Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:18][NH:19][C:20]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.FC(F)(F)S(O)(=O)=O>ClCCl>[CH3:18][NH:19][C:20]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][C:23]([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:22][CH2:21]1
Reactant: c1ccc2c(CCc3ccncc3)c[nH]c2c1
Reactant: CNC1(c2ccccc2)CCC(=O)CC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CCc2ccncc2)(c2[nH]c3ccccc3c2CCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
3-(2-pyridin-4-ylethyl)-1H-indole (667 mg, 3 mmol, synthesis cf. WO2008009415, indole unit Ind-14) together with 4-(methylamino)-4-phenylcyclohexanone (610 mg, 3 mmol, synthesis cf. WO2008009415, ketone unit Ket-15) was dissolved in abs. dichloromethane (45 ml) and mixed with trifluoromethane sulphonic acid (0.613 ml, 6.9 mmol). The batch was stirred for 64 h at RT, and a brown oil separated out. For work up the reaction solution was mixed with 1N NaOH (30 ml) and methanol (10 ml). The mixture was stirred a further 60 min. After separation of the phases the aqueous phase was extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over Na2SO4 and then concentrated to low volume. The raw product obtained (1.47 g) was purified by column chromatography [silica gel 60 (90 g); ethyl acetate/methanol 5:1 (1200 ml); ethyl acetate/methanol 1:1 (1200 ml)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([NH:23][NH2:24])=[O:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Cl.[C:31](=N)(OCC)[CH3:32]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]=[C:13]([C:18]4[CH:27]=[CH:26][CH:25]=[C:20]([C:21]5[O:22][C:31]([CH3:32])=[N:24][N:23]=5)[CH:19]=4)[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NNC(=O)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1nnc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)o1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 45.3 %

Procedure:
A mixture of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoic acid hydrazide (Starting material 8a-2) (58 mg, 0.15 mmol) and ethyl acetimidate hydrochloride (74 mg, 0.6 mmol) in pyridine (0.6 mL) was heated to 100° C. for 2 h. The mixture was cooled to 23° C., diluted with H2O (30 mL) and stirred for 20 min. The precipitate was collected by filtration, and the crude product was purified by chromatography on silica gel using ethyl acetate/hexane (2:1) as eluent. The purified product was crystallized from Et2O/hexane to give the title compound as light yellow solid (28 mg).
Reaction SMILES: C1(C(=[N:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([C:24]3[N:32]=[C:31]4[C:27]([N:28]=[C:29]([CH2:34][N:35]5[CH2:40][CH2:39][CH:38]([C:41]([OH:44])([CH3:43])[CH3:42])[CH2:37][CH2:36]5)[N:30]4[CH3:33])=[C:26]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:25]=3)[N:16]=2)C2C=CC=CC=2)C=CC=CC=1.Cl.NO>CO>[NH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]2[N:32]=[C:31]3[C:27]([N:28]=[C:29]([CH2:34][N:35]4[CH2:36][CH2:37][CH:38]([C:41]([OH:44])([CH3:43])[CH3:42])[CH2:39][CH2:40]4)[N:30]3[CH3:33])=[C:26]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[N:25]=2)[N:16]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3nc(N=C(c4ccccc4)c4ccccc4)c4ccccc43)nc21
Agent: Cl
Agent: NO
Solvent: CO
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3nc(N)c4ccccc43)nc21

