Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].O>CN(C)C=O>[CH2:33]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: Nc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(N)cc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 40.8 %

Procedure:
To a solution of 15.0 g of 4-aminophenol dissolved in 300 ml of N,N-dimethylformamide, was added 28.5 g of anhydrous potassium carbonate. Subsequently, 46.0 g of 1-bromooctadecane was added thereto at 80° C., and the mixture was stirred for 3.5 hours at 80° C. Water was added to the reaction mixture, and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The crude product obtained by removal of the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane—ethyl acetate—chloroform=5:1:1 to 1:1:1), followed by recrystallization from chloroform—methanol, to yield 20.28 g of 4-octadecyloxyaniline (melting point: 95-97° C.) (Reaction Scheme (58) described below).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[N:22][CH:23]=1>CN(C)C=O>[N+:24]([C:21]1[N:22]=[CH:23][C:18]([O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1
Yield: 38.6 %

Procedure:
4-hydroxybenzamide (150 mg, 1.1 mmol) and caesium carbonate (394 mg, 1.21 mmol) was dissolved in dimethylformamide (7 ml). 5-bromo-2-nitropyridine (244 mg, 1.21 mmol) was then added. The mixture was left at 50 degrees until the starting material was consumed according to TLC (1% methanol in ether). Purification by flash chromatography yielded 4-[(6-nitro-3-pyridinyl)oxy]benzamide (110 mg, 38%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][N:13]=[C:14]=[O:15]>C(#N)C>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:15]
Reactant: NCCSCc1ccccn1
Reactant: CN=C=O
Solvent: CC#N
Product: CNC(=O)NCCSCc1ccccn1

Procedure:
A mixture of 2-[(2-aminoethyl)thiomethyl]pyridine (7.0 g.) and methyl isocyanate (2.7 g.) in acetonitrile was heated for 18 hours in a pressure vessel at 100°. After cooling, the solid obtained was collected and recrystallised from acetonitrile/ether to give N-methyl-N'-[2-(2-pyridylmethylthio)ethyl]urea m.p. 63°-66°.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]1O)=[S:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]=1)=[S:4]
Reactant: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC(C)(C)C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(=S)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Yield: 49.4 %

Procedure:
A mixture of 7.0 g of N,2,2-trimethyl-3,4-dihydro-3-hydroxy-6-nitro-2H-1-benzopyran-4-carbothioamide, 3.0 g of p-toluenesulfonic acid monohydrate, and 300 ml of toluene was heated at reflux for 1 hour. The solvent was removed from the reaction mixture by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH2Cl2). Recrystallizatlon from a mixed solvent of CH2Cl2, diethyl ether, and hexane gave 3.25 g of N,2,2-trimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide represented by formula shown below.
Reaction SMILES: N1CCCCC1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].Cl>N1C=CC=CC=1>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=[CH:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccs1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccs1
Yield: 90.1 %

Procedure:
Piperidine (2.45 g, 0.056 mol) was added drop wise over a period of 10 min to a stirred solution of thiophene-2-carbaldehyde (4.00 g, 0.036 mol) and malonic acid (1.00 g, 0.18 mol) in pyridine (40 mL) at 0° C. and the resulting reaction mixture was refluxed for 2 h. The reaction mixture was poured into 2N HCl (100 mL) and the precipitated solid filtered. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 3-(2-thienyl)prop-2-enoic acid (5.00 g, 92%) as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH:14]1([NH:20][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2ccsc2c1NC1CCCCC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.055 g, 0.26 mmol) (Example 1, Step 2), cyclohexanamine (59 μL, 0.51 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.77 mmol) in isopropyl alcohol (0.87 mL) was heated at 90° C. for 2 h. The resulting mixture was concentrated to give the desired product, which was used directly in the next step. LCMS calculated for C13H16N3O2S (M+H)+: m/z=278.1. Found: 278.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[N:14]=[CH:13][C:12](=[O:16])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>C1COCC1>[O:16]=[C:12]1[NH:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][CH:40]=[C:32]([O:31][C:30]([F:29])([F:41])[F:42])[CH:33]=4)[CH:19]=[CH:18][CH:17]=3)[C:15]=2[N:14]=[CH:13]1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)cnc23)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
Method G1: 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one (43 mg, 0.169 mmol) and diisopropylethylamine (44 μL, 0.254 mmol) were mixed in dry THF (5.0 mL) and 3-trifluoromethoxybenzoyl chloride (57 mg, 0.254 mmol) was added. This mixture was heated to reflux for 17 h. After cooling at RT, the solvent was removed in vacuo. The obtained oily residue was dissolved in DCM and washed with water and dried over MgSO4. After evaporation of DCM, the residue was retaken in Et2O, triturated and filtered off to afford the title compound as a white solid (45 mg, 60%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: C1CCNC1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COCCCCN2CCCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with pyrrolidine in N,N-dimethylacetamide at room temperature to yield trans-N-methyl-N-[4-(4-pyrrolidin-1-yl-butoxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as yellow solid, MS: 491 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:15][N:16]([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.O>C(O)C.[Pt]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:15][N:16]([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(OC)cc1
Agent: [Pt]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CN(C)C)c1ccc(OC)cc1
Reaction time: 23 h
Yield: 74 %

