Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:31]=[CH:30][C:22]2[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=2[CH:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][NH:18][C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:28])([CH3:29])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Reactant: O=Cc1ccc(C#Cc2ccc(Cl)cc2)cc1
Product: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1

Procedure:
The titled compound was prepared following the procedure A using 4-[(4-chlorophenyl)ethynyl]benzaldehyde (intermediate which may be obtained according to methods disclosed in EP03103780.7) and 6-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one as a yellow powder (62%). 1H NMR (CDCl3, 300 MHz) δ 7.52-7.41 (m, 4H), 7.38-7.28 (m, 4H), 7.16 (d, J=2.7 Hz, 1H), 6.87-6.76 (m, 2H), 4.34 (s, 2H), 1.68 (s, 6H). M− (ESI): 416.1. HPLC, Rt: 5.45 min (Purity: 96%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:28][CH2:29][O:30][CH3:31])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:6][C:5]=2[N:4]=1.[OH-].[NH4+]>C(O)C.O>[NH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:11]2[C:10]3[CH:9]=[CH:8][C:7]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:6][C:5]=3[N:4]=[C:3]([NH2:2])[C:12]=2[N:13]=[C:14]1[CH2:28][CH2:29][O:30][CH3:31]
Reactant: COCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCN
Temperature: 70 °C

Procedure:
A solution of hydrochloric acid (9.25 mL of 2 M) in ethanol was added to tert-butyl {4-[4-amino-7-benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate (2 g, 4 mmol), and the reaction was heated at 70° C. for 5 hours. The reaction was allowed to cool to ambient temperature, and nitrogen gas was bubbled through the solution overnight. The solvent was removed under reduced pressure, and the residue was triturated with diethyl ether to provide a sticky solid, which was dissolved in water and treated with concentrated ammonium hydroxide until pH 11 was achieved. The solution was extracted with dichloromethane several times, and the combined extracts were concentrated under reduced pressure to provide 1-(4-aminobutyl)-7-benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a dark-brown oil.
Reaction SMILES: Cl.C(=O)(O)O.[CH:6]1([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH2:15][NH2:16])[CH2:10][CH2:9][CH2:8][CH2:7]1.[O-:22][C:23]#[N:24].[Na+]>O.C1COCC1>[CH:6]1([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH2:15][NH:16][C:23]([NH2:24])=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(CN)cc1OC1CCCC1
Reactant: N#C[O-]
Agent: Cl
Agent: O=C(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNC(N)=O)cc1OC1CCCC1
Yield: 97 %

Procedure:
25 ml of 5N HCl was added to a solution of 31.54 g of 3-cyclopentyloxy-4-methoxy-benzylamine carbonate and 8.30 g of sodium cyanate in 440 ml of water and 50 ml of THF over 15 minutes. After 3 hours another 0.83 g of sodium cyanate was added. After 20 hours the solid was collected, washed with water containing 5% of THF, suspended in 2.2 liters of ether and collected to give the title compound as a white solid (28.55 g) mp 134-5° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14]Br)=[CH:8][CH:7]=1.[CH:33]1[C:45]2[NH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]=2[CH:36]=[CH:35][CH:34]=1.[OH-].[Na+]>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][CH:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:42]3[C:43]4[NH:44][C:45]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:38]=4[CH:39]=[CH:40][CH:41]=3)=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:32])=[O:31])=[CH:29][CH:28]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)c2ccccc2NC(Cc2ccc(OCCc3cccc4c3[nH]c3ccccc34)cc2)C(=O)O)cc1
Yield: 53.8 %

Procedure:
To a solution of 2-[(2-(4-methylbenzoyl)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid methyl ester (0.24 g, 0.49 mmol) and carbazole (0.082 g, 0.49 mmol) in benzene (10 ml) is added tetrabutyl ammonium bromide (0.08 g) and 50% NaOH aqueous solution (0.084 g, 1.08 mmol), then the mixture is heated to reflux for 10 h. After cooled, benzene (30 ml) is added, and the mixture is washed with water (3×30 ml). Then the solvent is evaporated under a vacuum. The crude product is purified by silica gel chromatography using CHCl3/MeOH (4:1) as eluent to give the title compound (0.15 g, 54%). HRMS calcd for C37H32N2O4: 568.6692. Found: 568.6693. MA calcd for C37H32N2O4: C, 78.15%; H, 5.67%; N, 4.93%. Found: C, 78.36%; H, 5.64%; N, 4.91%.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[C:9]1=[O:37])(=O)=O.[NH4+:38].[OH-]>CC(O)C.O>[NH2:38][CH2:6][CH2:7][N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[N:10]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[CH:27][CH:28]=2)[C:9]1=[O:37]
Reactant: CS(=O)(=O)OCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: NCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 80 °C
Yield: 96 %