Procedure:
2-(1-((2-(3-(Diphenylmethyleneamino)-1H-indazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and hydroxylamine hydrochloride (12.4 mg) in MeOH (2 mL) were stirred overnight at room temperature. The crude was purified by reverse phase HPLC to give 129 as a white solid (32.6 mg). MS (Q1) 506.3 (M)+. 1H NMR (400 MHz, DMSO) δ 8.56 (d, 1H), 7.83 (d, 1H), 7.47 (t, 1H), 7.17 (t, 1H), 6.05 (s, 2H), 4.26 (s, 5H), 4.02 (s, 1H), 3.79 (s, 7H), 3.68 (s, 4H), 2.86 (t, 2H), 1.97 (t, J=2H), 1.66 (d, 2H), 1.33-1.11 (m, 4H), 1.02 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([Cl:21])[CH:14]=2)=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.CC(C)([O-])C.[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([Cl:21])[CH:14]=2)=[N:9][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Reactant: OCc1ccccn1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ncc(OCc2ccccn2)nc1NCc1ccc(OC)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a mixture of 2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-chloropyrazine (prepared in the above Example 297(3)) 71 mg and 2-hydroxymethylpyridine 25 mg in tetrahydrofuran 3 ml is added potassium tert-butoxide 26 mg under ice cooling. The mixture is stirred for 30 minutes at the same temperature and diluted a 10% aqueous citric acid solution. The solution is extracted with ethyl acetate and the extract is washed with water and an aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is purified and separated with silica gel chromatography (silica gel 5 g, solvent; chloroform:ethyl acetate=3:1) and crystallized from isopropyl ether to give 2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylmethoxy)pyrazine as a pale yellow crystalline powder, 25 mg. mp 132-133° C., MS(m/z): 415(M+H)+
Reaction SMILES: [ClH:1].CCOC(C)=O.[C:8]1([C:14]2[N:19]=[C:18]3[N:20]4[C:26]([C:27]5[CH:32]=[N:31][CH:30]=[CH:29][N:28]=5)=[N:25][N:24]=[C:21]4[CH:22]=[CH:23][C:17]3=[N:16][C:15]=2[C:33]2[CH:38]=[CH:37][C:36]([C:39]3([NH:43]C(=O)OC(C)(C)C)[CH2:42][CH2:41][CH2:40]3)=[CH:35][CH:34]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.C(Cl)Cl>[ClH:1].[C:8]1([C:14]2[N:19]=[C:18]3[N:20]4[C:26]([C:27]5[CH:32]=[N:31][CH:30]=[CH:29][N:28]=5)=[N:25][N:24]=[C:21]4[CH:22]=[CH:23][C:17]3=[N:16][C:15]=2[C:33]2[CH:34]=[CH:35][C:36]([C:39]3([NH2:43])[CH2:42][CH2:41][CH2:40]3)=[CH:37][CH:38]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc5nnc(-c6cnccn6)n5c4nc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1(c2ccc(-c3nc4ccc5nnc(-c6cnccn6)n5c4nc3-c3ccccc3)cc2)CCC1

Procedure:
A 4N solution of HCl in EtOAc (10 mL, 40 mmol) was added to stirred solution of tert-butyl{1-[4-(2-phenyl-9-pyrazin-2-yl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazin-3-yl)phenyl]cyclobutyl}carbamate (8-7, 0.110 g, 0.193 mmol) in MeOH (2 mL) and DCM (2 mL). After 4 hours the reaction mixture was concentrated in vacuo to give 1-[4-(2-phenyl-9-pyrazin-2-yl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazin-3-yl)phenyl]cyclobutanamine hydrochloride (8-8) as an orange/tan solid. HRMS (M+H)+: observed=471.2076, calculated=471.2040.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[CH:33]=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2/[CH:33]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2C=O)CC1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 70 °C
Yield: 40.9 %

