Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:25]([CH2:28][CH3:29])[CH2:26][OH:27])=[CH:6][CH:5]=1.[CH3:30]I>CN(C)C=O.[Cl-].[NH4+]>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:25]([CH2:26][O:27][CH3:30])[CH2:28][CH3:29])=[CH:6][CH:5]=1
Reactant: CCC(CO)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCC(COC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
Sodium hydride (60% in oil, 15.2 mg, 0.381 mmol) was added to a stirred solution of 2-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]butan-1-ol (108 mg, 0.254 mmol) in N,N-dimethylformamide (2.0 mL) at room temperature. After stirring 5 min, methyl iodide (71.7 mg, 0.508 mmol) was added to the mixture, and the mixture was stirred at room temperature for 5 hr. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (56.1 mg, 0.128 mmol, 50%).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[C:14]([OH:25])[CH:13]=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCCC1.C1C=CC=CC=1>[CH:1]1([NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[C:17]([C:18]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:16][CH:15]=[C:14]([O:25][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:13]=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCCCC1)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOCC1
Product: O=C(NC1CCCCC1)C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid cyclohexylamide (141 mg, 0.41 mmol) obtained in Step 3 was dissolved in tetrahydropyran/benzene (3 mL/2 mL), and 4-(2-hydroxyethyl)morpholine (99 μl, 0.82 mmol) and triphenylphosphine (215 mg, 0.82 mmol) were added thereto. Then, diisopropyl azodicarboxilate (149 μl, 0.82 mmol) was added slowly thereto at 0° C., and stirred for 2 hrs at RT. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 165 mg of the titled compound (yield: 88.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[I:13]I.[OH-].[K+].OS([O-])=O.[Na+]>CN(C=O)C>[I:13][C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:10][N:9]=1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: II
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.9 %

Procedure:
6-Nitro-indazol (4.0 g, 24.52 mmol), prepared using the procedure of Tetrahedron (1999), 6917-6922, was dissolved in 60 mL of DMF and iodine (12.4 g) and KOH (5.23 g) were added successively. The reaction mixture was stirred at room temperature for 1.5 hours, then poured into 10% aqueous NaHSO3. The aqueous mixture was extracted three times with 150 mL EtOAc, and the combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 7.01 g of crude 3-Iodo-6-nitro-1H-indazole.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C(N(CC)CC)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:16][CH2:17][N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-(4-fluoro-benzyl)-piperidine (0.117 g, 0.6 mmol) in acetonitrile (5 ml) is treated with 2-(2-bromo-ethyl)-isoindole-1,3-dione (0.152 g, 0.6 mmol) and with triethylamine (0.084 ml, 0.6 mmol). The mixture is shaken at RT for 72 hours and the solvent evaporated. The crude product is purified by flash silica chromatography (methanol:dichloromethane, 1:19 elution) to afford 2-{2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethyl}-isoindole-1,3-dione 1H NMR (400 MHz, CDCl3, selected values) δ 2.46 (d J 7.1 2H ), 2.60 (t J 6.8 2H ), 3.81 (t J 6.8 2H ), 6.94 (m 2H ), 7.05 (m 2H), 7.7 (dd J 3.0 5.3 2H), 7.84 (dd J 3.0 5.3 2H)
Reaction SMILES: [C:1]([C:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:29])=[C:13]([NH:15][C:16]2[NH:17][C:18]3[CH:24]=[C:23]([C:25](O)=[O:26])[C:22]([Cl:28])=[CH:21][C:19]=3[N:20]=2)[CH:14]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33].CCCP(O)(O)=O>CC#N>[C:1]([C:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:29])=[C:13]([NH:15][C:16]2[NH:17][C:18]3[CH:24]=[C:23]([C:25]([NH:33][CH2:32][C:31]([F:35])([F:34])[F:30])=[O:26])[C:22]([Cl:28])=[CH:21][C:19]=3[N:20]=2)[CH:14]=1)=[O:6])([CH3:2])([CH3:4])[CH3:3]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(C(=O)O)cc3[nH]2)c1