Procedure:
19.8 g (0.0795 mol) of ethyl α-(p-methoxyphenyl)-β-(dimethylamino)acrylate were dissolved in 740 ml of ethanol, in a 1 liter glass reactor, 30.6 9 of Pt/C type 18 catalyst (4.83% Pt and 59.70% water) were added, the mixture was first purged with nitrogen and then with hydrogen and finally a pressure of 600 psi H2 was applied. The mixture was left hydrogenating for 23 hours, was then filtered through Celite® 535 and was washed with 2×165 ml of ethanol. The ethanol was then removed under vacuum. The residue was dissolved in 30 ml of dichloromethane and was extracted with 50 ml and 2×15 ml of 2N hydrochloric acid. The operation continued with the acid aqueous phase that was basified with 40 ml of aqueous sodium hydroxide solution to pH 11. The product was extracted with 4×35 ml of ethyl acetate. The pooled organic phases were dried with sodium sulfate, filtered and evaporated to dryness under vacuum to give a pale yellow oil weighing 14.7 g, corresponding to ethyl α-(p-methoxyphenyl)-β-(dimethylamino)propionate (Yield: 74%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][C:9]=2[F:17])=[C:6]([N:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)[N:5]2[N:25]=[CH:26][N:27]=[C:4]2[N:3]=1.O.C(OC)(C)(C)C.[CH3:35][N:36](C)C=O>[C-]#N.C([N+](CC)(CC)CC)C>[C:35]([C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][C:9]=2[F:17])=[C:6]([N:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)[N:5]2[N:25]=[CH:26][N:27]=[C:4]2[N:3]=1)#[N:36]
Reactant: CN(C)C=O
Reactant: CC1CCN(c2c(-c3c(F)cc(C#N)cc3F)c(Cl)nc3ncnn23)CC1
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: O
Solvent: COC(C)(C)C
Product: CC1CCN(c2c(-c3c(F)cc(C#N)cc3F)c(C#N)nc3ncnn23)CC1

Procedure:
A mixture of 0.1 mol of 5-chloro-6-(2,6-difluoro-4-cyanophenyl)-7-(4-methylpiperidin-1-yl)-[1,2,4]-triazolo-[1,5-a]-pyrimidine (No. I-5) and 0.25 mol of tetraethylammonium cyanide in 750 ml of dimethylformamide (DMF) was stirred at 20–25° C. for 16 hours. After addition of water and methyl tert-butyl ether (MTBE), the organic phase was separated, washed with water, dried and freed from the solvent. After chromatography on silica gel, 6.33 g of the title compound were obtained from the residue.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH:12]([C:14](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:15])=[O:13].C(OCC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:14]([CH3:15])[CH:12]=[O:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(C=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(C=O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOc1ccc(C=C(C)C=O)cc1

