Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])[CH:13]=[CH:12]2>>[CH3:23][CH:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:10]=2)[CH:15]=1)[C:20]([OH:22])=[O:21]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCI
Product: CCCCCCOc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 1-iodohexane and racemic 6-hydroxy-α-methyl-2-naphthalene acetic acid. White crystals are obtained having a melting point of 88°-91° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][SH:9].Cl[C:11]1[CH:21]=[C:15]2[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:22])[N:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:11]1[CH:21]=[C:15]2[N:16]([CH3:20])[CH2:17][CH2:18][CH2:19][N:14]2[C:13](=[O:22])[N:12]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: SCc1ccccc1Cl
Product: CN1CCCn2c1cc(SCc1ccccc1Cl)nc2=O

Procedure:
The title compound or it salt was prepared by a procedure similar to that described for E62 starting from (2-chlorophenyl)methanethiol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: O[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)[Cl:19]>>[CH2:15]([O:14][C:12]([C:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:19])[C:3]=2[NH:10][C:9]=1[CH3:11])=[O:13])[CH3:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)[nH]c2c(O)ncnc12
Product: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12

Procedure:
A reaction flask, equipped with a mechanic stirrer, a reflux condenser and a nitrogen bubbler is charged with POCl3 (1200 mL). Ethyl 4-hydroxy-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate from example A3 (207.19 g; 1.00 mol) is added in several portions. The carefully stirred suspension is heated to gentle reflux for five hours.
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:21][C:8]=2[N:7]=1)([CH3:5])[CH2:3][CH3:4].[NH:26]1[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27]1.[H-].[Na+]>C1COCC1>[CH3:1][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][C:20]([S:22]([N:26]3[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27]3)(=[O:24])=[O:23])=[CH:21][C:8]=2[N:7]=1)([CH3:5])[CH2:3][CH3:4]
Reactant: O=Cc1cc[nH]c1
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C=O)c3)ccc2n1CC1CCOCC1
Yield: 72.5 %

Procedure:
Following the same procedure in Example 29, using 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (0.66 g, 1.7 mmol), 1H-pyrrole-3-carbaldehyde (0.14 g, 1.4 mmol) and sodium hydride (0.29 g, 60%, 7.2 mmol) in THF (15 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 0.45 g (71%) of a white solid as the title compound. MS (ESI) (M+H)+=443.93
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:43]3[CH2:42][CH2:41][N:40]([CH2:46][CH2:47][NH:48][C:49](=[O:51])[CH3:50])[CH2:45][CH2:44]3)=[O:36])[C:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)NCCN1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-(2-piperazin-1-yl-ethyl)-acetamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C36H46N7O3Cl2 [(M+H)+] 694.3034, observed 694.3035.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24]>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]([CH2:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3ccccc32)c1
Temperature: 0 °C
Yield: 49.3 %

Procedure:
To a solution of 2-phenyl-1H-indole (4.64 g, 24.0 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.96 g, 24.0 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 10 min. Methyl 3-(bromomethyl)benzoate (5.0 g, 21.8 mmol) was added to the obtained mixture, and the mixture was stirred at the same temperature for 2 hr. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the mixture washed with 5% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl 3-[(2-phenyl-1H-indol-1-yl)methyl]benzoate (3.67 g). Then, to a solution of the product in tetrahydrofuran (37 mL) was added lithium aluminum hydride (0.41 g, 10.7 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 2 hr. After completion of the reaction, sodium hydrogensulfate decahydrate (6.9 g, 21.4 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/1) to give the title compound (2.63 g, yield 79%) as a yellow oil. 1H NMR (CDCl3) δ: 1.57 (1H, m), 4.62 (2H, d, J=2.1 Hz), 5.37 (2H, s), 6.66 (1H, s), 6.93 (1H, m), 7.07 (1H, s), 7.11-7.20 (3H, m), 7.22-7.31 (2H, m), 7.33-7.48 (5H, m), 7.67 (1H, m).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9]Br.[C:11]([C:15]1[CH:16]=[C:17]([C:25](=[O:27])[CH3:26])[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[OH:21])([CH3:14])([CH3:13])[CH3:12].C(OCC)(=O)C>CN(C)C=O>[Br:7][CH2:8][CH2:9][O:21][C:20]1[C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]([C:25](=[O:27])[CH3:26])=[CH:16][C:15]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c(C(C)(C)C)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc([N+](=O)[O-])c(OCCBr)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.8 %