Agent: CCCP(=O)(O)O
Solvent: CC#N
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(C(=O)NCC(F)(F)F)cc3[nH]2)c1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of 2-[5-(tert.butylcarbonylaminomethyl)-2-chlorophenylamino]-6-chloro-benzimidazole-5-carboxylic acid (0.15 g, 0.345 mmol), 2,2,2-Trifluoroethylamine (2×0.027 ml, 0.345 mmol), 1-propylphosphonic-acid cyclic anhydride (PPA, 0.244 ml, 50% in EtOAc), 0.12 ml TEA and 10 ml MeCN was stirred for 48 h at 60° C. an concentrated. The residue was purified by chromatography to give the title compound. Yield 17 mg (10%) m/z: 516 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[OH:15])[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:16]I.[OH-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)COc1ccc(O)c(Cl)c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
Ethyl 4-hydroxyphenoxyacetate(1.5 g, 7.6 mmol) was reacted with SO2Cl2 (1.5 mL) to give ethyl 3-chloro-4-hydroxyphenoxyacetate (700 mg, ~80% pure) as a white powder. To a solution of ethyl 3-chloro-4-hydroxyphenoxyacetate(700 mg, 3.0 mmol) and MeI(0.280 mL, 4.5 mmol) in DMF(5 mL) at 0° C. was added 10M aq.NaOH(0.320 mL, 3.2 mmol). The mixture was stirred at r.t. for 12 h, then diluted with H2O and extracted with EtOAc to give ethyl 3-chloro-4-methoxyphenoxy-acetate (700 mg).
Reaction SMILES: [N+](C1C=CC(CCOC([NH:15][C:16]2[C:17]3[N:18]=[CH:19][N:20]([C:52]=3[N:53]=[CH:54][N:55]=2)[C@@H:21]2[O:51][C@H:48]([CH2:49][OH:50])[CH2:47][C@H:22]2[O:23][C:24](=[O:46])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=O)=CC=1)([O-])=O.C1CCN2C(=NCCC2)CC1.CC(O)=O>N1C=CC=CC=1>[C:31]([NH:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]([O:23][C@@H:22]1[CH2:47][C@@H:48]([CH2:49][OH:50])[O:51][C@H:21]1[N:20]1[C:52]2[N:53]=[CH:54][N:55]=[C:16]([NH2:15])[C:17]=2[N:18]=[CH:19]1)=[O:46])(=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCCC(=O)NCCCCCC(=O)O[C@@H]1C[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)OCCc3ccc([N+](=O)[O-])cc3)ncnc21
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCC(=O)NCCCCCC(=O)O[C@@H]1C[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21
Reaction time: 18 h

Procedure:
Compound 10 (160 mg, 0.208 mol) was co-evaporated twice with abs. pyridine and then dissolved in abs. pyridine (2 ml). DBU (158 mg, 1.04 mmol) was added, the mixture kept at r.t. for 18 h, then AcOH (62 mg, 1.04 mmol) added, and the soln. evaporated. The residue was diluted with CHCl3 (80 ml) and washed with a 10% citric acid soln. (2×50 ml), the aq. phase reextracted with CHCl3, the combined org. layer dried (MgSO4), evaporated, and co-evaporated with toluene, and the residue precipitated by MeOH and washed with Et2O: 103 mg (86%) of 12. UV (CH2Cl2: 259 (4.16). 1H-NMR ((D6)DMSO): 8.33, 8.13 (2s, H—C(8), H—C(2)); 7.68 (t, NH(CH2)5CO); 7.25 (s, NH2); 6.05 (d, H—C(1′)); 5.60 (m, H—C(2′)); 5.11 (t, OH—C(5′)); 4.32 (m, H—C(4′)); 3.65, 3.47 (2m, 2 H—C(5′)); 2.95 (q, 1 CH2 of NH(CH2)5CO); 2.6, 2.15 (2m, 2 H—C(3′)); 2.34, 2.00 (2t, 2 CH2 of NH(CH2)5CO, 2 H of Me(CH2)12Co); 1.65-1.15 (m, 28 H, 2 CH2 of NH(CH2)5CO, Me(CH2)12CO); 0.83 (t, Me(CH2)12CO). Anal. calc. for C30H50N6O5 ½ H2O (583.76): C 61.72, H 8.81, N. 14.39; found C 62.04, H 9.07, N 13.85.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(Cl)Cl.C(N(CC)CC)C>>[CH3:18][C@@:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=4)[CH:3]=3)[CH:8]=2)[CH2:16][O:15][C:14](=[O:17])[NH:13]1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@]1(c2ccc3cc(Oc4cccc(C(F)(F)F)c4)ccc3c2)COC(=O)N1
Reaction time: 10 h
