Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C(=O)CCC1=O.C(N(CC)CC)C.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.[CH2:28]([C:32]1[NH:33][C:34]2[CH2:39][CH:38]([C:40]([O:42][CH3:43])=[O:41])[NH:37][CH2:36][C:35]=2[N:44]=1)[CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH2:28]([C:32]1[NH:33][C:34]2[CH2:39][CH:38]([C:40]([O:42][CH3:43])=[O:41])[N:37]([C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:36][C:35]=2[N:44]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCc1nc2c([nH]1)CC(C(=O)OC)NC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc2c([nH]1)CC(C(=O)OC)N(C(=O)OCc1ccccc1)C2
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
N-Hydroxysuccinimide (0.69 g) and triethylamine (0.6 g) are dissolved in dry dimethylformamide (5 ml), and thereto is added dropwise benzyloxycarbonyl chloride (1.02 g) under ice-cooling. The mixture is stirred for 10 minutes, and thereto is added triethylamine (2.0 g). To the mixture is further added a solution of methyl 2-n-butyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylate hydrochloride (1.55 g) in dimethylformamide (5 ml), and the mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure, and thereto are added water and chloroform. The aqueous layer is extracted with chloroform, and the extract is combined with the chloroform layer, dried, and evaporated under reduced pressure to remove the solvent. The resulting oily residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give methyl 2-n-butyl-5-benzyloxycarbonyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylate (1.21 g) as pale yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:23][C:24](=O)[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[CH:32]=2)[C:28]([O:39][CH2:40][CH2:41][OH:42])=[C:27]([C:43]2[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=2)[CH:26]=1)C.CCOC(C)=O>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:24](=[O:23])[C:25]2[CH:30]=[C:29]([C:31]3[CH:32]=[C:33]([CH3:38])[CH:34]=[C:35]([CH3:37])[CH:36]=3)[C:28]([O:39][CH2:40][CH2:41][OH:42])=[C:27]([C:43]3[CH:44]=[C:45]([CH3:50])[CH:46]=[C:47]([CH3:49])[CH:48]=3)[CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cc(-c2cc(C)cc(C)c2)c(OCCO)c(-c2cc(C)cc(C)c2)c1
Reactant: NCCCCCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cc(C(=O)NCCCCCCCCc3ccccc3)cc(-c3cc(C)cc(C)c3)c2OCCO)c1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a cooled solution (0° C.) of 8-phenyloctyl amine (1.56 g, 7.58 mmol, 1.51 ml) in 10 mL anhydrous THF was added n-BuLi (5.1 mL, 7.96 mmol) as a solution in hexanes dropwise. After the addition, the reaction was warmed up to room temperature and was stirred for one-half hour at room temperature. Then the lithiated amine was cooled back down to 0° C. and was added to a cooled (0° C.) solution of 3,5-bis-(3,5-dimethylphenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (1.04 g, 2.49 mmol) in 10 mL anhydrous THF. The resulting reaction mixture was stirred for 5 min at 0° C. then allowed to warm up to room temperature. At that point, additional n-BuLi was added (2.04 mL, 3.18 mmol). When the reaction appeared to be practically complete (by TLC), it was worked up as in Step 2 of Example 135. After flash chromatography (25% EtOAc: 75% Hexanes), there yielded 850 mg, 59.4% of the amide as a yellow oil. 1H NMR (CDCl3) δ 1.25–1.40 (m, 8H); 1.40–1.64 (m, 5H); 2.37 (s, 12H); 2.57 (t, J=8.18 Hz, 2H); 3.25 (t, J=4.09 Hz, 2H); 3.36–3.47 (m, 4H); 6.06 (t, J=6.54 Hz, 1H); 7.02 (s, 2H); 7.11–7.19 (m, 4H); 7.20–7.48 (m, 5H); 7.69 (s, 2H).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[CH3:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36]#[N:37])=[N:32][CH:33]=2)[CH:14]=[C:15]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:16]=1>C(O)C>[OH:3][N:2]=[C:36]([NH2:37])[CH2:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([C:13]2[CH:14]=[C:15]([NH:17][C:18]3[N:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][N:19]=3)[CH:16]=[C:11]([CH3:10])[CH:12]=2)=[CH:33][N:32]=1
Reactant: NO
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CCC#N)nc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CCC(N)=NO)nc2)c1
Temperature: 80 °C