Procedure:
Potassium carbonate (4.65 g, 33.7 mmol) and 1,2-dibromoethane (31.7 g, 166.6 mmol) were added to a solution of 1-[3-(tert-butyl)-4-hydroxy-5-nitrophenyl]-1-ethanone (8.0 g, 33.7 mmol) in dimethylformamide (200 ml) and the mixture was stirred at room temperature for 12 hours. Ethyl acetate was added, the reaction mixture was washed with water and brine in that order and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield 1-[4-(2-bromoethoxy)-3-(tert-butyl)-5-nitrophenyl]-1-ethanone (8.1 g).
Reaction SMILES: C([O:4][CH:5]([CH2:21][O:22]C(=O)C)[CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:12]([O-:20])=[CH:11][C:10]=2[N:9]=[CH:8]1)(=O)C>CO.C[O-].[Na+]>[OH:4][CH:5]([CH2:21][OH:22])[CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:12]([O-:20])=[CH:11][C:10]=2[N:9]=[CH:8]1
Reactant: CC(=O)OCC(Cn1cnc2c[n+]([O-])c3ccccc3c21)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: [O-][n+]1cc2ncn(CC(O)CO)c2c2ccccc21

Procedure:
To a stirred solution of 4.0 g (0.0117 mole) of 1-(2,3-diacetoxypropyl)-1H-imidazo[4,5-c]quinolin-5-oxide (from Example 121, Part A) in 50 ml of methanol was added about 12 drops of 25% sodium methoxide solution. After one hour the product was collected by filtration, washed with methanol and recrystallized from ethanol to provide 1-(2,3-dihydroxypropyl)-1H-imidazo[4,5-c]quinolin-5-oxide, m.p. 240°-242° C. Analysis: Calculated for C13H13N3O3 : % C, 60.2; % H, 5.1; % N, 16.2; Found: % C, 60.0; % H, 5.0; % N, 15.8.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]1[N:10]2[C:11]([C:15]([O:17]CC)=O)=[C:12]([CH3:14])[N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.O>CN(C=O)C>[CH3:14][C:12]1[N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[N:10]2[C:11]=1[C:15](=[O:17])[NH:4]3
Reactant: CCOC(=O)c1c(C)nc2cccc(N)n12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cccc3[nH]c(=O)c1n23
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a suspension of 4.8 g (120 mmol) of sodium hydride (60% dispersion in oil) in 60 ml of DMF was added 10.23 g (40 mmol) of 5-amino-3-ethoxycarbonyl-2-methylimidazo[1,2-a]pyridine.hydrochloride with small portions. The mixture was stirred for 0.5 hour, then for 0.5 hour at 100° C., which was left standing for cooling. To the reaction mixture was added 60 ml of water. The mixture was washed with chloroform, to which was added, while stirring at room temperature, conc. HCl to make the pH of the solution 8. The resulting precipitate was collected by filtration, washed with water and ether, successively to give 5.97 g of the desired compound (86.1%, pale brown solid).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:16][CH2:17][C:18]1[CH:29]=[CH:28][C:21]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[CH:20][CH:19]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[CH:28][CH:29]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Reactant: C=CCOC(=O)c1ccc(CO)cc1
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc(OC)c(C(C)(C)C)c2)cc1

Procedure:
In a manner similar to Example 1(d), by reaction of 2.4 g (18 mmol) of 3-tert-butyl-4-methoxybenzoyl chloride with 1.9 g (10 mmol) of allyl 4-hydroxymethylbenzoate, 2.65 g (69%) of allyl ester are obtained in the form of a slightly yellow oil.
Reaction SMILES: [Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:25].I([C:29]1C=CC=C[C:30]=1C(O)=O)(=O)=O>CS(C)=O.O>[CH2:29]([SH:23]1[C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]([CH:24]=[O:25])=[C:2]1[Br:1])[CH3:30]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Br)sc21
Reactant: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: CC[SH]1C(Br)=C(C=O)c2c1n(C)c(=O)n(CCCOC1CCCCO1)c2=O
Temperature: 50 °C
Yield: 53.8 %

