Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=O.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17]>C(O)C.C(O)(=O)C>[CH2:20]([O:19][C:15](=[O:18])[NH:16][N:17]=[CH:13][C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:6][C:2]=1[CH3:1])[CH3:21]
Reactant: Cc1[nH]c(-c2ccccc2)nc1C=O
Reactant: CCOC(=O)NN
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)NN=Cc1nc(-c2ccccc2)[nH]c1C
Temperature: 0 °C

Procedure:
A mixture of 10.25 gm. of 5-methyl-2-phenyl-4-imidazolecarboxaldehyde and 5.72 gm. of ethyl carbazate in 30 ml. of ethanol containing one drop of acetic acid is boiled for 30 minutes. The mixture is cooled to 0° C. and concentrated under an air stream on a steam bath. A 50 ml. portion of carbon tetrachloride is added and the mixture is cooled to 0° C. overnight. The solid is collected giving the desired product, m.p. 209°-211° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:10]([OH:14])([OH:13])(=[O:12])=[O:11].CS[C:17](=[NH:19])[NH2:18]>C(O)C>[S:10]([OH:14])([OH:13])(=[O:12])=[O:11].[C:1]1([CH2:7][CH2:8][NH:9][C:17]([NH2:19])=[NH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:7][CH2:8][NH:9][C:17]([NH2:19])=[NH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: CCO
Product: N=C(N)NCCc1ccccc1
Yield: 127 %

Procedure:
2-Phenylethylamine (8.49 g, 70.1 mmol) and S-methylisothiourea sulfate (9.43 g, 33.9 mmol) was dissolved in 100 ml distilled water. Air was passed over the reaction mixture and through 50% NaOH (500 ml) and then through 5% cuprous sulfate (250 ml). The reaction mixture was heated at reflux for 5 hours. Evaporation of the solvent yielded a white powder. The product was isolated by crystallisation from 96% ethanol, washed with cold acetone and diethyl ether and dried in a desicator. After three crystallisations, the product contained only minor amounts of starting material. The reaction yielded 61.5% (9.14 g) 2-phenylethylguanidine hemisulfate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl-].[NH4+].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[NH:11]1[C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[N:2][N:13]=[N:12]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccnc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cncc(-c2nnn[nH]2)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 58 %