Yield: 21 %

Procedure:
(R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (Example 4, 65 mg, 0.27 mmol), 3-(trifluoromethyl)phenylboronic acid (101 mg, 0.54 mmol) and cupric acetate (48.5 mg, 0.000267 mol) were placed in a vial, purged with N2, following by methylene chloride (2 mL, 0.03 mol) and triethylamine (0.186 mL, 0.00134 mol) at 23° C. The reaction was allowed to stir for about for 10 hours, and filtrated. The crude material was then purified via chromatography (SiO2, 4 g, 0-35%) to give a pure product (22 mg, 31%). 1H NMR (CHLOROFORM-d) δ: 7.87 (d, J=9.0 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.45-7.52 (m, 2H), 7.37-7.43 (m, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.27-7.31 (m, 2H), 7.22 (d, J=8.3 Hz, 1H), 6.01 (s, 1H), 4.39-4.49 (m, 2H), 1.87 (s, 3H). MS (M+1): 388.20.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)=[CH:4][CH:3]=1.[CH3:18][CH2:19][C:20](=O)[CH2:21][C:22](=O)[CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[N:14]=[C:13]3[N:15]=[C:20]([CH2:19][CH3:18])[CH:21]=[C:22]([CH2:23][CH3:24])[N:12]3[N:11]=2)=[CH:16][CH:17]=1
Reactant: Nc1nc(CCCOc2ccc(Cl)cc2)n[nH]1
Reactant: CCC(=O)CC(=O)CC
Product: CCc1cc(CC)n2nc(CCCOc3ccc(Cl)cc3)nc2n1
Yield: 44 %

Procedure:
The title compound was prepared according to the experimentals described for Example 22 above from 3-[3-(4-chlorophenoxy)propyl]-1H-1,2,4-triazol-5-amine and 3,5-heptanedione in 44% yield; 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.31 (dd, 1H), 7.29 (dd, 1H), 7.11 (s, 1H), 6.96 (dd, 1H), 6.94 (dd, 1H), 4.08 (t, 2H), 3.07 (q, 2H), 2.97 (t, 2H), 2.86 (q, 2H), 2.20 (m, 2H), 1.33 (t, 3H), 1.27 (t, 3H).
Reaction SMILES: [C:1]1([C:11]([CH3:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[BrH:18]>[Cu](Br)Br.C(OCC)(=O)C>[C:1]1([C:11]([CH2:13][Br:18])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cccc2ccccc12
Reactant: Br
Agent: Br[Cu]Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1cccc2ccccc12

Procedure:
Methyl 1-naphthyl ketone (10.1 g.), in 50 ml. of a 1:1 mixture of chloroform and ethyl acetate is treated with 26.5 g. of copper (II) bromide. The resulting reaction mixture is heated under reflux with vigorous stirring until the evolution of hydrogen bromide ceases. When the reaction is complete the solvent is removed, ether is added and the copper (I) bromide is removed by filtration. Evaporation of the filtrate under reduced pressure yields crude bromomethyl 1-naphthyl ketone.
Reaction SMILES: [C:1]([C:5]1[NH:23][C:8]2=[C:9]3[C:14](=[C:15]4[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]4=[C:7]2[N:6]=1)[C:13](=[O:22])[NH:12][CH:11]=[CH:10]3)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:27]>CN(C=O)C>[C:1]([C:5]1[NH:23][C:8]2=[C:9]3[C:14](=[C:15]4[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]4=[C:7]2[N:6]=1)[C:13](=[O:22])[N:12]([CH3:27])[CH:11]=[CH:10]3)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2c3ccc(F)cc3c3c(=O)[nH]ccc3c2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c3[nH]c(C(C)(C)C)nc3c3ccc(F)cc3c2c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 2-tert-butyl-9-fluoro-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one (40 mg, 0.129 mmol) in dry DMF (1.5 mL) at 0° C. was added NaH (60 wt. %) (6 mg, 0.15 mmol). After stirring for 5 minutes, iodomethane (9 μL, 0.142 mmol) was added, and the reaction mixture was slowly warmed to room temperature over 2 h. The mixture was cooled in ice bath and the reaction was quenched with water. The reaction mixture was diluted with EtOAc, washed with water followed by brine, then dried over Na2SO4. After removal of the solvent the crude was purified by preparative thin layer chromatography (1:9 MeOH:CH2Cl2 as eluent) to obtain the title compound as a mixture of imidazole tautomers.