Procedure:
A suspension of 4-ethoxybenzaldehyde (20 g, 0.133 mol) and α-formylethylidenetriphenylphosphorane (46.6 g, 0.146 mol) in dried toluene (400 ml) was heated with stirring at reflux under an atmosphere of nitrogen for 40 h. The mixture was cooled, diethyl ether added and filtered through a pad of celite. The filtrate was evaporated and the residue taken up in diethyl e;her and the resulting suspension purified on flash silica eluting with hexane-diethyl ether (4:1). The resulting oil was crystallised from hexane-diethyl ether to give 3-(4-ethoxyphenyl)-2-methylpropenaldehyde as yellow crystals.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].N1C=C(C#C[C:23]2[CH:24]=[C:25]([CH:47]=[CH:48][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])N2C=CN=CC=12.N#N.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:48]2[CH:47]=[C:25]([CH:24]=[CH:23][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Reactant: C#Cc1cnc2ccccn12
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
3-Ethynylimidazo[1,2-a]pyridine (37 mg, 0.26 mmol), 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (103.4 mg, 0.2 mmol), (prepared as in Example 2), Pd[(PPh3)4] (11.6 mg, 5mol %), and Cul (2.9 mg, 7.5 mmol %) was placed in a vial with rubber septum. The mixture underwent 3 cycles of vacuum/filling with N2, and DMF (1.5 ml) and N,N-diisopropylethylamine (53 mL, 0.3 mmol) was added. The mixture was stirred at rt for 16 h, and the reaction was quenched with H2O. EtOAc and more water were added for extraction. The combined organic layer was dried (Na2SO4), filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluent: 5% MeOH in methylene chloride, MeOH was pre-saturated with ammonia gas), giving the titled compound as an off-white solid (53%, 56 mg): MS (M+H)+ 532.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[CH2:5]([S:7](Cl)(=[O:9])=[O:8])[CH3:6].CCOCC>C(N(CC)CC)C>[CH2:5]([S:7]([O:4][CH2:3][CH2:2][Br:1])(=[O:9])=[O:8])[CH3:6]
Reactant: OCCBr
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCS(=O)(=O)OCCBr
Reaction time: 1 h

Procedure:
A mixture containing 12.5 ml. of 2-bromoethanol, 12.9 ml. of ethane sulfonyl chloride and 100 ml. of ether was formed. Then, 14 ml. of triethylamine was added dropwise over a 55 minute period at 5°-10°C. and stirred for 1 hour. The mixture was allowed to come to room temperature and stirred for an additional 15 minutes. To the mixture was added 100 ml. of water, the ether layer was separated, dried over magnesium sulfate and evaporated to yield 17.6 grams of a yellow oil. nD30 1.4760.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClC(Cl)C>[Cl:15][CH2:16][C:17]([C:7]1[C:2]([F:1])=[CH:3][C:4]([F:9])=[CH:5][C:6]=1[F:8])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Fc1cc(F)cc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(CCl)c1c(F)cc(F)cc1F
Temperature: 0 °C
Yield: 43.6 %

Procedure:
To a mechanically stirred solution of 1,3,5-trifluorobenzene (6.0 mL, 58 mmol) in dichloroethane (14.0 mL) was added gradually AlCl3 (15.5 g, 116 mmol) in a period of 15 min with caution. Violent bumping and HCl gas evolution was observed. The mixture was carefully heated to reflux, and chloroacetyl chloride (5.5 mL, 69 mmol) was added drop wisely in a period of 45 min. The reaction mixture was heated at reflux for additional 6.0 h. The solution was cooled, carefully poured onto an ice/water slush (200 mL) and the aqueous solution was extracted with ether (3×50 mL). The combined ethereal layers were washed with 10% aqueous HCl (2×30 mL), 1.0 N aqueous NaOH (3×30 mL), and brine (25 mL). The solution was dried over MgSO4 and concentrated under reduced pressure to give 2-chloro-1-(2,4,6-trifluorophenyl)ethanone (5.28 g) as yellow solids in 51% yield: 1H NMR (500 MHz, CDCl3) δ 6.79-6.76 (m, 2 H), 4.50 (s, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[NH:25]1[CH2:29][CH2:28][CH:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:26]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:25]3[CH2:29][CH2:28][CH:27]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH2:26]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: C1CC(N2CCOCC2)CN1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC(N4CCOCC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-(pyrrolidin-3-yl)morpholine to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.84 (m, 1H) 2.04-2.20 (m, 1H) 2.29-2.39 (m, 1H) 2.39-2.48 (m, 5H) 2.77-2.97 (m, 1H) 3.24-3.35 (m, 1H) 3.37-3.84 (m, 8H) 7.65 (dd, J=8.08, 1.52 Hz, 1H) 7.72 (s, 1H) 7.78 (d, J=7.83 Hz, 1H) 8.13 (s, 1H) 8.19 (td, J=5.49, 2.40 Hz, 1H) 8.36 (br. s., 1H) 8.65 (s, 1H) 13.03 (br. s., 1H); ESI-MS m/z [M+H]+ 459.2.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)=[O:13])=[N:8][N:7]=1.O1C=CC=C1C1OC(NC(C2C=CC=C(I)C=2)=O)=NN=1.[S:41]([C:45]1[CH:50]=[CH:49][C:48](B2OC(C)(C)C(C)(C)O2)=[CH:47][CH:46]=1)(=[O:44])(=[O:43])[NH2:42]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:48]3[CH:49]=[CH:50][C:45]([S:41](=[O:44])(=[O:43])[NH2:42])=[CH:46][CH:47]=3)=[CH:16][CH:15]=2)=[O:13])=[N:8][N:7]=1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1ccc(I)cc1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Agent: O=C(Nc1nnc(-c2ccco2)o1)c1cccc(I)c1
Product: NS(=O)(=O)c1ccc(-c2ccc(C(=O)Nc3nnc(-c4ccco4)o3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50 described below, using N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-4-iodobenzenecarboxamide prepared in Reference Example 1 instead of N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-3-iodobenzenecarboxamide and using commercially available 4-sulfamoylphenylboronic acid pinacol ester instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[C:11]([CH3:12])[C:6]=2[O:5][C:4](=[O:19])[CH:3]=1.[C:20]1([C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N+]=[N-])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOCC>CN(C=O)C>[C:20]1([CH:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:1][C:2]2[C:7]3[CH:8]=[CH:9][C:10]([CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][O:14]4)=[C:11]([CH3:12])[C:6]=3[O:5][C:4](=[O:19])[CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: Cc1c(C2CCCCO2)ccc2c(O)cc(=O)oc12
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1c(C2CCCCO2)ccc2c(OC(c3ccccc3)c3ccccc3)cc(=O)oc12
Temperature: 40 °C
Reaction time: 3 h
Yield: 22.7 %

