Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C[Al](C)C.[N:14]1([C:20]2[N:21]=[C:22]([CH2:33][C:34](OCC)=[O:35])[N:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24](=[O:26])[CH:25]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1.O1CCCC1>[N:1]1([C:34](=[O:35])[CH2:33][C:22]2[N:23]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:24](=[O:26])[CH:25]=[C:20]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:21]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1-c1ccccc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)n1-c1ccccc1)N1CCc2ccccc21
Temperature: 90 °C
Yield: 3.8 %

Procedure:
56 mg of indoline and 0.36 ml of 2M trimethyl aluminum in toluene are successively added to a solution of 65 mg of ethyl (4-morpholin-4-yl-6-oxo-1-phenyl-1,6-dihydropyrimidin-2-yl)acetate in 3 ml of tetrahydrofuran and 1.5 ml of toluene. The reaction mixture is heated at 90° C. for 4 hours and then concentrated under reduced pressure. The residue is purified twice by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (98/2, V/V) and then with ethyl acetate, so as to give 3 mg of 2-[2-(2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3-phenyl-3H-pyrimidin-4-one in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [OH:1][C@H:2]([CH3:19])[CH2:3][CH2:4][C:5]1[C:10]([O:11][CH2:12][O:13][CH3:14])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:15][C:16](=[O:18])[CH3:17].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].[Cl-].[Na+]>C(#N)C.C(OCC)(=O)C>[CH3:27][S:28]([O:1][C@@H:2]([CH2:3][CH2:4][C:5]1[C:10]([O:11][CH2:12][O:13][CH3:14])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:15][C:16](=[O:18])[CH3:17])[CH3:19])(=[O:30])=[O:29]
Reactant: COCOc1cccc(NC(C)=O)c1CC[C@@H](C)O
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCOc1cccc(NC(C)=O)c1CC[C@@H](C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A solution of (R)—N-(2-(3-hydroxybutyl)-3-(methoxymethoxy)phenyl)acetamide (4.0 g, 14.96 mmol) in acetonitrile (40 mL) was treated with triethylamine (3.13 mL, 22.44 mmol) and cooled to 0° C. Methanesulfonyl chloride (1.46 mL, 18.7 mmol) was slowly added and a precipitate formed immediately. The slurry was stirred at 0° C. After 3 h, the reaction mixture was diluted with ethyl acetate and poured into 5% aqueous sodium chloride solution (50 mL). The layers were separated, and the organic layer washed with additional 5% aqueous sodium chloride solution (40 mL). The combined aqueous layers were extracted with ethyl acetate, and the combined organic layers were concentrated under reduced pressure. The residue was dissolved in toluene (50-75 mL), which was then removed under reduced pressure to afford (R)-4-(2-acetamido-6-(methoxymethoxy)phenyl)butan-2-yl methanesulfonate (5.17 g, 100%) as an amber syrup. The crude was used without further purification. MS (ESI, pos. ion) m/z 250 [M−95].+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-:20])[CH:3]=1
Reactant: Brc1cncc2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(Br)c2ccccc2c1
Reaction time: 18 h
Yield: 101.5 %

Procedure:
A solution of 4-bromoisoquinoline (4.16 g, 18.6 mmol) in chloroform (100 mL) was added dropwise over 1 h to a solution of 70% mCPBA (12.4 g, 50.3 mmol) in chloroform (100 mL) at rt. After stirring 18 h, the reaction mixture was washed with 1 N NaOH (2×150 mL), dried (MgSO4) and concentrated under reduced pressure to afford compound 13A (4.23 g, 94%) as an off-white solid. 1H NMR(400 MHz, CDCl3) □ 8.71 (s, 1H), 8.43 (s, 1H), 8.09 (d, 1H, J=8 Hz), 7.70 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH2:45][C:46]1[S:47][C:48]([CH3:51])=[N:49][N:50]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:45][C:46]2[S:47][C:48]([CH3:51])=[N:49][N:50]=2)=[O:43])=[C:18]([F:23])[CH:17]=1
Reactant: Cc1nnc(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nnc(C)s4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-methyl-1,3,4-thiadiazole (52 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 52 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][N:12]([CH:14](OC)OC)[CH3:13]>>[CH3:11][N:12]([CH3:14])/[CH:13]=[CH:9]/[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:10]
Reactant: CC(=O)c1cccc(F)c1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1cccc(F)c1
Yield: 92 %

