Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:22]C(C)=O)[CH:5]=[C:6]([C:18]([F:21])([F:20])[F:19])[C:7]=1[O:8][C:9]([F:17])([F:16])[CH:10]([F:15])[C:11]([F:14])([F:13])[F:12]>Cl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:18]([F:19])([F:20])[F:21])[C:7]=1[O:8][C:9]([F:16])([F:17])[CH:10]([F:15])[C:11]([F:14])([F:13])[F:12])[NH2:22]
Reactant: CC(=O)Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(C(F)(F)F)c1

Procedure:
42.2 g of 3-chloro-4-(1,1,2,3,3,3-hexafluoropropoxy)-5-(trifluoromethyl)acetaminobenzene are boiled for 16 hours at reflux in a mixture of 200 ml of concentrated hydrochloric acid and 400 ml of ethanol. The bulk of the solvent is then distilled off and the residue is made alkaline and extracted with ether. The ethereal extract is dried over sodium sulfate and the solvent is removed by evaporation in vacuo. Fractional distillation of the residue, affords the title compound as a yellowish oil with a boiling point of 115°-120° C./4·10-2 torr (a compound of formula II).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][SH:11])=[N:5][N:4]=[N:3]1.[CH:12]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>[OH-].[Na+].CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][S:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:5][N:4]=[N:3]1
Reactant: BrC1CCCCC1
Reactant: Cn1nnnc1SCCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCSC1CCCCC1
Yield: 55.1 %

Procedure:
1-Methyl-5-(3-mercaptopropyl)thio-1,2,3,4-tetrazole (1.9 g) is dissolved in 1 N aqueous sodium hydroxide (30 ml), and thereto is added dropwise a solution of cyclohexyl bromide (2.0 g) in acetone (20 ml) with stirring under ice-cooling. After the addition, the mixture is stirred at room temperature for 3 hours. Acetone is distilled off and water is added to the residue, and the mixture is extracted with ether. The ether solution is washed with diluted aqueous sodium hydroxide and saturated aqueous sodium chloride, and dried over sodium sulfate. After ether is distilled off, the residue is purified by column chromatography (Kieselgel 60), followed by eluting with n-hexane-ether (4:1) to give 1-methyl-5-(3-cyclohexylthiopropyl)thio-1,2,3,4-tetrazole (1.5 g), colorless liquid, nD18 =1.5433.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[OH:13])[CH3:3].[SH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22].C([O-])(O)=O.[Na+]>ClCCl>[S:22]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][S:14][CH:9]1[C:8]1[CH:11]=[CH:12][C:5]([O:4][CH2:2][CH3:3])=[C:6]([OH:13])[CH:7]=1
Reactant: CCOc1ccc(C=O)cc1O
Reactant: SCc1ccccc1S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1ccc(C2SCc3ccccc3S2)cc1O
Yield: 71.2 %

Procedure:
Hydrogen chloride gas was bubbled for three minutes at 22° C. through a solution of 4-ethoxy-3-hydroxybenzaldehyde (0.50 g, 3.0 mmol) and 2-(mercaptomethyl)benzenethiol (0.52 g, 3.3 mmol) in dichloromethane (15 ml). After an additional 15 min. the reaction mixture was poured into saturated NaHCO3 (50 ml) and extracted with dichloromethane (2×75 ml). The combined organic layer was washed with brine (30 ml), dried (Na2SO4), filtered and concentrated providing a crude solid. This solid was triturated with hexane and then purified by flash chromatography using a gradient of hexanes (100%) up to hexanes (70%:30%). Concentration of the product containing fractions provided the above subtitle compound (0.65 g, 70%) as a cream colored solid. 1H NMR (300 MHz, CDCl3, ppm) δ 1.46 (t, J=7 Hz, 3H), 3.98 (s, 3H), 4.13 (q, J=7 Hz, 2H), 5.44 (s, 1H), 5.68 (br s, 1H), 6.80 (d, J=8 Hz, 1H), 6.99 (dd, J=8 Hz, J2=2 Hz, 1H), 7.13 (d, J=2 Hz, 1H), 7.15-7.35 (m, 4H); 13C NMR (75 MHz, CDCl3, ppm) δ 15.1, 34.4, 51.2, 64.9, 111.6, 114.6, 120.0, 126.2, 127.7, 128.6, 129.4, 132.2, 135.1, 135.9, 146.0, 146.2; MS calculated for C16H16O2S2-H 303 observed 303.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:21](=[O:22])[N:20]([CH3:23])[C:8]2[N:9]=[C:10]([NH:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[CH:12][C:7]=2[CH:6]=1.C(N(CC)C(C)C)(C)C.[C:38](OC(=O)C)(=[O:40])[CH3:39].CCCCCC>CC(C)=O>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:21](=[O:22])[N:20]([CH3:23])[CH:8]2[N:9]=[C:10]([N:13]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:38](=[O:40])[CH3:39])[N:11]=[CH:12][CH:7]2[CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(NC3CCOCC3)nc21
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C1=NC2C(C=N1)C=C(Oc1ccc(F)cc1F)C(=O)N2C)C1CCOCC1
Temperature: 125 °C