Procedure:
2-(3-(4-(4-Chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)ethyl methanesulfonate (85.0 mg, 0.153 mmol) is dissolved in a mixture solvent of iPrOH (0.5 mL) and concentrated ammonia aqueous solution (0.5 mL). The reaction mixture is heated at 80° C. for 2 h, cooled down to room temperature, taken in H2O (10 mL), and extracted with EtOAc (3×5 mL). The combined organic layer is dried over MgSO4 and evaporated in vacuo to provide the crude title compound (69.7 mg, 96% yield) as a colorless oil-like product; HPLC-MS calculated for C24H21ClF3N3O2 (M+H+) 476.1, found 476.1.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3]([S:5][CH2:6][CH3:7])=[NH:4].C(=O)([O-])[O-].[K+].[K+].[P:15](=[O:21])(Cl)([S:18][CH3:19])[O:16][CH3:17]>C(#N)C>[CH3:17][O:16][P:15]([S:18][CH3:19])([N:4]=[C:3]([S:5][CH2:6][CH3:7])[N:2]([CH3:8])[CH3:1])=[O:21]
Reactant: COP(=O)(Cl)SC
Reactant: CCSC(=N)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCSC(=NP(=O)(OC)SC)N(C)C
Yield: 64.2 %

Procedure:
To a mixture of 6.6 g of N,N-dimethylcarbamimidothioic acid, ethyl ester, 8.0 g of finely powdered potassium carbonate and 50 ml of acetonitrile was added dropwise 8.0 g of phosphorochloridothioic acid, O,S-dimethyl ester. The mixture was stirred until no starting material could be detected by GLC (Gas Liquid Chromatography). The salts were then removed by filtration, the filtrate concentrated under vacuum, the residue taken up in ether, the ether solution washed once with water, once with 5% aqueous sodium hydroxide, once with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under vacuum and the residue distilled in a Kugelrohr (bath temperature 140° C., pressure 0.3 mm) yielding 8.2 g (64% of theoretical) of N'-(methoxy(methylthio)phosphinyl)-N,N-dimethylcarbamimidothioic acid, ethyl ester as a colorless oil. The IR and NMR spectra are identical to those obtained from the compound prepared by method A.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+]>OS(O)(=O)=O>[N+:12]([C:7]1[C:2]([OH:1])=[CH:3][C:4]([C:8]([F:11])([F:9])[F:10])=[N:5][CH:6]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc(C(F)(F)F)cc1O
Temperature: 25 °C

Procedure:
25 mL of fuming H2SO4 under cold conditions (0° C.) is added dropwise to a stirred solution of 4-hydroxy-2-trifluoromethylpyridine [Chemistry of Heterocyclic Compounds 1997, 33, 995-996] (4 g, 24.5 mmol) in concentrated H2SO4 (10 mL). HNO3 (fuming, 90%, 25 mL) is added carefully to the above mixture with caution to keep the offset of any exotherm under control, and the reaction is allowed to warm to room temperature slowly. After heating at 120° C. for 6 h with stirring, the resulting mixture is cooled to room temperature, poured into ice-cold water maintaining the pH around 1 with the addition of 10N NaOH solution, and then extracted with CHCl3. The combined organic phase is washed successively with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo to afford 5-nitro-2-trifluoromethyl-pyridin-4-ol as an yellow solid. 1H NMR (300 MHz, CDCl3) δ 9.33 (s, 1H), 7.50 (s, 1H).
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1.C(O)(=O)C.C(=O)(O)[O-].[Na+].Cl[C:45]1[C:50]([N+:51]([O-:53])=[O:52])=[CH:49][CH:48]=[CH:47][N:46]=1>CS(C)=O.O>[CH3:32][N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([C:22]2[C:21](=[O:33])[NH:20][C:19](=[O:34])[C:18]=2[C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:8][CH2:7][CH2:6][NH:5][C:45]3[C:50]([N+:51]([O-:53])=[O:52])=[CH:49][CH:48]=[CH:47][N:46]=3)[CH:10]=2)=[CH:24]1
Reactant: Cn1cc(C2=C(c3cn(CCCN)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cn1cc(C2=C(c3cn(CCCNc4ncccc4[N+](=O)[O-])c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 100 °C
Yield: 52.9 %