Procedure:
To a solution of 3-cyanopyridine (1.1 g, 10.6 mmol) in DMF (15 mL) was added ammonium chloride (718 mg, 13.4 mmol) and sodium azide (824 mg, 12.7 mmol) and the resultant slurry was vigorously stirred at 90° C. for 15 h. The DMF was removed in vacuo, the residue was dissolved in aqueous potassium hydroxide (1 M, 20 mL), washed with EtOAc (2×25 mL), the aqueous layer was adjusted to pH ˜3 with aqueous HCl (6 N) and the solid was collected by filtration to afford the title compound 64 (904 mg, 46% yield) as a white solid: mp=239-241° C. dec.; 1H NMR (CDCl3) δ 9.21 (m, 1H), 8.76 (m, 1H), 8.39 (m, 1H), 7.64 (m, 1H); LRMS (ESI) m/z calcd for C6H6N5 [M+H]+ 148. found 148; HRMS (ESI) m/z calcd for C6H6N5 [M+H]+ 148.0623. found 148.0624; HPLC>99% (tR=4.88 min, 60 (A):40 (B): 0.009 (C); tR=3.74 min, 60 (A):40 (B): 0.02 (C)).
Reaction SMILES: [N:1]1([C:10]2[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:12][C:13]3[C:18]([N:19]=2)=[CH:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][CH:14]=3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[N:1]1([C:10]2[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:12][C:13]3[C:18]([N:19]=2)=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCc4ccccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCc4ccccc43)nc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(indolin-1-yl)-2-phenylquinoxaline-6-carboxylate (90 mg, 0.24 mmol, 1.00 equiv) in methanol (15 mL). Then a solution of sodium hydroxide (47.2 mg, 1.18 mmol, 5.00 equiv) in water (2 mL) was added. The resulting solution was stirred for 2 hrs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was diluted in 20 mL of water. The pH value of the aqueous solution was adjusted to 4-5 with aqueous hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 80 mg (92%) of 3-(indolin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as an orange solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:7]([C:10]([CH3:16])([CH3:15])[CH2:11][C:12](Cl)=[O:13])=[N+:8]=[N-:9]>ClCCCl>[N:7]([C:10]([CH3:16])([CH3:15])[CH2:11][C:12]([N:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH3:1])=[O:13])=[N+:8]=[N-:9]
Reactant: CCCCNC
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Solvent: ClCCCl
Product: CCCCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a stirred ice cold solution of N-methylbutan-1-amine (8.88 mL, 2 equiv, 74.4 mmol) in anhydrous DCE (65 mL) was added 3-azido-3-methylbutanoyl chloride (6.02 g, 37.2 mmol) in small portions over 5 min. The reaction was removed from the ice bath and stirred at room temperature for 1 h. The reaction mixture was poured into a separatory funnel and washed with 1 M HCl (2×100 mL). The organic layer was separate and dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a yellow oil (7.11 g, 90.1%). This material was used without further purification. 1HNMR (CDCl3, 400 MHz): δ 0.91-0.98 (m, 3H), 1.27-1.37 (m, 2H), 1.46 (s, 6H), 1.47-1.57 (m, 2H), 2.49 (s, 2H), 2.92 (s, 1.35H), 3.02 (s, 1.48H) methyl rotamers, 3.28-3.39 (m, 2H). LRMS (ESI+) for C10H20N4O (212.2); Found: 213 (MH+).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:8][CH2:7][CH2:6][NH:5]2)[CH2:3][O:2]1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][C:27]([C:29]([N:31]3[CH2:34][CH:33]([O:35][C:36]4[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=4)[CH2:32]3)=[O:30])=[N:26][N:25]=2)=[CH:20][CH:19]=1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:3]1[C:4]2([CH2:8][CH2:7][CH2:6][N:5]2[CH2:40][C:39]2[CH:38]=[CH:37][C:36]([O:35][CH:33]3[CH2:34][N:31]([C:29]([C:27]4[O:28][C:24]([C:21]5[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=5)=[N:25][N:26]=4)=[O:30])[CH2:32]3)=[CH:43][CH:42]=2)[CH2:1][O:2]1
Reactant: C1CNC2(C1)COC2
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCCC56COC6)cc4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
2-Oxa-5-azaspiro[3.4]octane (0.03 g, 0.26 mmol) was dissolved in dichloromethane (2 ml). Triethylamine (0.04 ml, 0.29 mmol) was added, followed by 4-(1-(5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.1 g, 0.26 mmol) and finally sodium triacetoxyhydroborate (0.112 g, 0.53 mmol). The mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with dichloromethane (10 ml) and subsequently shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a residue, which was purified by preparative reverse-phase. HPLC at pH 10 to give 0.075 g (60%) of the desired product as a solid. 1H NMR (600 MHz, DMSO) δ 1.62 (dt, 2H), 2.1-2.15 (m, 2H), 2.49 (t, 2H), 3.88 (s, 3H), 3.91 (s, 2H), 4.09 (ddd, 1H), 4.43 (d, 2H), 4.54 (ddd, 1H), 4.63 (ddd, 1H), 4.80 (d, 2H), 5.09 (ddd, 1H), 5.16 (ddd, 1H), 6.86 (d, 2H), 7.17-7.21 (m, 2H), 7.30 (d, 2H), 8-8.04 (m, 2H). MS (APCI+) m/z 477.2 [M+H]+, LC purity: 95%
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:11][C@@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[CH2:6]1)=[N+]=[N-].[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(OCC)(=O)C>[C:13]([NH:1][CH2:4][C@@H:5]1[O:11][C@@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[CH2:6]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: [N-]=[N+]=NC[C@@H]1CN2C(=O)C[C@@H]2O1
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN2C(=O)C[C@@H]2O1
Yield: 89 %

Procedure:
(3S,5S)-3-azidomethyl-4-oxa-1-azabicyclo [3,2,0] heptan-7-one (710 mg, 4.23 mmole) was hydrogenated in the presence of acetic anhydride (431 mg, 4.23 mmole) in ethyl acetate (20 ml) at 50 psi for 1 hr. After removal of solvent, the residue was purified by silica gel column chromatography using ethyl acetate-acetone (5:1) as eluent and the title compound was obtained as solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[N-:10]=[N+:11]=[N-:12].[Na+].CCOCC.OS(O)(=O)=O>[OH-].[Na+]>[N:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCCCCBr
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: [N-]=[N+]=NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.9 %