Procedure:
To a solution of 6-bromo-5-(bromomethyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy) propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 2, Step 3, 800 mg, 1.61 mmol) in DMSO (10 mL) was added 2-iodoxybenzoic acid (541.7 mg, 1.93 mmol). The reaction was heated at 50° C. for 1.5 h, cooled to RT, diluted with water (20 mL) and extracted with EA (3×10 mL). The combined organic layers were washed with aq. NH4Cl (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give ethyl 6-bromo-1-methyl-2,4-dioxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1,2,3,4-tetrahydro thieno[2,3-d]pyrimidine-5-carbaldehyde (400 mg, 57.5% yield) as a white solid. LCMS: [MH+-THP] 347 and TR=1.665 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][N:18]=1>>[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]3[CH3:11])=[CH:4][CH:3]=2)=[O:22])=[CH:19][N:18]=1
Reactant: CN1C(=O)C(C)(C)c2ccc(N)cc21
Reactant: COc1ccc(C(=O)O)cn1
Product: COc1ccc(C(=O)Nc2ccc3c(c2)N(C)C(=O)C3(C)C)cn1

Procedure:
Prepared in analogy to example 1b from 6-amino-1,3,3-trimethylindolin-2-one and 6-methoxynicotinic acid. The title compound was obtained as light yellow foam.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[O:56][N:55]=[CH:54][C:53]=2[C:57](O)=[O:58])=[CH:48][CH:47]=1>CN(C=O)C>[CH3:45][C:46]1[CH:47]=[CH:48][C:49]([C:52]2[O:56][N:55]=[CH:54][C:53]=2[C:57]([N:10]2[CH2:11][C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]([CH2:12][OH:13])[CH2:9]2)=[O:58])=[CH:50][CH:51]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: OCC1CNCC1c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2oncc2C(=O)N2CC(CO)[C@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
A solution of (4-phenylpyrrolidin-3-yl)methanol (7 mg, 0.033 mmol), TBTU (13 mg, 0.039 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (11 μL, 0.066 mmol, 2 equ.) in DMF (0.3 mL) was added to 5-(4-methylphenyl)isoxazole-4-carboxylic acid (7 mg, 0.033 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (4 mg). MS (ESI, pos. ion) m/z calcd for C22H22N2O3: 362.1630, found 362.1629.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:21])[CH2:12][NH:13][C:14]2[C:15](=[O:20])[NH:16][N:17]=[CH:18][CH:19]=2)[CH2:7][CH2:6]1.Br[CH2:31][C:32]#[C:33][CH3:34]>>[CH2:31]([N:16]1[C:15](=[O:20])[C:14]([NH:13][CH2:12][C:11]([N:8]2[CH2:9][CH2:10][CH:5]([O:4][C:3]3[CH:22]=[C:23]([C:26]([F:29])([F:27])[F:28])[CH:24]=[CH:25][C:2]=3[Cl:1])[CH2:6][CH2:7]2)=[O:21])=[CH:19][CH:18]=[N:17]1)[C:32]#[C:33][CH3:34]
Reactant: CC#CCBr
Reactant: O=C(CNc1ccn[nH]c1=O)N1CCC(Oc2cc(C(F)(F)F)ccc2Cl)CC1
Product: CC#CCn1nccc(NCC(=O)N2CCC(Oc3cc(C(F)(F)F)ccc3Cl)CC2)c1=O
Yield: 9 %

Procedure:
Compound 46 is prepared from intermediate 7b and from 1-bromo-but-2-yne following synthesis method 6 (yield: 9%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][O:20][CH3:21]>C(O)C>[CH3:13][O:14][CH2:15][CH2:16][N:17]([CH2:18][CH2:19][O:20][CH3:21])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: COCCNCCOC
Solvent: CCO
Product: COCCN(CCOC)c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 90.6 %

Procedure:
4 g (0.0212 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 50 ml of ethanol and 6.32 ml (0.0424 mol) of bis(2-methoxyethyl)amine are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 5.47 g of yellow powder are obtained, ie a yield of 90.6%.
Reaction SMILES: [OH:1][CH:2]([C:4]1([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH3:3].[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1.C(N(CC)CC)C>C1C=CC=CC=1>[OH:1][CH:2]([C:4]1([N:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1)[CH3:3]
Reactant: CC(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(O)C1(N(C(=O)C2CC2)c2ccccc2)CCN(CCc2ccccc2)CC1
Yield: 66.1 %