Procedure:
The title compound was prepared in 92% yield from 1-(3-fluorophenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.93 (3H, s), 3.15 (3H, s), 5.65 (1H, d, J=12.4 Hz), 7.11-7.16 (1H, m), 7.34-7.39 (1H, m), 7.57-7.67 (2H, m), 7.81(1H, d, J=12.4 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9]2)[N:3]=1.C(B(CC)[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)C.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.CCOC(C)=O.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>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[CH:11]=[CH:12][N:8]([C:4]2[N:3]=[C:2]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:7]=[CH:6][CH:5]=2)[CH:9]=1
Reactant: CCB(CC)c1cccnc1
Reactant: Clc1cccc(-n2ccc(-c3ccccn3)c2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: c1ccc(-c2ccn(-c3cccc(-c4cccnc4)n3)c2)nc1

Procedure:
2-Chloro-6-(3-pyridin-2-yl-1H-pyrrol-1-yl)pyridine (256 mg, 1.0 mmol), diethyl-(3-pyridyl)borane (162 mg, 1.1 mmol), bis(triphenylphosphine)palladium dichloride (35 mg, 0.05 mmol), and potassium carbonate (345 mg, 2.5 mmol) were combined in 3 mL of 1:1 DME:H2O and heated via microwave irradiation for 5 min at 160° C. The reaction was diluted with 50 mL EtOAc and partitioned with H2O (50 mL). The EtOAc layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by SiO2 chromatography, eluting with a 20-75% EtOAc in hexanes gradient to afford 6-(3-pyridin-2-yl-1H-pyrrol-1-yl)-2,3′-bipyridine as a tan solid that was dissolved in ether and precipitated as an HCl salt by slow addition of 6 equivalents of 1N HCl in ether. H-NMR (CD3OD, 500 MHz) δ 9.82 (s, 1H), 9.48 (d, 1H), 9.14 (dd, 1H), 8.95 (d, 1H), 8.62 (d, 1H), 8.52 (dd, 1H), 8.44 (d, 1H), 8.28 (dd, 1H), 8.17-8.25 (m, 2H), 8.04 (m, 1H), 7.95 (d, 1H), 7.78 (dd, 1H), 7.15 (m, 1H). MS (ESI) 299.44 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][CH2:22][OH:23]>CN(C)C=O>[OH:23][CH2:22][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)C=Cc1ccc(O)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(OCCO)cc1
Yield: 43.1 %