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]([O:36][C:37]1[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[CH:42][C:38]=1[CH2:39][NH:40][CH3:41])([CH3:35])[CH3:34]>ClCCl>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]([N:40]([CH3:41])[CH2:39][C:38]2[CH:42]=[CH:43][CH:44]=[C:45]([O:46][CH3:47])[C:37]=2[O:36][CH:33]([CH3:34])[CH3:35])=[O:8])[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: CNCc1cccc(OC)c1OC(C)C
Reactant: COc1cc(C(OC(C)=O)C(=O)O)cc(OC)c1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1cccc(CN(C)C(=O)C(OC(C)=O)c2cc(OC)c(OC)c(OC)c2)c1OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A solution of α-acetoxy-3,4,5-trimethoxyphenyl-acetic acid (5.0 g) in dichloromethane (40 ml) was reacted with 1,1′-carbonyldiimidazole (2.92 g) at room temperature for 30 minutes. The solution was refluxed for 30 minutes, after which 2-isopropoxy-3-methoxy-N-methylbenzylamine (3.26 g) dissolved in dichloromethane (10 ml) was added. The mixture was stirred at room temperature for 2 hours, after which it was washed with aqueous hydrochloric acid (20 ml, is 1M) followed by aqueous sodium hydrogen carbonate (20 ml, 0.5 M). The organic phase was dried and concentrated to dryness, leaving crude 2-(3,4,5-trimethoxyphenyl)-2-acetoxy-N-methyl-N-(2-isopropoxy-3-methoxybenzyl)acetamide (7.27 g).
Reaction SMILES: [C:1]([C:5]1N=C(N2CC[C@H](O)C2)[C:8]2[C:9](=[N:11][N:12]([CH2:14]C3C(C)=NON=3)N=2)[N:10]=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].ClCC1N(C)N=C(C)N=1>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:1][C:5]3[N:12]([CH3:14])[N:11]=[C:9]([CH3:8])[N:10]=3)[N:39]=2)[N:36]=1)([CH3:29])([CH3:28])[CH3:30]
Reactant: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Agent: Cc1nc(CCl)n(C)n1
Product: Cc1nc(Cn2nc3nc(C(C)(C)C)nc(N4CC[C@H](O)C4)c3n2)n(C)n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole and isolated as colorless gum. MS (m/e): 372.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>CCOC(C)=O.CO.[Pd]>[C:4]1([NH2:1])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2ccccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cccc2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
5-Aza-benzimidazole (312 mg, 2.62 mmol, 1 equiv.) in 5 mL anhydrous DMSO was treated with potassium tert-butoxide (294 mg, 2.62 mmol, 1.0 equiv.) at room temperature. When the mixture was completely homogeneous, 4-fluoro-1-nitro-naphthalene (500 mg, 2.62 mmol, 1 equiv.) was added in one portion and the mixture was heated to 60° C. for 0.5 h. The reaction was allowed to cool, then quenched with dilute aqueous NaHCO3 solution. The product was extracted with a mixture of EtOAc, THF and acetone. The organic extracts were washed with water and brine, then dried (Na2SO4), filtered and the solvents removed in vacuo. 1H NMR revealed a 1:1 ratio of regioisomers. The products were purified by column chromatography on SiO2 using EtOAc/MeOH eluent mixtures. 1-(4-Nitro-naphthalen-1-yl)-1H-imidazo[5,4-c]pyridine was isolated at high Rf and 1-(4-nitro-naphthalen-1-yl)-1H-imidazo[4,5-c]pyridine at lower Rf, and overlapping fractions were in between. The overall yield was 357 mg (47%). Each nitro-naphthalene from above (˜100 mg, 0.4 mmol) was separately dissolved in 10 mL EtOAc and 5 mL of MeOH. Ammonium formate was then added (100 mg, 1.6 mmol or 4 equiv.) and 10% palladium-on-carbon (˜60 mg). The mixture was stirred for 0.5 h at 50° C., then allowed to cool, filtered through diatomaceous earth and the solvents were removed in vacuo to afford ˜80 mg of each naphthyl-amine 5a and 5b, which could be coupled with anilines or pyrazolamines to form ureas by the procedures described in Examples 2-4 above.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:20])([CH3:19])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]([C:21]#[C:22][CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].ClC1N=CC2C=C(C(OCC)OCC)N(CCNC(=O)OC(C)(C)C)C=2N=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:21]=[C:22]([CH:23]([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[N:8]([C:9]([CH3:19])([CH3:20])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[C:6]=2[N:7]=1