Procedure:
To a mixture of 6-chlorooxindole (0.84 g, 5 mmol) and 4-(4-chloro-2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (1.7 g, 5 mmol) in methanol (10 mL) was added pyrrolidine (0.4 mL, 5 mmol) dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and the precipitate was collected, dried to give the title compound as a bright yellow solid (1 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([NH:36][C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc(OCCN3CCC(N)CC3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 14 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (60 mg, 0.26 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamine (80 mg, 0.26 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed by 1-hydroxybenzotriazole (38 mg, 0.29 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (57 mg, 0.30 mmol, 1.15 eq) and N,N-diisopropylethylamine (100 μL, 0.58 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide as an off-white solid (18 mg, 13% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[CH2:17](N(CC)CC)[CH3:18]>C1COCC1>[OH:16][C@H:12]([CH2:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[NH:9][N:8]=[CH:7]2)[C:13]([O:15][CH2:17][CH3:18])=[O:14]
Reactant: CCN(CC)CC
Reactant: Cc1cc(CC(=O)C(=O)O)cc2cn[nH]c12
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](O)Cc1cc(C)c2[nH]ncc2c1
Temperature: -25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2.31 g (7.2 mmol) (1R)—B-chlorodiisopinocampheylborane in 20 mL THF was added dropwise within 30 min to a solution of 1.3 g (5.96 mmol) 3-(7-methyl-1H-indazol-5-yl)-2-oxo-propionic acid and 0.84 mL (7.2 mmol) triethylamine in 50 mL THF cooled to approx. −25° C. and the reaction mixture was kept for 1.5 h at this temperature and then heated to RT within another hour. The mixture was evaporated down i.vac., the residue was taken up in 100 mL 4 M ethanolic HCl and stirred overnight at RT. 200 mL EtOAc and 200 mL 15% K2CO3 solution were added, the organic phase was separated off and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was purified chromatographically by HPLC.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:11]>CO.O>[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:11]
Reactant: O=C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])c1ccccc1

Procedure:
50 mmol benzoic acid is dissolved in 50 mL methanol. 50 mmol NaOH dissolved in 50 mL water is added slowly to the benzoic acid solution prepared while stirring to obtain sodium benzoate. 50 mmol silver nitrate dissolved in 50 mL water is added to the sodium benzoate solution, and then white precipitate forms fast. The precipitate is silver benzoate formed by exchange of Na+ and Ag+ by ionization tendency, washed to remove unreacted silver nitrate and NaOH with water, filtered and further washed several times to remove unreacted benzoic acid with methanol, and dried at 50° C. to obtain final silver benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1([S:19](Cl)(=[O:21])=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.O>O1CCOCC1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:19]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)(=[O:21])=[O:20])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1ccc(O)cc1)c1cccc2ccccc12
Reaction time: 4.5 h
Yield: 72.3 %

Procedure:
To a solution of 4-aminophenol (4.5 g) in dioxane (20 ml) was added dropwise a solution of 1-naphthalenesulfonyl chloride (4.4 g) in dioxane (20 ml). The mixture was further stirred at room temperatue for 4.5 hours and poured into water. The precipitate was collected by filtration, recrystallized from ethanol and decolored with activated carbon to give N-(ρ-hydroxyphenyl)-1-naphthalenesulfonamide (4.2 g), mp 195-196° C.
Reaction SMILES: [C:1](=[N:14][C:15]1[C:20]([F:21])=[C:19]([CH2:22][O:23][Si](C(C)(C)C)(C)C)[CH:18]=[CH:17][N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[C:1](=[N:14][C:15]1[C:20]([F:21])=[C:19]([CH2:22][OH:23])[CH:18]=[CH:17][N:16]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(N=C(c2ccccc2)c2ccccc2)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccnc(N=C(c2ccccc2)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of benzhydrylidene-[4-(tert-butyldimethylsilyloxymethyl)-3-fluoropyridin-2-yl]-amine (14 mg, 32 μmol) and tetrabutylammonium fluoride (1 mol/L in THF) (65 μL, 65 μmol) in THF (0.5 mL) was stirred at room temperature for 30 minutes. Ethyl acetate was then added to the reaction solution, and the solution was washed with sodium hydrogen carbonate solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The resultant residue was purified by silica gel column chromatography to yield the title compound.
Reaction SMILES: [CH:1]1([N:14]2[CH2:30][CH2:29][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][CH2:19][CH:18]3[OH:28])[CH2:16][CH2:15]2)[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH2:7][CH2:6][CH2:5][CH:4]3[CH2:3][CH2:2]1.[C:31]([O-:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([O-:36])=[O:35].C(O)(=O)/C=C/C(O)=O>C(OCC)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[CH:1]1([N:14]2[CH2:30][CH2:29][C:17]3([N:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][CH2:19][C:18]3=[O:28])[CH2:16][CH2:15]2)[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH2:7][CH2:6][CH2:5][CH:4]3[CH2:3][CH2:2]1
Reactant: OC1CCN(c2ccccc2)C12CCN(C1CCC3CCCc4cccc1c43)CC2
Reactant: O=C([O-])/C=C/C(=O)[O-]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: O=C1CCN(c2ccccc2)C12CCN(C1CCC3CCCc4cccc1c43)CC2