Procedure:
30 g (168 mmol) of methyl 3-(4-hydroxyphenyl)-acrylate (Example 1), 29 g (210 mmol) of anhydrous K2CO3 and a spatula tip of KI were placed in 200 ml of dimethylformamide. 14.91 g (185 mmol) of 2-chloroethanol were added dropwise at 85° C. within 5 minutes while stirring. The batch was stirred at 85° C. for a further 3 days. Subsequently, the salts were filtered off and the filtrate was concentrated to dryness in a water-jet vacuum. 16.1 g of methyl (E)-3-[4-[2-hydroxyethoxy]-phenyl]-acrylate were obtained in the form of white crystals after recrystallization from i-propanol.
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:18](=O)[CH3:19])[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:21][C:22]1([CH3:30])[O:27][C:26](=[O:28])[CH2:25][C:24](=[O:29])[O:23]1.N1C=CC=CC=1>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:21][C:22]1([CH3:30])[O:27][C:26](=[O:28])[C:25](=[C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:13]=2)[CH3:19])[C:24](=[O:29])[O:23]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=C1C(=O)OC(C)(C)OC1=O)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
A 1.0M solution of titanium tetrachloride in DCM (9.3 mL, 9.3 mmol) was injected dropwise to THF (15 mL) cooled to 0° C. A solution of 1-(3-(benzyloxy)phenyl)ethanone (1.0 g, 4.42 mmol) (commercially available from Aldrich) and 2,2-dimethyl-1,3-dioxane-4,6-dione (701 mg, 4.86 mmol) (commercially available from Aldrich) in THF (5 mL) was then injected dropwise into the flask followed by dropwise addition of pyridine (1.8 mL, 22.1 mmol). The reaction temperature was allowed to warm to room temperature and the mixture was stirred overnight. The reaction was then quenched with water, extracted with EtOAc, dried over MgSO4, and filtered. The solvent was removed and the resulting crude mixture was purified by silica gel flash chromatography (hexane:EtOAc=4:1 to 1:1) to afford 5-(1-(3-(benzyloxy)phenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 103.B (855 mg, 55% yield).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([NH:1][CH2:2][C@H:3]([OH:13])[CH2:4][O:5][C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:23])=[O:24])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: O=C1CCN(c2ccc(S(=O)(=O)NCc3ccccc3)cc2)CC1
Product: O=S(=O)(NCc1ccccc1)c1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 4-((2S)-3-Amino-2-hydroxy-propoxy)-phenol and Reference Example 70, N-benzyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as a tan solid. 1H NMR (DMSO) δ 1.27 (m, 2H), 1.86 (m, 2H), 2.75(m, 3H), 2.91(t, 2H, J=8.4 Hz), 3.82(m, 5H), 3.89(s, 2H), 4.89(m, 1H), 6.67 (d, 2H, J=6.6 Hz), 6.76(d, 2H, J=6.6 Hz), 7.02 (d, 2H, J=6.6 Hz), 7.26 (m, 5H), 7.57 (d, 2H, J=6.6 Hz), 7.78(bs, 1H), 8.87(bs, 1H); MS (ES) m/z: 512.1 (MH+); HRMS for C27H33N3O5S: 511.2215 (MH+)
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[C:4]([OH:6])=O.C(N(CC)CC)C.[Cl:22][C:23]1[CH:34]=[C:27]2[C:28](OC(=O)[NH:32][C:26]2=[CH:25][CH:24]=1)=[O:29]>C(#N)C.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[NH:32][C:4](=[O:6])[CH:3]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])[NH:2][C:28](=[O:29])[C:27]=2[CH:34]=1
Reactant: NC(Cc1ccccc1Cl)C(=O)O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=C1NC(Cc2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
2-Amino-3-(2-chlorophenyl)propanoic acid hydrochloride (3.0 g, 12.7 mmol) was suspended in acetonitrile (50 mL) and water (5 mL), triethylamine (3.57 mL, 25.4 mmol) was added which caused a precipitate to form and inefficient stirring. Water (10 mL) was added until all solids were dissolved. 5-Chloroisatoic anhydride (2.51 g, 12.7 mmol) was added in portions, waiting until each portion dissolved before adding the next. Successive portions required longer periods of time, up to 15 minutes for the last portions. After the last portion was added, the suspension was sonicated for several minutes then stirred at ambient temperature overnight. The clear solution was concentrated in vacuo then azeotroped twice with acetone. The residue was redissolved in acetic acid (30 mL) and heated to 130° C. for 6 hours. The mixture was concentrated in vacuo to an oil, diluted with ethyl acetate (150 mL), washed with water (3×50 mL) then brine, dried with sodium sulfate, filtered and concentrated to a brown solid. This solid was resuspended in ethyl acetate (20 mL) and hexanes (10 mL) then slurried at ambient temperature for 30 minutes. Filtration provided 7-chloro-3-(2-chlorobenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (2.4 g, 56%). 1H-NMR (300 MHz, DMSO-d6) δ 2.97 (m, 1H), 3.23 (m, 1H), 4.00 (m, 1H), 7.12 (d, 1H, J=8.79 Hz), 7.27 (m, 2H), 7.40 (m, 2H), 7.58 (dd, 1H, J1=8.79 Hz, J2=2.64 Hz), 7.67 (d, 1H, J=2.64 Hz), 8.73 (d, 1H, J=6.15 Hz), 10.59 (s, 1H); ESI m/z 335.0, 337.0.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18]CC)=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27]C)=[O:26])[CH:3]=1.CO.[OH-].[Na+].O>C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1
Reactant: CCCc1c2nc(C(=O)OC)cc(Cl)c2cc2c(=O)cc(C(=O)OCC)oc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1c2nc(C(=O)O)cc(Cl)c2cc2c(=O)cc(C(=O)O)oc12
Yield: 65.5 %