Procedure:
Hydroxylamine hydrochloride (147 mg, 2.11 mmol) and potassium carbonate (292 mg, 2.11 mmol) were added to 3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanenitrile (135 mg, 0.352 mmol) in ethanol (587 μL). The reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resultant reside was diluted with dichloromethane (2.00 mL), filtered through a short silica get pad and was concentrated under reduced pressure to yield crude N′-hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanimidamide. The crude oxime was diluted with dioxane (1.00 mL) and CDI (57.1 mg, 0.352 mmol), then DBU (106 μL, 0.704 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, diluted with 1:1 DMSO:methanol (2.00 mL) and filtered. The residue was direct purification by reverse phase chromatography (10-80% MeCN in water+0.5% TFA, linear gradient) to yield 3-{2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]ethyl}-1,2,4-oxadiazol-5(4H)-one as the TFA salt. MS APCI calc'd for C21H18F3N6O2 [M+H]+ 443. found 443. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.87-8.71 (m, J=18.2 Hz, 2H), 8.11-8.00 (m, 1H), 7.96 (s, 1H), 7.56 (s, 1H), 7.53-7.44 (m, 1H), 7.28 (d, 1H), 7.21 (s, 1H), 3.16 (t, 2H), 2.99 (t, 2H), 2.36 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([C:22]([F:25])([F:24])[F:23])[CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:11]([C:22]([F:25])([F:23])[F:24])[CH:10]=1
Reactant: C=Cc1cc(CNC(=O)OC(C)(C)C)cc(C(F)(F)F)c1NS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cc(CN)cc(C(F)(F)F)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 149.8 %

Procedure:
(4-Methanesulfonylamino-3-trifluoromethyl-5-vinylbenzyl)carbamic acid tert-butyl ester (89.3 mg, 0.23 mmol) and CF3COOH (5˜6 drops) were added into methylene chloride. The mixture was stirred for 12 hr. The reaction mixture was purified according to step 6 of Example 8 to give a title product (101.4 mg, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)[CH:29]=[O:30].[Cl-].[NH4+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:29]=[O:30])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(Br)c2)C1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=O)c2)C1
Reaction time: 0.25 h
Yield: 43 %

Procedure:
The solution of 1.3 g (3.6 mmol) (R)-2-(3-bromo-benzyl)-morpholine-4-carboxylic acid tert-butyl ester in 80 mL diethyl ether was cooled down to −100° C. and treated dropwise with 2.6 mL (3.9 mmol; 1.5M solution in n-pentane) tert-butyllithium. After 15 min. 0.31 mL (4.0 mmol) N,N-dimethylformamide were added and the reaction stirred for another 1.5 h. The solution was poured on 10% aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel with n-hexane:ethyl acetate (2:1 v/v) as eluant to give the desired compound as colorless oil (43%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:5]=1[NH:16]C(=O)C)([O-:3])=[O:2].[OH-].[Na+]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[C:5]=1[NH2:16])([O-:3])=[O:2]
Reactant: CC(=O)Nc1c(-c2ccncc2)cccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(-c2ccncc2)cccc1[N+](=O)[O-]
Yield: 92.7 %

Procedure:
To a solution of N-(2-nitro-6-(pyridin-4-yl)phenyl)acetamide (XCIII) (3.94 g, 15 mmol, 1 eq) in methanol (20 mL) was added 2 N aqueous NaOH solution (50 mL) and the mixture was refluxed until the starting material was consumed completely, the precipitate was collected by filtration to afford the 2-nitro-6-(pyridin-4-yl)aniline (XCIV) (3.0 g, 13.9 mmol, 91% yield) as yellow solid. ESIMS found for C11H9N3O2 m/z 216 (M+H).
Reaction SMILES: [ClH:1].Cl.C[O:4][C:5]([C:7]1[CH:8]=[C:9]([O:13][CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH3:20])[CH:10]=[N:11][CH:12]=1)=[O:6].[OH-].[Na+]>>[ClH:1].[ClH:1].[CH3:20][N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[CH2:14][O:13][C:9]1[CH:10]=[N:11][CH:12]=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=1
Reactant: COC(=O)c1cncc(OC[C@@H]2CCCN2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC[C@H]1COc1cncc(C(=O)O)c1

