Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C:5]([NH2:8])([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.[C:19]([O:23][C:24]([NH:26][C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:2][O:3][C:4](=[O:9])[C:5]([CH3:7])([CH3:6])[NH:8][C:28](=[O:29])[C:27]([CH3:32])([CH3:31])[NH:26][C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25]
Reactant: COC(=O)C(C)(C)N
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
Aminoisobutyric acid methyl ester hydrochloride 2 (11.44 g, 74.47 mmol) and N,N-diisopropylethylamine (9.63 g, 74.5 mmol) were dissolved in DMF (400 mL) and the solution added to solid N-tert-butoxycarbonyl α,α-dimethylglycine (15.14 g, 74.49 mmol). The solution/suspension was cooled to 0° C. (icebath) and HOBt hydrate (11.41 g, 74.51 mmol) and then EDC hydrochloride (15.71 g, 81.95 mmol) added together with more DMF (100 mL). The reaction mixture was stirred for 30 min at 0° C., after which the icebath was removed and stirring continued for 66 h at room temperature. The solvent was evaporated and the residue taken up in EtOAc (500 mL). The solution was washed with 2 M HCl (3×175 mL), 7.5% (w/w) K2CO3 solution (3×175 mL) and saturated brine (175 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording a slightly yellowish solid (17.04 g). The solid (16.72 g) was washed with hexane (4×70 mL) affording an off-white solid (14.72 g, 67%), with spectral characteristics in accordance with literature data2,3; 1H NMR (200 MHz; DMSO-d6) δ 7.57 (s, 1H, NH(Aib2)), 6.63 (br s, 1H, NH(Aib1)), 3.55 (s, 3H, OCH3), 1.37 (s, 9H, (CH3)3), 1.34 (s, 6H, CH3), 1.28 (s, 6H, CH3); 13C NMR (75 MHz, DMSO-d6) δ 174.5, 174.0, 154.1, 78.0, 55.5, 55.1, 51.7, 28.1, 24.8, 24.7; HRMS (m/z): [M+Na]+ calcd. for C14H26N2O5Na, 325.1739. found, 325.1746; Anal. Calcd. for C14H26N2O5: C, 55.61; H, 8.67; N, 9.26. Found: C, 55.9; H, 8.7; N, 9.2.
Reaction SMILES: Cl[C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:4](=[O:14])[C:5]2[C:6]([N:13]=1)=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2.[CH:22]([NH:24][NH2:25])=O>C(#N)C>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:3]1[C:4](=[O:14])[C:5]2[C:6](=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[N:13]2[CH:22]=[N:24][N:25]=[C:2]12
Reactant: CSc1ncc2c(=O)n(-c3ccccc3Cl)c(Cl)nc2n1
Reactant: NNC=O
Solvent: CC#N
Product: CSc1ncc2c(=O)n(-c3ccccc3Cl)c3nncn3c2n1

Procedure:
A mixture of Example 1B (0.150 g, 0.442 mmol) and formohydrazide (0.066 g, 1.11 mmol) in acetonitrile (7 mL) was heated at 150° C. for 15 minutes in a Biotage microwave reactor. The solid was filtered. The filtrate was concentrated, treated with saturated aqueous NaHCO3 and extracted with ethyl acetate (2×). The combined organic layers were dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/ethyl acetate (3:7 to 2:8) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C=O)C.C(OCC)(=O)C.[Cl-].[NH4+]>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: CC(=O)Oc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Oc1ccc(Cn2cc(Br)cn2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-bromo-1H-pyrazole (500 mg, 3.40 mmol), 4-(chloromethyl)phenyl acetate (659 mg, 3.57 mmol), and potassium carbonate (1.18 g, 8.50 mmol) was diluted with DMF (5 mL) at ambient temperature. The reaction mixture was heated to 40° C. for 4 hours. The reaction mixture was then diluted with sodium hydroxide (2.0 M in water, 3.40 mL, 6.80 mmol) and stirred for an additional 30 minutes at 40° C. The reaction mixture was then cooled to ambient temperature and diluted with ethyl acetate (200 mL) and saturated aqueous ammonium chloride solution (50 mL). The organic layer was separated and washed with water (50 mL) and then brine (25 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica (0-100% ethyl acetate/hexanes) to afford 4-((4-bromo-1H-pyrazol-1-yl)methyl)phenol. MS ESI calc'd. for C10H10BrN2O [M+H]+ 253 and 255. found 253 and 255. 1H NMR (500 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.98 (s, 1H), 7.51 (s, 1H), 7.08 (d, J=8.5 Hz, 2H), 6.69 (dd, J=7.0 Hz, 2.0 Hz, 2H), 5.14 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[S:4].N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:11][N:5]1[C:6](=[O:7])[CH:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[S:4]