Procedure:
Ethyl 6-chloro-8-methoxycarbonyl-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2-carboxylate (1.313 g) was suspended in refluxing methanol (300 mls) and 0.1 M sodium hydroxide solution (65 mls) was added dropwise, with stirring. The whole was then refluxed for ten minutes, cooled, poured into water and acidified. The precipitated product was extracted into ethyl acetate, washed with water, dried with magnesium sulphate, filtered and volatiles removed in vacuo, affording 1.05 g of the crude sub-title compound as a yellow solid. This yellow solid was dissolved in sodium bicarbonate solution, filtered and the filtrate acidified. The precipitated product was collected by filtration, washed with water and dried to give 0.77 g of the sub-title compound. MP 340° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18]
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(NCc1ccccc1Cl)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-chlorobenzylamine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-chlorobenzyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (88%) as a colorless solid: mp 148-150° C.; 1H NMR (300 MHz, DMSO-d6) δ9.12 (t, J=5.8 Hz, 1H), 7.57 (dd, J=7.2, 1.5 Hz, 1H), 7.51-7.24 (m, 6H), 7.23-7.11 (m, 3H), 7.00 (dd, J=7.2, 7.2 Hz, 1H), 6.86 (d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.40 (s, 1H), 5.15-4.95 (m, 2H), 4.86 (d, J=9.4 Hz, 1H), 4.71 (d, J=9.4 Hz, 1H), 4.57-4.41 (m, 2H), 3.01-2.88 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.8, 169.0, 161.6, 161.2, 142.8, 136.6, 135.9, 134.6, 132.6, 132.5, 130.8, 129.7, 129.4, 129.2, 129.1, 128.4, 127.7, 127.0, 124.2, 123.6, 120.9, 120.4, 119.6, 109.7, 92.9, 80.4, 72.6, 57.4, 41.4, 41.1, 28.8; MS (ES+) m/z 537.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[CH:20]12[CH2:26][CH:23]([NH:24][CH2:25]1)[CH2:22][O:21]2.O>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([N:24]2[CH2:25][C@@H:20]3[CH2:26][C@H:23]2[CH2:22][O:21]3)[CH:7]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: C1OC2CNC1C2
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1nc(Cl)cc(N2C[C@@H]3C[C@H]2CO3)n1
Temperature: 50 °C
Reaction time: 12 h
Yield: 92.4 %

Procedure:
The mixture of 4,6-dichloro-2-(methylthio)pyrimidine (450 mg, 2.31 mmol), DIEA (894 mg, 6.92 mmol) and 2-oxa-5-azabicyclo[2.2.1]heptane (328 mg, 2.42 mmol) in DMF (5 mL) was stirred at 50° C. for 12 h. Water (20 mL) was added to and extracted with ethyl acetate (2×20 mL). The organic layers were dried over Na2SO4, filtered and concentrated to give (1S,4S)-5-(6-chloro-2-(methylthio)pyrimidin-4-yl)-2-oxa-5-azabicyclo-[2.2.1]heptane (550 mg, 92.5% yield) as a white solid, which was used for next step without further purification LCMS (ESI): [MH]+=258.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH2:15][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)([C:12](N)=[O:13])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:25].[K+]>C(O)CO.O.C(O)(=O)C>[CH2:1]([N:8]1[CH2:16][CH2:15][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)([C:12]([OH:25])=[O:13])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)c1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: OCCO
Product: Cc1cccc(NC2(C(=O)O)CCN(Cc3ccccc3)CC2)c1