Procedure:
Oxidation of 8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (mixture of diastereoisomers) according to the general method of example 20 and formation of the fumarate with fumaric acid in diethyl ether yielded the title compound, pale brown solid, m.p. 144° C. and MS: m/e=401.5 (M+H+).
Reaction SMILES: C(N=[C:10]=[S:11])(=O)C1C=CC=CC=1.[C:12]([C:15]1[NH:19][CH:18]=[N:17][C:16]=1[NH:20][CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)(=[O:14])[NH2:13].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl.CO>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[NH2:23][CH2:22][CH2:21][N:20]1[C:16]2[N:17]=[CH:18][NH:19][C:15]=2[C:12](=[O:14])[NH:13][C:10]1=[S:11]
Reactant: CC(C)(C)OC(=O)NCCNc1nc[nH]c1C(N)=O
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
Benzoyl isothiocyanate (1.3 mL, 9.8 mmol) was added to tert-butyl {2-[(5-carbamoyl-1H-imidazol-4-yl)amino]ethyl}carbamate (2.5 g, 9.3 mmol, obtained from Example 26(a)) in dichloromethane (25 mL) and methanol (0.050 mL) at 0° C. The mixture was allowed to reach r.t. and stirred for 3 h. After removal of solvents, the residue was dissolved in ammonia (7 N in methanol, 30 mL) and subjected to microwave heating at 80° C. for 5 h. The solvent was then evaporated and the Boc-protected product was purified by silica gel column chromatography (dichloromethane/methanol 95:5) which gave 1.5 g (52% yield). This material (1.5 g, 4.9 mmol) was dissolved in dichloromethane (50 mL) and treated with trifluoroacetic acid (7 mL). After 2 h, the mixture was concentrated, diethyl ether was added and the solid was collected and dried in vacuo to afford 1.1 g (67% yield) of the title compound as its trifluoroacetic acid salt.
Reaction SMILES: ClCCCC([O:11]C(=O)C)CCCCC.BrCC#CC(OC(=O)C)CCCCC.C([O:32][CH:33]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:34]#[C:35][CH2:36][N:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48]CC)=[O:47])[C:38]#[N:39])(=O)C>>[OH:32][CH:33]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:34]#[C:35][CH2:36][N:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])[C:38]([NH2:39])=[O:11]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: CCCCCC(C#CCN(C#N)CCCCCCC(=O)OCC)OC(C)=O
Agent: CCCCCC(C#CCBr)OC(C)=O
Product: CCCCCC(O)C#CCN(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-bromo-4-acetoxy-2-nonyne (Example I, Step 3). The product of Step A is thus ethyl 7-[N-(4-acetoxy-2-nonynyl)cyanamido]heptanoate. The subsequent steps yield 7-[N-(4-hydroxy-2-nonynyl)cynamido]heptanoic acid (B), and 7-[1-(4-hydroxy-2-nonynyl)ureido]heptanoic acid (C).
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(=O)C)=[C:19]([CH3:28])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[OH-].[K+]>O1CCCC1.CO>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH3:28])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CC(=O)Oc1c(C)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
To a solution of acetic acid 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenyl ester (6.5 g, 14.3 mmol) in tetrahydrofuran (240 mL) and methanol (80 mL) at room temperature was added dropwise aqueous potassium hydroxide (17.2 mL of a 1N solution, 17.2 mmol). After 4 h at room temperature the reaction mixture was placed in the freezer for 18 h. The reaction was removed from the freezer and allowed to stir at room temperature. More aqueous potassium hydroxide (41.5 mL of a 1N solution, 41.5 mmol), tetrahydrofuran (50 mL), and methanol (10 mL) were added. The mixture was diluted with water (500 mL), acidified with 1N aqueous solution of hydrochloric acid, and extracted with diethyl ether. The diethyl ether layer was washed twice with water (500 mL), and dried (MgSO4). Concentration under reduced pressure gave a residue which was adsorbed onto silica gel. Chromatography with petroleum ether:ethyl acetate (97:3, then 95:5) gave the title compound as a white foamy solid (5.5 g, 93%): NMR (CDCl3): δ8.41 (s, 1H), 8.16 (d, 1H), 7.64-7.54 (m, 2H), 7.46-7.40 (m, 1H), 6.89 (s, 2H), 2.41 (s, 3H), 2.23 (s, 6H), 1.60 (s, 3H); MS(−ESI): [M−H], 1 bromine isotope pattern, 409/411.
Reaction SMILES: [CH3:1]C1C=CC(C2C=NN(C)C=2)=C(C=1)C(OC)=O.Br[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[N:22][C:23]([NH:29][CH2:30][C@@H:31]1[C@H:36]([CH3:37])[CH2:35][CH2:34][CH2:33][N:32]1[C:38]([C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[N:47]1[N:51]=[CH:50][CH:49]=[N:48]1)=[O:39])=[N:24]2.CB1OB(C)OB(C)O1>>[CH3:37][C@@H:36]1[CH2:35][CH2:34][CH2:33][N:32]([C:38]([C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=2[N:47]2[N:51]=[CH:50][CH:49]=[N:48]2)=[O:39])[C@@H:31]1[CH2:30][NH:29][C:23]1[N:22]=[CH:21][C:20]2[C:25](=[CH:26][CH:27]=[CH:28][C:19]=2[CH3:1])[N:24]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3c(Br)cccc3n2)c1
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Agent: CB1OB(C)OB(C)O1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3c(C)cccc3n2)c1