Reactant: CCOC(=O)Cl
Reactant: CN1C(=O)CC(=O)N(C)C1=S
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1C(=O)N(C)C(=S)N(C)C1=O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
155 g (0.9 mol) of 1,3-dimethyl-2-thiobarbituric acid, 88,3 g (1.12 mol) of pyridine and 9 g of 4-dimethylaminopyridine are dissolved in 660 ml of dichloromethane and the solution is cooled to 0° C. Then 102 g (0.94 mol) of ethyl chloroformate are added dropwise over 1 hour. The mixture is subsequently stirred for 12 hours at 0° C., then allowed to warm to room temperature and worked up after a further 7 hours as follows. 600 ml of dichloromethane are added and the solution is washed with three 1000 ml portions of water, dried over Na2SO4 and the solvent is evaporated off. The crude product is recrystallised from ethanol. Melting point 90°-93° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[N:32][CH:33]=4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Cl.[NH2:37][OH:38].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[OH:38][NH:37][C:34](=[NH:35])[C:31]1[CH:30]=[CH:29][C:28]([C:13]2[N:9]3[N:10]=[CH:11][CH:12]=[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[C:8]3=[N:15][C:14]=2[C:16]#[C:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:33][N:32]=1
Reactant: N#Cc1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of compound 39a (0.20 g, 0.44 mmol), hydroxylamine hydrochloride (0.20 g, 2.9 mmol) and sodium carbonate (0.20 g, 1.9 mmol,) in ethanol (4 mL) was stirred at 80° C. for 1 h. The reaction mixture was cooled to rt, and the solids formed were collected by filtration and washed with Et2O (2×30 mL) to obtain compound 42a as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H22N8O2: 491.2 (M+H). Found: 491.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Br[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].O>C(#N)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][CH2:2]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C1CCNCC1
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1CCN(CC(=O)OCc2ccccc2)CC1
Reaction time: 4 h

Procedure:
To a suspension (39 mL) of tert-butyl piperidine-4-carboxylate (2.6 g) in acetonitrile was added diisopropylethylamine (4.4 mL), subsequently, benzyl bromoacetate (2.0 mL) was added at room temperature in portions, and the mixture was stirred for 4 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. This was washed with an aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3→0:1) to obtain the title compound (3.4 g) having the following physical property values.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[N:21]1[C:29]([NH2:30])=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[N:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:30][C:29]1[N:21]=[CH:22][N:23]=[C:24]2[C:28]=1[N:27]=[CH:26][N:25]2[CH2:2][C:3]1[O:4][C:5](=[O:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=c1oc(CBr)c(-c2cccc(F)c2)c2ccccc12
Reactant: Nc1ncnc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ncnc2c1ncn2Cc1oc(=O)c2ccccc2c1-c1cccc(F)c1
Yield: 62.6 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1, using 3-(bromomethyl)-4-(3-fluorophenyl)-1H-isochromen-1-one (intermediate C4, 50 mg, 0.150 mmol), commercially available 9H-purin-6-amine (40.6 mg, 0.300 mmol) and K2CO3 (41.5 mg, 0.300 mmol) to give the title compound (36.4 mg, 62.6%) as a colourless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:33][CH2:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:39]4[CH:38]=[CH:37][CH:36]=[C:35]([CH2:34][OH:33])[CH:40]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: OCc1cccc(B(O)O)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CO)c4)cc23)CC1
Temperature: 160 °C