Procedure:
The above compound was prepared by a literature procedure [W. M. Rothe and K. Gehrke, Makromol Chem. 83, 1 (1965)] as follows: To a solution of 6-bromohexanoic acid (21.6 g, 0.11 mol) in 3.3N sodium hydroxide (33.3 ml) was added sodium azide (8.33 g, 1.27 mol) and the mixture stirred at room temperature for 5 min. Ether (5 ml) was then added and the reaction mixture was refluxed for 6 h, cooled to room temperature and acidified with 2N H2SO4 to pH 2. The oily layer which formed was separated and the aqueous layer extracted with ether (25 ml). The organic extract was combined with the oily layer and the resulting solution dried (Na2SO4) and evaporated to yield 14.5 g (83.6%) of title compound as an oil; ir (neat) νmax : 2097 (N3), 1708 cm-1 (C=O); 1Hmr (CDCl3) δ: 1.2-2.0 (m, 6H, 3CH2), 2.4 (m, 2H,--CH2CO--), 3.3 (m, 2H, CH2N3), 11.5 (s, 1H, CO2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[CH:39][N:38]=1)=[O:36]>ClCCl>[CH3:33][O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:45])=[CH:39][N:38]=1)=[O:36]
Reactant: COC(=O)c1ccc(N=C=O)cn1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (67.8 mg, 0.67 mmol) (Aldrich), followed by the addition of solution of 5-isocyanato-pyridine-2-carboxylic acid methyl ester in toluene (from Example 83c supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-5-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-pyridine-2-carboxylic acid methyl ester as a white solid. (Yield 83 mg, 56.1%).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=1)(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])=[CH:33][CH:34]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(NS(C)(=O)=O)cc1

Procedure:
A mixture of 2,2-diphenyl-5-methylaminopentanamide (0.3 g-see Preparation 3), N-[4-(2-methanesulphonyloxyethyl)phenyl]methanesulphonamide (0.3 g-see Preparation 18), sodium bicarbonate (0.5 g) and acetonitrile (10 ml) was heated under reflux for 8 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.12 g.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]2[C:24]=1[O:23][C:22](=[O:25])[CH:21]=[C:20]2[NH:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=1[Cl:34]>>[Cl:34][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([Cl:33])[C:27]=1[NH:26][C:20]1[C:19]2[C:24](=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:16]([O:35][CH3:36])=[CH:17][CH:18]=2)[O:23][C:22](=[O:25])[CH:21]=1
Reactant: CCCCCNC
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Product: CCCCCN(C)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from N-methylpentan-1-amine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.41 (br s, 1H), 8.57 (s, 2H), 7.85 (d, 1H), 7.05 (d, 1H), 4.23 (br s, 1H), 3.96 (t, 2H), 3.87 (s, 3H), 2.61 (br, 4H), 2.39 (br s, 3H), 1.70 (m, 2H), 1.60 (m, 2H), 1.47 (m, 4H), 1.23 (m, 4H), 0.83 (t, 3H); MS (ESI): 522.1.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[NH2:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:18]1([CH:17]([NH:16][C:2]2[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(NC(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Yield: 76.6 %

Procedure:
A reaction vessel was charged with 120 ml of toluene and 11.0 g (42.4 mmol) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate (prepared as described in U.S. Pat. No. 4,199,506). Then, 15.5 g (86 mmol) of aminodiphenylmethane was added in one portion. The resulting yellowish-orange solution was refluxed under nitrogen for 9 days. Then, solvent was removed from the mixture under reduced pressure to yield a yellowish-orange solid material, which was flash chromatographed (~38 ml/min) on silica gel using 10% ethyl acetate in hexane solvent. There was obtained 13.2 g of a thick yellow oil which solidified upon standing to a yellow solid product (m.p.=92°-95° C.) identified in Table I.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH:19]([CH3:21])[CH3:20])[CH:7]=1
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 18.0 g of 5-fluoro-2-nitrophenol, 29.0 g of caesium carbonate and 13.7 ml of 2-iodopropane in 119 ml of DMF is stirred at ambient temperature overnight. The mixture is concentrated under vacuum and the residue is taken up with 250 ml of water and extracted twice with 250 ml of ethyl acetate. The organic phases are washed twice with 200 ml of a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum, so as to obtain 17 g of crude product. The crude product is purified on 400 g of silica, elution being carried out with cyclohexane/ethyl acetate (95/5), so as to obtain 13.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene in the form of a light yellow oil.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[CH:18]1([O:6][C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=2[O:8][CH3:9])[CH:2]=[O:1])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 60 °C