Procedure:
The title compound was prepared following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using ((2S,3R)-2-(((5-bromoquinazolin-2-yl)amino)methyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane. ESI-MS (m/z): 456 [M+1]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2>Br>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: COc1ccc2cnccc2c1
Agent: Br
Product: Oc1ccc2cnccc2c1
Yield: 82.2 %

Procedure:
6-Methoxyisoquinoline (16 g, 0.1M) and 48% aqueous HBr (600 ml) were refluxed together for 6 hours and the mixture was then evaporated to dryness in vacuo. The residue was dissolved in H2O and basified with solid Na2CO3. The resulting precipitated solid was filtered off and recrystallised from isopropanol to give 6-hydroxyisoquinoline (12 g, 82%), m.p. 218°-20° C. (lit.* 220° C.).
Reaction SMILES: [OH:1][C@@H:2]([CH3:35])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14](CC3C=CC=CC=3)[C:13]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:12][C:11]=2[N:10]([CH3:34])[C:8]1=[O:9].[H][H]>C(O)C.[Pd]>[OH:1][C@@H:2]([CH3:35])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[NH:14][C:13]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[N:12][C:11]=2[N:10]([CH3:34])[C:8]1=[O:9]
Reactant: [H][H]
Reactant: C[C@H](O)CCCCn1c(=O)c2c(nc(CNC(=O)OC(C)(C)C)n2Cc2ccccc2)n(C)c1=O
Agent: [Pd]
Solvent: CCO
Product: C[C@H](O)CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O
Yield: 81.6 %

Procedure:
To a solution of (S)-1-(5-hydroxyhexyl)-7-benzyl-8-(N-BOC-aminomethyl)-3-methylxanthine (0.6 g, 1.24 mmol) in ethanol (60 ml) was added 10% palladium on carbon catalyst (0.5 g). The mixture was treated with hydrogen gas (50 psi) on a Parr shaker for 18 hours. Removal of the catalyst by filtration and evaporation of the solvent under reduced pressure provides (S)-1-(5-hydroxyhexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.4 g, 82% yield) as a white solid.