Yield: 45.8 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (20.0 mg, 0.048 mmol), K3PO4 (21.0 mg, 0.096 mmol) and [3-(hydroxymethyl)phenyl]boronic acid (30.0 mg, 0.193 mmol) in dioxane/H2O (2 mL/0.7 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (5.0 mg, 0.0048 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160° C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (10 mL), dried over MgSO4, concentrated, and purified by reverse phase HPLC method A (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (9.7 mg, 46%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:13])[CH3:12])=[CH:8][S:7][C:6]=1[CH3:14])=[O:4].[OH-].[Na+]>CO>[C:11]([NH:10][C:9]1[C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:14])[S:7][CH:8]=1)(=[O:13])[CH3:12]
Reactant: COC(=O)c1c(NC(C)=O)csc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1csc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 28 h
Yield: 90.9 %

Procedure:
A mixture of 4-acetylamino-2-methyl-thiophene-3-carboxylic acid methyl ester (250 mg, 1.17 mmol) in methanol (4.0 mL) at 25° C. was treated with a 1N aqueous sodium hydroxide solution (3.5 mL, 3.51 mmol). The reaction was stirred at 25° C. for 28 h. At this time, the reaction was concentrated in vacuo, diluted with water (15 mL), and then acidified to pH=2 by the addition of a 1N aqueous hydrochloric acid solution. The resulting slurry was cooled to 0° C. The solid was collected by filtration, washed with water, and the dried in vacuo to afford 4-acetylamino-2-methyl-thiophene-3-carboxylic acid (212 mg, 90.9%) as a tan solid: LR-MS for C8H9NO3 (M−H)+ at m/z=198.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([Cl:18])[N:12]=[C:11]([Cl:19])[C:10]=1[C:20]([O:22]C(C)(C)C)=[O:21]>ClCCl>[NH2:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([Cl:18])[N:12]=[C:11]([Cl:19])[C:10]=1[C:20]([OH:22])=[O:21]
Reactant: CC(C)(C)OC(=O)c1c(Cl)nc(Cl)c(C(=O)O)c1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1c(C(=O)O)c(Cl)nc(Cl)c1C(=O)O

Procedure:
In scheme (V), 5-(tert-butoxycarbonyl)-4-(tert-butoxycarbonylamino)-2,6-dichloronicotinic acid (4) is first treated with 25% trifluoracetic acid (TFA) in dichloromethane (DCM) at room temperature (25° C.) for 2 hours, removing one of the two Boc groups and forming 4-amino-5-(tert-butoxycarbonyl)-2,6-dichloronicotinic acid (5). A stronger condition (reflux at 60° C., 25% TFA in DCM, 2 h) is then used to maximize hydrolysis of the tert-butyl ester of 4-amino-5-(tert-butoxycarbonyl)-2,6-dichloronicotinic acid (5) and obtain 4-amino-2,6-dichloropyridine-3,5-dicarboxylic acid (6).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH:13]=[O:14])[CH2:5][CH:4]([OH:15])[CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[O:16]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH:13]=[O:14])[CH2:5][C:4](=[O:15])[CH2:3]1
Reactant: O=CN1CC(O)CS(=O)(=O)c2ccccc21
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=CN1CC(=O)CS(=O)(=O)c2ccccc21
Yield: 95.5 %

Procedure:
A solution of 1,1-dioxo-5-N-formyl-3-hydroxy -2,3,4,5-tetrahydro-[1,5]-benzothiazepine (0.443 g, 1.83 mmole) from Example 15, in 5 mL of acetone was treated with Jones reagent (0.54 mL, 1.40 mmole), and the solution was heated to reflux for 15 minutes. An additional 0.15 mL of Jones reagent was added and the reaction was heated for 20 minutes longer. The cooled solution was filtered through MgSO4, and the solvents were removed under reduced pressure. The residue was triturated with chloroform and filtered. Evaporation of the filtrate afforded the product (0.418 g, 95% yield) D.C.I.M.S. 240 [M+H].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:23]1[CH:24]=[CH:25][C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:27]([CH:37]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][N:34]=[N:33][CH:32]=1)=[O:29].CS(C)=O.CO>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:23]2[CH:24]=[CH:25][C:26]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:27]([CH:37]=2)[C:28]([NH:30][C:31]2[CH:36]=[CH:35][N:34]=[N:33][CH:32]=2)=[O:29])[CH:4]=[N:3]1
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Solvent: CS(C)=O
Product: Cn1cc(-c2ccc(OCc3ccccc3)c(C(=O)Nc3ccnnc3)c2)cn1
Temperature: 140 °C