Procedure:
A solution of 100 mg of 3-[1-(3-aminopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione acetate, containing an extra equivalent of acetic acid, in 10 ml of dimethyl sulphoxide (DMSO) was treated with 35 mg of sodium bicarbonate and 36 mg of 2-chloro-3-nitropyridine. The mixture was heated at 60° C. for 1 hour and at 100° C. for 2 hours. The solution was allowed to cool, water was added and the precipitate was filtered off and chromatographed on silica gel with 1% to 5% methanol in dichloromethane. The product was purified further by crystallization from hexane/ethyl acetate to give 60 mg of 3-(1-methyl-3-indolyl)-4-[1-[3-(3-nitro-2-pyridylamino)propyl]-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 218°-220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:4]2[C:5]([N:7]([C:10]3([C:16](O)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6].S(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:4]2[C:5]([N:7]([C:10]3([C:16]([Cl:24])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C1c2cccc(Cl)c2C(=O)N1C1(C(=O)O)CCCCC1
Solvent: c1ccccc1
Product: O=C1c2cccc(Cl)c2C(=O)N1C1(C(=O)Cl)CCCCC1
Reaction time: 2 h

Procedure:
In a 12 liter flask is placed 1.5 kg. of the 1-(3-chlorophthalimido)cyclohexanecarboxylic acid and 7500 ml. benzene. The mixture is stirred and heated to boiling, and then 696 grams thionyl chloride added dropwise. After the addition, heating is continued for 2 hours. The volume of the solution is reduced by one-half, the solution filtered, and the remaining solvent removed under reduced pressure. The acid chloride is used for the preparation of the carboxamides without further purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([NH:12][C:13](=[NH:16])[NH:14][CH3:15])=[O:11].[CH3:17]OC(OC)N(C)C.[NH4+].[OH-].CC(O)C.CCOC(C)=O.CO>CC#N.C(Cl)(Cl)Cl.O>[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:15]=[N:14][C:13]([NH:16][CH3:17])=[N:12][C:10]1=[O:11]
Reactant: CNC(=N)NC(=O)Nc1ccccc1C
Reactant: COC(OC)N(C)C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1ncn(-c2ccccc2C)c(=O)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a magnetically stirred suspension of 9.72 g (40 mmol) of 1-(2-methylphenyl)-3-methylamidinourea hydrochloride in 30 ml of CH3CN was added 9.52 g (80 ml) of N,N-dimethylformamide dimethylacetal. After the mixture had been further diluted with 25 ml CH3CN and stirred for 5 minutes, all of the solid had dissolved. TLC(3% NH4OH/IPA showed a new spot; about equal in size to a spot in starting material; (EtOAc/MeOH; 9:1) shows mostly a new spot. The solution was refluxed for two hours. The reaction mixture was allowed to cool to ambient temperature. The reaction mixture was then poured into CHCl3 /H2O and separated. The aqueous layer was extracted with CHCl3 (for a total of 3×50 ml). The organic layers were combined and washed with H2O (2×50 ml). The aqueous layers were combined and back-extracted with CHCl3 (1×50 ml). All organic layers were combined, dried, filtered and concentrated in vacuo to yield the product which was recrystallized from absolute EtOH, filtered and washed with cold absolute EtOH and air-dried. The product was 1-(2-methylphenyl)-4-methylaminodihydro-1,3,5-triazin-2-one, melting point 191.5°-192.5° C.
Reaction SMILES: Cl.[OH:2][C:3]([CH3:22])([CH3:21])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[C@@H:12]([NH2:19])[CH2:13][C@@H:14]([O:16][CH2:17][CH3:18])[CH3:15])=[N:6]1.C(N(CC)C(C)C)(C)C.OC(C)(C)CN1C=CC(NC(=O)[C@@H](N2[CH2:51][C:50]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH2:60][CH3:61])[C:54]=3[F:62])=[CH:49][C:48]2=[O:63])CC(C)C)=N1>C(#N)C>[OH:2][C:3]([CH3:22])([CH3:21])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[C@@H:12]([N:19]2[CH2:51][C:50]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH2:60][CH3:61])[C:54]=3[F:62])=[CH:49][C:48]2=[O:63])[CH2:13][C@@H:14]([O:16][CH2:17][CH3:18])[CH3:15])=[N:6]1
Reactant: CCO[C@@H](C)C[C@H](N)C(=O)Nc1ccn(CC(C)(C)O)n1
Reactant: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOc1cccc(OC2=CC(=O)N([C@@H](C[C@H](C)OCC)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1F
Yield: 50.1 %