Reactant: CCOC(C#Cc1cnc(Cl)nc1NC(C)(C)CNC(=O)OC(C)(C)C)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOC(OCC)c1cc2cnc(Cl)nc2n1CCNC(=O)OC(C)(C)C
Agent: [F-]
Product: CCOC(OCC)c1cc2cnc(Cl)nc2n1C(C)(C)CNC(=O)OC(C)(C)C

Procedure:
tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2-methyl-propyl]carbamate is synthesized by treating tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamate with TBAF using similar experimental conditions as described for the synthesis tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate. LCMS (ESI) (M+H) 427
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:17][C:11]2[N:12]=[CH:13][NH:14][C:15](=O)[C:10]=2[C:9]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.P(Cl)(Cl)([Cl:28])=O.O.N>S1(CCCC1)(=O)=O>[Cl:28][C:15]1[C:10]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[O:17][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2c(-c3ccccc3F)oc3nc[nH]c(=O)c23)cc1
Agent: N
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(Cl)c23)cc1
Temperature: 25 °C

Procedure:
Stir a mixture of 20 g (0.06 mol) 6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4(3H)-one in 78 ml sulpholane and 11 ml (18 g, 0.12 mol) phosphoryl chloride for 1 h at 120° C. After cooling to room temperature, add the reaction solution dropwise to a mixture of 1000 ml water and 100 ml 25% aqueous ammonia solution, stirring vigorously and cooling with ice. Filter off the solid that is precipitated at 10° C. and wash several times with water. Dissolve the solid in 700 ml ethyl acetate again and wash the solution twice with 500 ml water each time. Dry the organic phase over sodium sulphate, filter, and concentrate the filtrate by vacuum evaporation. Mix the residue with 60 ml diisopropyl ether, filter, and dry under vacuum. 18 g (81% of theor.) of the title compound is obtained.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH3:26])[CH:20]=3)[CH3:18])[CH:11]=2)[CH2:6]1)=[O:4].[Li+].[OH-].Cl>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH:17]([NH:16][C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=2)[CH2:9][N:7]2[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]2)[CH3:18])=[CH:20][C:21]=1[CH3:26]
Reactant: COC(=O)C1CN(Cc2cccc(NC(C)c3ccc(Cl)c(C)c3)c2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(C)Nc2cccc(CN3CC(C(=O)O)C3)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of INT 4 (85 mg, 0.23 mmol) in THF (2.2 mL) was added 1 M LiOH (1.1 mL, 1.14 mmol). The resulting mixture was stirred at room temperature for 19 hours. The mixture was acidified to pH 5 with 1 M HCl. The organic solvent was removed. More 1 M HCl was added to adjust the pH to 3. The mixture was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH) to give Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](F)=[CH:4][C:3]=1[CH2:10][OH:11].[Cl:12]C1C=CC(F)=CC=1C>>[Cl:12][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([F:1])=[C:3]([CH2:10][OH:11])[CH:4]=1
Reactant: Cc1cc(F)ccc1Cl
Reactant: Cc1cc(F)c(CO)cc1F
Product: Cc1cc(F)c(CO)cc1Cl

Procedure:
(5-Chloro-2-fluoro-4-methyl-phenyl)-methanol was prepared in analogous fashion to (2,5-difluoro-4-methyl-phenyl)-methanol using 2-chloro-5-fluorotoluene as starting material. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 1H, J=6.8 Hz), 6.92 (d, 1H, J=10 Hz), 4.69 (s, 2H), 2.34 (s, 3H) ppm.