Procedure:
55 g of 4-hydroxy-8-methyl-7-(tetrahydro-2H-pyran-2-yl)-2H-1-benzopyran-2-one is introduced into 250 ml of anhydrous dimethylformamide heated to 40° C., and a solution of 58.3 g of diphenyldiazomethane in 250 ml of DMF is added dropwise. The addition is made over 3 hours while maintaining the temperature at 40° C. Several portions of 3 g of diphenyldiazomethane are added again and agitation is carried out for one hour at 40° C. The reaction medium is poured into 2 l of sulphuric ether. The organic solution is washed with an aqueous solution of sodium bicarbonate, with a solution of soda (0.1 M), with water and with salt water followed by evaporation to dryness. The residue is agitated in an isopropyl ether-hexane mixture (1-2) followed by separation. The insoluble part is dried. 20.5 g of sought product is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)=[CH:6][N:7]=1.CN(C=O)C.[Br:24][CH2:25][CH2:26]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:26][CH2:25][Br:24])[CH:9]=2)=[CH:6][N:7]=1
Reactant: BrCCBr
Reactant: CNC(=O)c1nc(-c2cccc(O)c2)cnc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1nc(-c2cccc(OCCBr)c2)cnc1N
Temperature: 85 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
3-Amino-6-(3-hydroxyphenyl)-N-methylpyrazine-2-carboxamide (1.01 g, 4.1 mmol) was taken into DMF (10 mL) followed by addition of 1,2-dibromoethane (10 mL) and cesium carbonate (2.7 g, 8.2 mmol). The mixture was warmed to 85° C. over 5 days followed by addition of another aliquot of cesium carbonate and 1,2-dibromoethane and heating was continued an additional 4 hours. The mixture was diluted with an excess of ethyl acetate and washed with water (3×) then brine and dried over anhydrous magnesium sulfate. Filtration and concentration ill vacuo followed by purification of the residue using silica gel flash chromatography using ethyl acetate:hexanes (1:1) as eluent. The pure fractions were combined and concentrated then dried in vacuo to give 3-amino-6-{3-[(2-bromoethyl)oxy]phenyl)-N-methylpyrazine-2-carboxamide (486 mg, 34% yield) was a yellow solid: MS (EI) for C14H16N4O2Br: 351, 353 (MH+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(O)c1cccc(Br)n1
Product: O=C(O)c1cccc(-c2ccc(F)cc2)n1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (1 g, 4.95 mmol) was coupled 4-fluoro-phenylboronic acid (693 mg, 4.95 mmol) acid using Method F to give the title compound.