Procedure:
A sample of the compound from Example 100 above is hydrolyzed with 1N NaOH according to standard methods. The product is purified by chromatography on silica gel and converted into the title compound by treatment with HCl in ether according to Example 14c.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]([C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1)=[O:11])[CH2:6][C:7](=[O:9])[NH2:8].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[CH:33]=[C:32]([C:34](O)=[O:35])[S:31][C:30]=2[CH:37]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[CH:33]=[C:32]([C:34]([NH:4][C@@H:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)[CH2:14][CH2:13]3)=[O:11])[CH2:6][C:7](=[O:9])[NH2:8])=[O:35])[S:31][C:30]=2[CH:37]=1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)CC(N)=O)CC2)CC1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](CC(N)=O)NC(=O)c3cc4ccc(Cl)cc4s3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the subtitled compound was prepared from 1-(D-asparaginyl)-4-(1-methylpiperidin-4-yl)piperazine trihydrochloride and 6-chlorobenzo[b]thiophene-2-carboxylic acid (40%).
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][CH:43]=[CH:42][C:5]=1[C:6](=[O:41])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:30]=2)=[O:27])[C:9]1=[O:40])([O-])=O>[C].[Pd].CCO>[NH2:1][C:4]1[CH:45]=[CH:44][CH:43]=[CH:42][C:5]=1[C:6](=[O:41])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:24])[C:20]([CH3:23])([CH3:21])[CH3:22])[CH2:11][CH:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:30]=2)=[O:27])[C:9]1=[O:40]
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccccc3N(CC(=O)c3ccccc3[N+](=O)[O-])C2=O)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)C)c3ccccc3N(CC(=O)c3ccccc3N)C2=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
Etanol (20 ml) and 10% palladium carbon (70 mg) were added to 1-[1-(2-nitrophenacyl)-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (700 mg), the mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The reaction mixture was filtrated and the filtrate was concentrated under reduced pressure, to thereby to obtain 280 mg of the title compound as colorless oil.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:4]=[C:5](/[CH:12]=[CH:13]/[C:14]([O:16]CC)=[O:15])[N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12>CCO.C1COCC1>[N:3]1[CH:4]=[C:5](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12
Reactant: CCOC(=O)/C=C/c1cnc2ccccn12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1cnc2ccccn12
Temperature: 50 °C

Procedure:
A 1M aqueous solution of KOH (2.2 mL) was added to a solution of (E)-ethyl 3-(imidazo[1,2-a]pyridin-3-yl)acrylate (0.19 g, 0.88 mmol) in EtOH:THF (1:1 v/v) (10 mL). The resulting solution was heated at 50° C. for 3 h. After completion of the reaction the reaction mixture was evaporated and water (10 mL) was added to the residue. This solution was carefully acidified to pH 4 with a 3 M HCl aqueous solution. Since the product, (E)-3-(imidazo[1,2-a]pyridin-3-yl)acrylic acid, was soluble in water, the solution was concentrated under reduced pressure and the solid residue was used directly for the next step. ES+(M+H)+189.
Reaction SMILES: Cl.Cl.[CH:3]1([N:9]2[CH2:14][CH2:13][N:12]([CH:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=3)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br>C(O)(=O)C>[CH:3]1([N:9]2[CH2:10][CH2:11][N:12]([CH:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[CH2:13][CH2:14]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COc1cccc(CC(c2ccccc2)N2CCN(C3CCCCC3)CC2)c1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: Oc1cccc(CC(c2ccccc2)N2CCN(C3CCCCC3)CC2)c1

