. The crude product, after removal of solvent, is chromatographed on silica gel using 5% methanol in chloroform as eluant. Appropriate fractions are combined, the solvent removed and product distilled through a short path still to give 2.32 g (24.1% yield) of N,N-diisopropyl-N'-(2-dimethylaminoethyl)-N'-(4,6-dimethyl-2-pyridyl)urea as a colorless oil boiling at 148°/0.35 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1>C1COCC1.C(O)(=O)C.O>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[N:6][CH:7]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1
Reactant: Nc1cncnc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2cncnc2)nc(N2CCOCC2)n1
Reaction time: 0.25 h
Yield: 44.5 %

Procedure:
To a solution of 0.186 g (1.96 mmol) of 5-aminopyrimidine in THF (4 mL) at 0° C. was added 1.1 mL of NaHMDS (2 M solution in THF), and the mixture was stirred for 15 min. A solution of 0.238 g (0.65 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (5 mL) was added and the resulting mixture was stirred for 1 hr at RT. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried and concentrated. Chromatography on alumina, eluting first with CH2Cl2/EtOAc (1:9) and then with CH2Cl2/EtOAc (1:3) to CH2Cl2/EtOAc (7:3) gave an off-white powder. Recrystallization from ethanol gave 0.123 g (47% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(5-pyrimidinyl)-1,3,5-triazin-2-amine: mp 290-292° C.; 1H NMR (CDCl3) δ9.07 (s, 2H), 9.02 (s, 1H), 8.37 (d, J=7.2 Hz, 1H), 7.89 (dd, J=7.7, 1.5 Hz, 1H), 7.57 (t, J=53.7 Hz, 1H), 7.47-7.40 (m, 2H), 7.11 (s, 1H), 3.95-3.92 (m, 4H), 3.83 (br s, 4H); Anal. Calcd. for C19H17F2N9O: C, 53.65; H, 4.1; N, 29.6. Found: C, 53.4; H, 4.2; N, 29.4%.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH2:4][CH2:3][C:2]1=[O:11].[BH3-]C#N.[Na+].Cl>O1CCOCC1.CCOC(C)=O>[NH:1]1[C@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: O=C1CCC2=C(CCCC2)N1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CC[C@@H]2CCCC[C@H]2N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3,4,5,6,7,8-hexahydro-1H-quinoline-2-one (0.1 g, 0.66 mmol) in dioxane (10 mL) containing a catalytic quantity (40 μL) was added NaCNBH3 (0.67 g). The reduction was left to stir for 20 hrs at r.t., and then diluted with EtOAc. The organic phase was treated with dilute HCl (3×), and the combined organics were washed with saturated HCO3−, brine, dried over Na2SO4, filtered and concentrated to afford the mainly traits product (98 mg, 95%, 15-20% cis isomer). MS (+ES) m/z 254 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22]([NH:24][NH:25][C:26](=O)[C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[O:23])[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:35])[CH:7]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22]4[O:23][C:26]([C:27]5[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=5)=[N:25][N:24]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:35])[CH:7]=1
Reactant: COC(=O)COc1cc(C)c(-c2nc3ccc(C(=O)NNC(=O)c4ccc(Cl)cc4)cc3[nH]2)c(C)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COC(=O)COc1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccc(Cl)cc5)o4)cc3[nH]2)c(C)c1
Reaction time: 0.33 h

Procedure:
To a 5 mL microwave vial was added 0.2010 g (0.369 mmol) of (4-{6-[N′-(4-Chloro-benzoyl)-hydrazinocarbonyl]-1H-benzoimidazol-2-yl}-3,5-dimethyl-phenoxy)-acetic acid methyl ester, 5 mL of THF, and 0.1890 g (0.793 mmol) of burgess reagent. The suspension was placed in the microwave at 150° C. for 20 min. The brownish solution was concentrated and the residue was purified by silica gel (ACN/DCM, 1:9 to 5:5) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 6 H) 3.72 (s, 4 H) 4.86 (s, 2 H) 6.81 (s, 2 H) 7.68-7.74 (m, 2.5 H) 7.87 (d, J=8.46 Hz, 0.5 H) 7.97-8.04 (m, 1 H) 8.15-8.24 (m, 2.5 H) 8.45 (s, 0.5 H) 12.93 (d, J=15.66 Hz, 1 H). MS (m/z) 489.1 M (+1), tR=1.40, Meth 10
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[NH:18][C:19](=[O:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>CCOC(C)=O.CCO.[Ni]>[NH2:15][C:13]1[CH:12]=[CH:11][C:10]([NH:18][C:19](=[O:21])[CH3:20])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(N)cc1OCc1ccccc1
Yield: 85.1 %

Procedure:
N-(2-Benzyloxy-4-nitro-phenyl)-acetamide (418) (5 g, 17.5 mmol) was dissolved in a mixture of EtOAc (25 mL) and EtOH (25 mL). The solution was chilled on an ice bath. Raney Nickel (5 mL, 50% slurry in water) followed immediately by anhydrous hydrazine (10 mL) were added. Violent bubbling was observed. The ice bath was removed after 10 minutes and the slurry continued to stir until all bubbling had ceased (˜30 minutes). LC-MS and TLC (Rf: 0.15 compared to Rf: 0.5 for compound 418 in 1:1 hexane/EtOAc) indicated complete reduction at this point. The reaction mixture was passed through a plug of silica gel, concentrated, dissolved in EtOAc (250 mL), washed with water (2×75 mL), brine (2×75 mL), dried over MgSO4 and concentrated to give the desired product (419) as a beige solid (3.82 g, 14.9 mmol, 85.3% yield). LC-MS (ESI): (exact mass: 256.12) m/e=257.1 [M+1]+ (100%), 513.2 [2M+1]+ (15%).