Procedure:
A suspension of (2S,4S)-2-amino-4-ethoxy-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochloride salt (prepared as in Example 95, 124.5 mg, 0.335 mmol) in acetonitrile (7 mL) was treated with N,N-diisopropylethylamine (0.25 mL). At this time a solution of (E)-4-bromo-3-(3-ethoxy-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 114, 117 mg, 0.337 mmol) in acetonitrile (2 mL) was added and the resulting solution refluxed for 64 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (2 mL) and transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 1.5 h. The mixture was concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica 12 g, 10% to 70% (10% methanol/dichloromethane)/hexanes,) which afforded (2S,4S)-4-ethoxy-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (87 mg, 50%): HR-ES-MS (m/z) calculated for C26H35FN4O6 [M+H]+ 519.2614, observed 519.2615. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95-1.19 (m, 12H), 1.36 (t, J=6.0 Hz, 3H), 1.75-2.02 (m, 2H), 3.15-3.30 (m, 1H), 3.33 (br. s., 1H), 3.40-3.55 (m, 1H), 3.89 (br. s., 2H), 4.06-4.21 (m, 2H), 4.29 (d, J=18.4 Hz, 1H), 4.49 (d, J=18.4 Hz, 1H), 4.67 (br. s., 1H), 4.85-4.99 (m, 2H), 6.44 (br. s., 1H), 6.91-7.06 (m, 1H), 7.05-7.29 (m, 2H), 7.53 (br. s., 1H), 10.69 (br. s., 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH:20]([N:23]([CH3:25])[CH3:24])[CH2:19]2)=[CH:14][CH:13]=1>>[CH3:24][N:23]([CH3:25])[CH:20]1[CH2:21][CH2:22][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:2]([OH:1])=[N:3][CH:4]=3)=[CH:13][CH:14]=2)[CH2:19]1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Reactant: O=C(O)c1ccc(O)nc1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(O)nc3)cc2)C1

Procedure:
6-Hydroxynicotinic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 326.17 (C18H22N4O2); MS (ESI): 327 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: C([O:3][C:4](=O)/[N:5]=[C:6](\OCC)/[CH3:7])C.Cl.[CH:13]([NH:16][NH2:17])([CH3:15])[CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:13]([N:16]1[C:4](=[O:3])[NH:5][C:6]([CH3:7])=[N:17]1)([CH3:15])[CH3:14]
Reactant: CC(C)NN
Reactant: CCOC(=O)/N=C(/C)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nn(C(C)C)c(=O)[nH]1
Reaction time: 17 h

Procedure:
To a solution of [1-ethoxy-eth-(Z)-ylidene]-carbamic acid ethyl ester (834 mg, 5.24 mmol) in toluene (15 mL) was added isopropyl hydrazine hydrochloride (637 mg, 5.76 mmol) followed by triethylamine (803 μL, 5.76 mmol). The reaction vessel was sealed and stirred at 45° C. for 45 minutes before the addition of triethylamine (803 μL, 5.76 mmol). The resultant mixture was heated to 90° C. and stirred for 17 hours, then cooled and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, gradient 0% to 8% 2M NH3/MeOH in DCM) to give 2-Isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one as an off white solid (329 mg, 44%). LCMS: RT=2.16 min, [M+Na]+=164
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH2:14]O)[CH2:10]2)=[CH:4][CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.[C-]#N.[Na+].[N:43]1C=CC=C[CH:44]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH2:14][C:44]#[N:43])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CC#N
Product: N#CCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The reaction mixture of 51 mg (0.114 mmol) of 2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-2-(3,5-difluorophenyl)ethanol, 24 mg (0.137 mmol) of methanesulfonic anhydride, 14 mg (0.285 mmol) of sodium cyanide and 11 uL (0.137 mmol) pyridine in 5 mL of acetonitrile was stirred for 12 h at rt, and then concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to the title compound; 1NMR (CDCl3) δ 3.29 (s, 2H), 3.96 (s, 2H), 4.01 (s, 2), 4.54 (s, 1H), 6.69-6.75 (m, 3H), 7.29-6-7.7.38 (m, 8H); Mass Spectrum m/e=455 (M+1 35Cl, 35Cl) and 457 (M+1 35Cl, 37Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4](I)[CH:3]=1.[CH3:15][C:16]1[CH:20]=[CH:19][NH:18][N:17]=1.C([O-])([O-])=O.[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:18]2[CH:19]=[CH:20][C:16]([CH3:15])=[N:17]2)[CH:3]=1
Reactant: OC(c1ccc(Cl)cc1I)C(F)(F)F
Reactant: Cc1cc[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccn(-c2cc(Cl)ccc2C(O)C(F)(F)F)n1
Temperature: 130 °C
Yield: 33 %