Procedure:
A mixture of dl-1-cyclohexyl-4-[2-(3-methoxyphenyl)-1-phenylethyl]piperazine dihydrochloride (3.3 g), 47% hydrobromic acid (33 ml) and glacial acetic acid (16 ml) is refluxed for 5 hours. The reaction mixture is allowed to cool and the precipitated crystals are collected by filtration, washed with acetone and recrystallized from methanol to give the desired compound as dihydrobromide (2.9 g), melting point: 268°-270° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][NH:9][C:10]2[N:19]=[C:18]([N:20]([CH3:22])[CH3:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([O:36][C:37]([F:40])([F:39])[F:38])[CH:27]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]3[N:19]=[C:18]([N:20]([CH3:22])[CH3:21])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)=[CH:23][CH:24]=2)(=[O:34])=[O:33])=[C:28]([O:36][C:37]([F:39])([F:38])[F:40])[CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)c1nc(NCc2ccc(CN)cc2)nc2ccccc12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc(NCc2ccc(CNS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)cc2)nc2ccccc12

Procedure:
A solution of N2-(4-aminomethyl-benzyl)-N4,N4-dimethyl-quinazoline-2,4-diamine hydrochloride (50.0 mg, 0.131 mmol), 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (53.3 mg, 0.157 mmol) and diisopropylethylamine (91 μl, 0.524 mmol) in 2-propanol (1.5 mL) was stirred at ambient temperature for 2 hr. The resulting mixture was concentrated, and the residue was purified by column chromatography (silica gel, 10% MeOH in CH2Cl2) to give 4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-2-trifluoromethoxy-benzenesulfonamide as a white crystalline compound (40 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[C:25]([OH:31])(=[O:30])[CH2:26][CH2:27][C:28]#[CH:29]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:29]#[C:28][CH2:27][CH2:26][C:25]([OH:31])=[O:30])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: C#CCCC(=O)O
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: O=C(O)CCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 8 h
Yield: 13.4 %

Procedure:
To a mixture of the title compound of Example 5 (0.457 g), copper iodide (0.010 g) and dichlorobis(triphenylphosphine)palladium (II) (0.035 g) in 15 mL diethylamine is added 4-pentynoic acid (0.098 g). The reaction is allowed to stir overnight. The solvents are evaporated and the residue is chromatographed on silica, eluting with 10% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and condensed. The residue is recrysallized from acetone/hexanes to yield 0.057 g of the desired product as a tan solid.
Reaction SMILES: [CH2:1]([P:3](=[O:17])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=O)[S:4][CH2:5][CH2:6][CH3:7])[CH3:2].[F:18][C:19]([F:31])([F:30])[C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1>CO.C(Cl)Cl>[CH2:1]([P:3](=[O:17])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[N:27][NH:26][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:31])[F:30])=[CH:29][CH:28]=1)[S:4][CH2:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCCSP(=O)(CC)Oc1ccccc1C=O
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCSP(=O)(CC)Oc1ccccc1C=NNC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of S-propyl O-(2-formylphenyl) ethylthiophosphonate (0.02 mole) in methanol (50 ml) and 4-trifluoromethylbenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml) with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product S-propyl O-[2-(4-trifluoromethylbenzoylhydrazonomethyl)phenyl] ethylthiophosphonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13](O)=[O:14])=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1.[CH3:39][N:40]1[CH2:45][CH2:44][CH:43]([NH:46]C)[CH2:42][CH2:41]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([NH:46][CH:43]1[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]1)=[O:14])=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1
Reactant: CNC1CCN(C)CC1
Reactant: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)O)cnc12
Product: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)NC3CCN(C)CC3)cnc12