Procedure:
A solution of 4-(1-hydroxyethyl)-4-(N-phenylamino)-1-(2-phenylethyl)-piperidine (0.200 g), cyclopropylcarboxylic acid chloride (1 g) and triethylamine (2.2 g) in dry benzene (30 ml) was stirred for 2.5 hours at 60°-65° C. After cooling the mixture was washed with dilute sodium carbonate solution, dried over MgSO4 and then concentrated. The residue was chromatographed on silica gel using chloroform-methanol 76:1 as eluant to give the title compound (0.160 g), which with oxalic acid gave an oxalate salt, m.p. 158°-159° C.
Reaction SMILES: ClC1C=CC(O[CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=CC=1.Cl.N[C@@H](CCN1CC([C:40](=[O:49])[C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([F:48])[CH:42]=2)C1)CO>>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([C:40]([CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:10]2)=[O:49])=[CH:42][C:43]=1[F:48]
Reactant: N[C@H](CO)CCN1CC(C(=O)c2ccc(Cl)c(F)c2)C1
Reactant: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)s1
Agent: Cl
Product: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(C(=O)c3ccc(Cl)c(F)c3)C2)s1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-urea in Example 99 except using (S)-2-amino-4-[3-(4-chloro-3-fluoro-benzoyl)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:28])[CH2:17][S:18][C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[NH:21][CH:22]=[N:23]4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37].CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH:16]([O:28][C:36](=[O:38])[CH3:37])[CH2:17][S:18][C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[NH:21][CH:22]=[N:23]4)[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: OC(CSc1ncnc2nc[nH]c12)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(CSc1ncnc2nc[nH]c12)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 70 h
Yield: 65 %

Procedure:
To a solution of 6-[1-[1-[bis(4-fluorophenyl)methyl]-piperazin-4-yl]-2-hydroxy-3-propanylthio]purine (1.0 g, 0.002 mol) in CH2Cl2 (7 mL), acetic anhydride (0.2 mL, 0.002 mol) in Et3N (0.2 mL, 0.002 mol) was added dropwise over 5 min at room temperature under nitrogen. After 70 h, CH2Cl2 (50 mL) was added and the solution was extracted with saturated NaHCO3 (2×100 mL), H2O (1×100 mL), and saturated brine (1×100 mL); the organic layer was dried over Na2SO4. Solvent removal of the dried organic layer gave a solid which was dried in vacuo at 40° C. to give pure product (0.7 g, 64.8%), mp 105°-109° C. (dec). DCI/MS (M+1) 539. 400 MHz 1H NMR (CDCl3) δ: 8.7 (s, 1H), 8.2 (s, 1H), 7.3 (m, 4H), 6.95 (m, 4H), 5.3 (m, 1H), 4.2 (s, 1H), 3.4 and 4.0 (m, 2 H), 2.65 (m, 2H), 2.6 (m, 4H), 2.4 (m, 4H), 2.0 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=O)[CH3:30])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].Cl.[NH2:33][OH:34].C([O-])(=O)C.[Na+]>C(O)C>[C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29](=[N:33][OH:34])[CH3:30])=[CH:27][CH:28]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(C)=NO)cc1
Yield: 85.7 %

Procedure:
To a solution of 3-acetyl-2-(4-acetylbenzyl)-6-bromo-4-phenyl-2H-isoquinolin-1-one (95 mg) in ethanol (10 ml) were added hydroxylamine hydrochloride (17 mg) and sodium acetate (29 mg) at room temperature and the mixture was heated under reflux for 6 hrs. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1→3/2) to give the title compound (84 mg, 86%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([CH:18]=O)=[CH:13][N:12]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([NH2:9])=[N:17][C:15]2[N:16]=[C:11]([NH2:10])[N:12]=[CH:13][C:14]=2[CH:18]=1
Reactant: N#CCc1ccccn1
Reactant: Nc1ncc(C=O)c(N)n1
Product: Nc1ncc2cc(-c3ccccn3)c(N)nc2n1

Procedure:
The procedure of Example 1 was followed to react 0.84 mL of 2-pyridylacetonitrile and 1.0 g of 2,4-diamino-5-pyrimidinecarboxaldehyde to afford the title compound, mp 312-321° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:13])=[CH:4][CH:3]=1.I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH3:21])[C:9]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1NCCc2ccc(Cl)c(F)c21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc(Cl)c(F)c2C1=O
Yield: 28.3 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-chloro-8-fluoro-3,4-dihydro-2H-isoquinolin-1-one (I-33d: 150 mg, 0.753 mmol) was reacted with 3-iodo-4-methyl-pyridine (165 mg, 0.73 mmol), 1,4-dioxane (10 mL), copper iodide (143 mg, 0.075 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (32 mg, 0.225 mmol) and potassium phosphate (399 mg, 1.88 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 60 mg of the product (27.6% yield).