Procedure:
1-(4-Chloro-2-iodo-phenyl)-2,2,2-trifluoro-ethanol (0.840 g, 2.5 mmol), 3-methyl pyrazole (0.230 g, 2.8 mmol), CuI (0.190 g, 1.0 mmol), K2CO3 (0.863 g, 6.25 mmol), (1R,2R)-N,N′-dimethyl-cyclohexane-1,2-diamine (0.071 g, 0.5 mmol) and toluene (10 ml) were combined in a 20 ml pressure tube, and the mixture was heated at 130° C. (oil bath temperature) for 12 h. The mixture was diluted with ethyl acetate and washed with H2O (2×20 ml), brine, and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography using 5-10% ethyl acetate in hexane as solvent to afford 1-[4-chloro-2-(3-methyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethanol (240 mg).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:9][S:10](Cl)(=[O:12])=[O:11])[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.Cl.[F:15][C:16]([F:35])([CH:32]([F:34])[F:33])[CH2:17][O:18][C:19]1[CH:31]=[CH:30][C:22]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>ClCCl.C(N(CC)CC)C>[CH3:1][C@:2]1([CH2:9][S:10]([N:27]2[CH2:28][CH2:29][CH:24]([O:23][C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:35])[CH:32]([F:34])[F:33])=[CH:31][CH:30]=3)[CH2:25][CH2:26]2)(=[O:12])=[O:11])[NH:3][C:4](=[O:8])[NH:5][C:6]1=[O:7]
Reactant: FC(F)C(F)(F)COc1ccc(OC2CCNCC2)cc1
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]1(CS(=O)(=O)N2CCC(Oc3ccc(OCC(F)(F)C(F)F)cc3)CC2)NC(=O)NC1=O
Reaction time: 16 h
Yield: 24.1 %

Procedure:
[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulphonyl chloride (0.453 g) was added to a solution of 4-{4-(2,2,3,3-tetrafluoropropoxy)phenoxy]-piperidine hydrochloride (0.69 g) in dichloromethane (25 ml) and triethylamine (1.7 ml) at ambient temperature. Stirred for 16 hours and evaporated to dryness. The residue was purified by column chromatography (using λ230 nm as the detecting wavelength) eluting with a 0-10% methanol and dichloromethane. Yielded a solid product, which was dried under vacuum at 50° C. to yield the title compound (0.24 g). NMR Spectrum: (DMSOd6) δ 10.7 (s, 1H), 8.0 (s, 1H), 6.95 (m, 4H), 6.6 (tt, 1H), 4.5 (m, 2H), 4.4 (m, 1H), 3.5 (d, 1H), 3.3 (m, 3H), 3.1 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H), 1.35 (s, 3H). Mass Spectrum M−H− 495.89
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[C:27]([CH3:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[F:32].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C1COCC1.CN(C=O)C>[F:32][C:31]1[C:26]([NH:25][C:13](=[O:15])[C:12]2[CH:16]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=[C:10]([CH3:18])[C:11]=2[CH3:17])=[C:27]([CH3:34])[C:28]([OH:33])=[CH:29][CH:30]=1
Reactant: Cc1c(O)ccc(F)c1N
Reactant: Cc1cc(-c2cccc(F)c2)cc(C(=O)O)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2c(F)ccc(O)c2C)c1C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of 5-(3-fluorophenyl)-2,3-dimethyl-benzoic acid (intermediate III(m)) (500 mg, 2.0 mmol, 1.0 eq) in CH2Cl2 (10 mL) at 0° C. was added oxalyl chloride (770 mg, 6.1 mmol, 3.0 eq) and DMF (0.1 mL) and the reaction was stirred for 1 h. The solvent and excess reagent were removed under reduced pressure and the residue obtained was dissolved in THF (10 mL) and added to a mixture of 3-amino-4-fluoro-2-methyl-phenol (intermediate X(e)) (280 mg, 2.0 mmol, 1.0 eq) and Na2CO3 (860 mg, 8.1 mmol, 4.0 eq) in THF (10 mL) at 0° C. The reaction was stirred for 3 h, then filtered and concentrated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 400:1 to 4:3) to give the title compound as a brown solid (300 mg, 40%).