Procedure:
A solution of 1-benzyl-4-(3-methylphenylamino)-isonipecotamide (4.5 g, 13.9 mmol) and potassium hydroxide (3. g, 53.5 mmol) in ethylene glycol (35 mL) was heated under reflux. The resulting mixture was diluted with water and neutralized with acetic acid. The white solid precipitated was filtered, washed with chloroform to provide 1-benzyl-4-(3-methylphenylamino)piperidine-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]=O)=[C:6]([NH2:10])[N:5]=[CH:4][N:3]=1.[CH:11]([O-])=O.[Na+].C(O)=O.O>C(N)=O.[Pd]>[N:5]1[C:6]([NH2:10])=[C:7]2[C:2]([N:1]=[CH:11][NH:8]2)=[N:3][CH:4]=1
Reactant: Nc1ncnc(N)c1N=O
Reactant: O=C[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: NC=O
Solvent: O=CO
Solvent: O
Product: Nc1ncnc2nc[nH]c12
Reaction time: 0.5 h
Yield: 90 %

Procedure:
13.9 g (0.1 mol) 4,6-diamino-5-nitrosopyrimidine was suspended in 50 ml formamide, 6.8 g (0.1 mol) sodium formate, 27.0 g (0.5 mol) 85% formic acid and 0.5 g palladium catalyst were added according to example 1 and the mixture was heated for 4 hours to 110° C. The decolorized suspension was subsequently heated for 3 hours to 180° C. and then cooled. In order to improve the processing, 50 ml water was added and the solid was filtered. The filter cake was dissolved in 160 ml 5% sodium hydroxide solution and the insoluble Pd catalyst was separated. The clear filtrate was adjusted with sulphuric acid to a pH value of 8.5 after a 30 minute treatment at 50° C. with 3 g active carbon. In this process a colorless precipitate separated out from adenine which was suction filtered, washed twice with 30 ml water and dried in a vacuum at 80° C. 12.2 g adenine (0.090 mol, 90% of theory) was obtained in this way as a white powder.
Reaction SMILES: [OH-:1].[K+].Cl.[NH2:4]O.[CH2:6]([N:8]([CH2:22][CH3:23])[CH2:9][C:10]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=O)[CH3:7]>CO.O>[CH2:6]([N:8]([CH2:22][CH3:23])[CH2:9][C:10]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[N:4][OH:1])[CH3:7]
Reactant: [OH-]
Reactant: CCN(CC)CC(=O)c1cccc2ccccc12
Reactant: NO
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCN(CC)CC(=NO)c1cccc2ccccc12
Reaction time: 8 h

Procedure:
To a cooled solution of 97.6 g (1.48 mol) of potassium hydroxide in 320 mL of methanol add a solution of 20.8 g (0.3 mol) of hydroxylamine hydrochloride in 48 mL of water at 20° C. To this basic solution add a solution of 16 g (0.064 mol) of 2-(diethylamino)-1-(naphthalen-1-yl)ethanone in 20.8 mL of methanol at 20° C. Stir the reaction mixture overnight. The reaction mixture is concentrated in vacuo. Add methylene chloride and extract with 3×200 mL of water. Dry the organic layer over sodium sulfate. Remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)=[N:4]1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>CN(C=O)C>[N:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:3]2[CH:7]=[CH:6][C:5]([NH2:8])=[N:4]2)=[CH:22][CH:23]=1
Reactant: ClCc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccn(Cc2ccncc2)n1
Temperature: 50 °C
Yield: 83 %

Procedure:
NaH (0.9 g., 60% suspension in liquid paraffin) is dissolved in DMF (10 ml) and 2-(1H-pyrazole-3-yl)-isoindole-1,3-dione (11.7 mmol) is added at 0° C. To this solution is added 4-chloromethyl-pyridine (11.7 mmol) and the mixture is heated to 50° C. for 16 hours. The solvent is removed in vacuo. The residue is dissolved in ethanol (100 ml) and hydrazinium-hydroxide (70 ml) is added and the mixture is heated to 120° C. for 9 days. The solvent is removed in vacuo. 1-Pyridine-4-ylmethyl-1H-pyrazole-3-ylamine is obtained after column chromatography as colorless oil in a yield of 83%; LC-MS (method B): 0.44 min, 175.15 (M+H+);