Procedure:
To a magnetically-stirred solution of isovanillin (557 mmol, 85.0 g) in dry DMF (500 mL) at room temperature was added powdered K2CO3 (558 mmol, 77.1 g) in one portion followed by the dropwise addition of neat cyclopentyl bromide (614 mmol, 91.5 g; 65.9 mL). The resulting suspension was warmed to 60° C. and the reaction monitored by TLC until complete. Upon completion, the reaction mixture was cooled to room temperature and the DMF was removed in vacuo. The residue was partitioned between H2O and EtOAc, the aqueous phase extracted with EtOAc and the combined organic layers were washed with H2O. The organics were dried (Na2SO4) and concentrated in vacuo to afford the alkylated product (317 mmol, 70.1 g; 57%) as a viscous oil which was of sufficient purity to be used as such in subsequent transformation.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[O:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[CH2:41][NH2:42]>>[O:36]1[CH2:40][CH2:39][CH2:38][CH:37]1[CH2:41][NH:42][C:30](=[O:32])[CH:29]([C:26]1[CH:27]=[CH:28][C:23]([C:21]2[CH:20]=[CH:19][C:18]3[N:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:35])[F:34])=[O:6])[CH:9]=4)[CH:15]=[N:16][C:17]=3[CH:22]=2)=[CH:24][CH:25]=1)[CH3:33]
Reactant: NCc1ccco1
Reactant: CC(C(=O)O)c1ccc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cc1
Product: CC(C(=O)NCC1CCCO1)c1ccc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cc1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 14 starting from 2-(4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}phenyl)propanoic acid and 2-furanmethanamine, tetrahydro- (Aldrich, Cat. No. 131911). LCMS (M+H)+: m/z=566.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:26]=[C:23]([CH:24]=[O:25])[C:22]([OH:27])=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:27][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:28])[F:29])=[CH:26][C:23]=1[CH:24]=[O:25]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(OC(F)(F)F)cc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 5-trifluoromethoxysalicylaldehyde (412 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-trifluoromethoxybenzaldehyde.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:18]([CH3:30])[CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:31]([O-:33])=[O:32].CS(C)=O>O>[CH3:1][O:2][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:18]([CH3:30])[CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:31]([O-:33])=[O:32]
Reactant: Cc1cc(Nc2ncnc3cc(Cl)c([N+](=O)[O-])cc23)ccc1OCc1ccccn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1[N+](=O)[O-]
Temperature: 18 °C
Yield: 83.4 %

Procedure:
After appropriate repetition of the previous steps, sodium methoxide (11 g) was added portionwise to a stirred mixture of 7-chloro-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-6-nitroquinazoline (20 g) and DMSO (200 ml) which was cooled in a water bath to approximately 18° C. The resultant mixture was stirred at ambient temperature for 4 hours. The mixture was poured slowly onto a mixture of ice and water. The precipitate was isolated to give 7-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-6-nitroquinazoline (16.5 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:27][CH:28]([F:31])[CH2:29]I.C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[N:24]([CH2:29][CH:28]([F:31])[F:27])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Reactant: FC(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1CC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (100 mg, 0.271 mmol) was suspended in acetonitrile (5 ml). 1,1-Difluoro-2-iodoethane (0.053 ml, 116 mg) and cesium carbonate (124 mg, 0.380 mmol) were added and the resulting mixture was stirred overnight at RT. Next day 2 ml of THF and 50 μl of 1,1-difluoro-2-iodoethane was added and the stirring was continued for three more nights. Another 0.2 ml of 1,1-difluoro-2-iodoethane was added and the reaction mixture was stirred overnight. The reaction mixture was evaporated. 3 ml of N,N-dimethyl formamide was added and the mixture filtered. Filtrate was purified with LC/MS-trigger. Yield 27.4%. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 2.44 (s, 3H), 4.19-4.33 (m, 3H), 4.39 (dd, 1H), 4.51-4.62 (m, 1H), 5.82-6.13 (m, 1H), 6.61 (d, 1H), 7.49 (d, 1H), 7.52 (s, 1H), 7.64-7.71 (m, 2H), 7.85 (dd, 1H), 8.00 (d, 1H).