Procedure:
8-Methoxy-N-(1-methyl-4-piperidinyl)-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxamide was prepared by coupling 8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid and commercially available 1-methyl-4-(methylamino)piperidine as described for Example 17, Step 5: mp 230°-232 ° C.; 1H NMR (Me2SO-d6, 400 MHz), 3:1 mixture of amide rotamers, a:b) δ 9.09 (s, 1Ha), 8.84 (s, 1Hb), 8.58 (s, 1Hb), 8.51 (s, 1Ha), 7.98 (d, J=7.9 Hz, 1Ha), 7.93 (d, J=7.9 Hz, 1Hb), 7.78 (d, J=8.7 Hz, 2Hb), 7.71 (d, J=8.7 Hz, 2Ha), 7.65 (d, J=8.3 Hz, 1 H), 7.51 (t, J= 8.5 Hz, 1 H), 7.43 (m, 5Hb), 7.30 (m, 5Ha), 7.24 (d, J=7.5 Hz, 1 H), 6.91 (d, J=8.7 Hz, 2Ha), 6.77 (d, J=8.7 Hz, 2Hb), 3.96 (s, 3 H), 3.74 (m, 2 H), 3.46 (s, 2 H), 3.32 (b, 2 H), 2.80 (d, J=11.6 Hz, 4Ha), 2.69 (s, 3Hb), 2.64 (d, J=12.2 Hz, 4Hb), 2.58 (s, 3Ha), 2.06 (s, 3Ha), 2.00 (t, J=13.9 Hz, 2 H), 1.97 (s, 3Hb), 1.72 (m, 4 H), 1.56-1.59 (m, 4 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18](F)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Br:8].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: Fc1cc2c(Nc3ccc(Br)c(Br)c3)ncnc2cn1
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNc2cc3c(Nc4ccc(Br)c(Br)c4)ncnc3cn2)cc1
Temperature: 70 °C
Reaction time: 138 h
Yield: 94.5 %

Procedure:
A mixture of compound 207 (3.40 g, 8.54 mmol) and 4-methoxybenzylamine (11.2 mL, 85.4 mmol) in dry DMSO (22 mL) was stirred under a nitrogen atmosphere at 70° C. (bath temperature) for 138 h. The mixture was then cooled and poured into water (400 mL). Petroleum ether (400 mL) was added and stirred at room temperature for 30 min. The layers were allowed to separate and the petroleum ether layer was decanted. This procedure was repeated with more petroleum ether (400 mL). It was filtered and washed solid with water (3×30 mL). The sticky yellow/orange solid was stirred with acetone (100 mL) at room temperature for ca. 30 min. to give a fine orange precipitate. Water (200 mL) was added and stirred further at room temperature for 2 h. The solid was collected by suction-filtration, washed with water/acetone (2:1) (5×30 mL), and dried in vacuum over silica-gel/KOH to give pure N4-(3,4-dibromophenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (216) (4.16 g, 95%) as a greenish yellow solid, mp 166-169° C.; 1H NMR δ [(CD3)2SO] 9.72 (s, 1H), 8.77 (s, 1H, 8.42 (s, 1H), 8.40 (br s, 1H), 7.89 (br d, J=7.7 Hz, 1H), 7.76 (d, J=8.7, Hz, 1H), 7.40-7.25 (m, 3H), 7.17 (s, 1H), 6.88 (br d, J=8.3 Hz, 2H), 4.49 (d, J=5.9 Hz, 2H), 3.71 (s, 3H). Anal. Calcd for C21H17Br2N5O.0.25hexane: C, 50.35; H, 3.85; N, 13.05%. Found C, 50.56; H, 3.54; N, 12.87%.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[N:13]=[C:14]3[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16][N:15]3[C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1>O1CCOCC1.ClCCl>[ClH:1].[CH:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:11]1[N:15]3[CH2:16][CH2:17][NH:18][CH2:19][C:14]3=[N:13][C:12]=1[C:3]([NH2:2])=[N:4]2
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3c(N)nc4ccccc4c32)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1nc2ccccc2c2c1nc1n2CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (300 mL of a 4 N solution in 1,4-dioxane) was added to a solution of tert-butyl 6-amino-10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate (34.74 g, 102.36 mmol) in dichloromethane (300 mL). The reaction was stirred overnight at ambient temperature and then concentrated under reduced pressure. The resulting solid was suspended in dichloromethane, isolated by filtration, and washed sequentially with dichloromethane, diethyl ether, hexane, and diethyl ether. The solid was then triturated with methanol and isolated by filtration to provide 11.58 g of 8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine hydrochloride as a white solid. The filtrate was concentrated under reduced pressure, dissolved in water, and precipitated with 1,4-dioxane to provide an additional 6.95 g of product.