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (56.9 mg, 0.273 mmol), 1M Na2CO3 (0.52 ml, 0.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (18 mg, 6 mol %) were added to a solution of 5-bromo-2-[(phenylmethyl)oxy]-N-4-pyridazinylbenzamide (may be prepared as described in Example 6; 100 mg, 0.26 mmol) in 1,2-dimethoxyethane (3 ml). The solution was heated at 140° C. in microwave for 35 minutes. The solvent was removed in vacuo to give a residue. Trituration with 1:1 dimethyl sulfoxide/methanol (0.6 ml) gave the product as a solid which was washed with methanol (2 ml) and ethyl acetate (5 ml) to yield the title compound as a grey solid. 45 mg.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12]C(C)(C)C)=[O:11])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:18]=[CH:17][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C2CCCO2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(C2CCCO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To a solution of tert-butyl 4-(tetrahydrofuran-2-yl)benzoate (350 mg, 1.41 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated to give 4-(tetrahydrofuran-2-yl)benzoic acid (200 mg, 74%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.BrC1C=CC=CC=1>COC(C)(C)C>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[NH:16][C:10]([C:4]1[C:3](=[O:15])[N:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=1[OH:9])=[O:12]
Reactant: Nc1cnccn1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: Brc1ccccc1
Solvent: COC(C)(C)C
Product: Cc1cc(O)c(C(=O)Nc2cnccn2)c(=O)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
211 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 95 mg of aminopyrazine were added to 6 ml of bromobenzene, and the mixture was stirred for 3 hours under the heat-refluxing condition. The reaction mixture was cooled to room temperature, and t-butyl methyl ether was added to the mixture. The resulting solid was collected by filtration, washed with t-butyl methyl ether, and dried to obtain 258 mg of N-(2-pyrazinyl)-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 1) represented by the formula:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[CH:20]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:35][CH2:34][C:29]3(OCC[O:30]3)[CH2:28][CH2:27]2)[CH2:22][CH2:21]1.C(O)=O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[CH:20]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:27][CH2:28][C:29](=[O:30])[CH2:34][CH2:35]2)[CH2:22][CH2:21]1
Reactant: CCCCCC1CCC(c2ccc(C3CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2F)CC1
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(=O)CC4)CC3)c(F)c2F)CC1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
The compound (46) (36.7 g), formic acid (120 g) and toluene (120 ml) were put in a reaction vessel under a nitrogen atmosphere, heated under reflux for 3 hours, and cooled slowly to room temperature. Water (300 ml) and toluene (300 ml) were added and mixed thereto. The mixture was allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder. The residue was further purified by means of recrystallization from a mixed solvent of toluene and heptane (toluene: heptane=1:1 by volume), and dried, giving 15.3 g of 4′-(2,3-difluoro-4-(4-pentylcyclohexyl)phenyl)bi(cyclohexane)-4-one (47). The yield based on the compound (46) was 45.9%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:21])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].C(N(CC)CC)C>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:21][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:27]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(NC(=O)c2cccc(Cl)c2)ccc1OCCN1CCCC1
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 3-(1-methyl-1H-pyrazol-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (0.029 g, 0.10 mmol) in CH2Cl2 (1.5 mL) was added 3-chlorobenzoyl chloride (0.015 mL, 0.12 mmol) and triethylamine (0.018 mL, 0.13 mmol). The reaction was stirred for 1 h, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown oil (0.037 g, 87%). LCMS m/z (%)=425 (M+H35Cl, 100), 427 (M+H37Cl, 42). 1H NMR (400 MHz, DMSO-d6) δ: 10.40 (s, 1H), 8.01-8.00 (m, 1H), 7.94-7.87 (m, 2H), 7.72 (d, J=2.6 Hz, 1H), 7.70-7.67 (m, 1H), 7.60-7.55 (m, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.31 (d, J=1.8 Hz, 1H), 4.32-4.28 (m, 2H), 3.69 (s, 3H), 3.58-3.52 (m, 2H), 3.35-3.25 (m, 2H), 2.95-2.82 (m, 2H), 1.95-1.85 (m, 2H), 1.78-1.68 (m, 2H).