Procedure:
A mixture of 6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (Example 23) (1.0 g, 2.57 mmol), N,N-diisopropylethylamine (0.498 g, 0.67 mL, 3.86 mmol) in acetic anhydride (1.42 g, 1.02 mL, 13.9 mmol) was heated to 123-127° C. for 2 hours. The volatiles were evaporated at 60° C. to provide a thick residue which was dissolved in 4 mL of acetone at 67-70° C. To the resulting solution was added 5 mL of hexane maintaining a temperature of 53-55° C. This mixture was allowed to cool to ambient temperature over 18 hours. The resulting solid was filtered and washed with 3×3 mL of 1:2 acetone:hexane. The rinsed solid was suspended in 5 mL of hexane and heated to reflux for 45 minutes. After cooling to ambient temperature, the slurry was filtered and the solid washed with hexane and dried under vacuum. (0.903 g, mass spec. M+1=431, MP=185.3-186.9° C.).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([Li])CCC.[I:25]I>O1CCCC1>[I:25][C:11]1[N:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=1
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cccnc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3cccnc32)cc1
Temperature: -78 °C
Yield: 100.1 %

Procedure:
A solution of 1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [54.4 g, Reference Example 9(a)] in dry tetrahydrofuran (1200 mL) cooled to −78° C., was treated with a solution of butyllithium in hexanes (2.5M, 92 mL) over a 20 minute period. The solution was maintained at −78° C. for 30 minutes, then a solution of iodine (101 g) in tetrahydrofuran (600 mL) was added until the iodine colour persisted (ca. 300 mL). The mixture was allowed to warm slowly to ambient temperature and the solvent removed under vacuo. The residue was partitioned between ethyl acetate (1000 mL) and water (500 mL) and the aqueous layer was extracted twice with ethyl acetate (500 mL). The combined organics were combined, dried over sodium sulfate and removed under reduced pressure to give a yellow solid which was triturated with diethyl ether to give the title compound (79.6 g) as a pale yellow solid, m.p. 105-107° C. MS: 399 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:14])=[CH:5][CH:4]=1.[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]([CH2:7][OH:8])[C:10]=1[C:9]([N:16]([CH3:17])[CH3:15])=[O:14]
Reactant: CNC
Reactant: COc1ccc2c(c1OC)C(=O)OC2
Solvent: CCO
Product: COc1ccc(CO)c(C(=O)N(C)C)c1OC
Yield: 100 %

Procedure:
A mixture of 30 g of 6,7-dimethoxy 3H-isobenzofuranone, prepared according to the method described in Example IV, 1 liter of ethanol and 300-400 cm3 of dimethylamine was agitated for several hours and then evaporated under vacuum at 30° - 35° C. The crystallized product was washed with heptane. The 2,3-dimethoxy N,N-dimethyl 6-hydroxymethyl benzamide was obtained in a yield of 100%. F = 90° C.
Reaction SMILES: [CH3:1][CH:2]([Mg]Cl)[CH2:3][CH3:4].[P:7]([Cl:10])(Cl)Cl>C(OCC)C>[CH3:1][CH:2]([P:7]([CH:2]([CH2:3][CH3:4])[CH3:1])[Cl:10])[CH2:3][CH3:4]
Reactant: ClP(Cl)Cl
Reactant: CCC(C)[Mg]Cl
Solvent: CCOCC
Product: CCC(C)P(Cl)C(C)CC

Procedure:
In the manner of Examples 6 and 7, 2-butyl magnesium chloride (800 cm3 of a 2 M solution in diethyl ether supplied by Aldrich Chemical Co.) was reacted with phosphorus trichloride (110 g) in diethyl ether (450 cm3) to give di-2-butychlorophosphine (77.8 g, b.p. 84° C. at a pressure of 15 mm of mercury), and this compound was further reacted with hexamethyldisilazane and sulphur to give N-(di-2-butylphosphinothioyl)-P,P-di-2-butylphosphinothioic amide (m.p. 110°-114° C. 31 p NMR in CDCl3, multiplet 87.9 ppm downfield of H3PO4). In this compound of Formula I, R1 =R2 =R3 =R4 =2-butyl.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.C([O-])([O-])=O.[Na+].[Na+]>>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH3:11])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2cccc(F)c2)cc1
Yield: 59 %

Procedure:
The title compound (D23) (40 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-piperidine-2-carboxamido)ethyl)benzoate (D12) (50 mg, 0.17 mmol) and 3-fluorobenzyl bromide (0.042 ml, 0.34 mmol). (Na2CO3: 2.5 eq; reaction time: 3 hrs; 60° C.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:51]([O:55][C:56](=[O:68])[NH:57][CH2:58][CH2:59][CH:60]([NH2:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([CH3:54])([CH3:53])[CH3:52].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([O:5][C:6](=[O:50])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:67][CH:60]([C:61]5[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=5)[CH2:59][CH2:58][NH:57][C:56]([O:55][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:68])[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)c4)nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3n2)CC1
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCC(Nc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)c1)c1ccccc1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A sealed tube was charged with {4-[3-(3-bromo-phenyl)-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 43 supra) (500 mg, 0.686 mmol), (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 2 supra) (258 mg, 1.03 mmol), DavePhos (54 mg, 0.137 mmol), K2CO3 (142 mg, 1.03 mmol), Pd2(dba)3 (31 mg, 0.0343 mmol) and 1,4-dioxane (14 mL). This mixture was stirred at 120° C. for 15 hours under an atmosphere of N2. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH, 200:1 to 50:1), then by prep-HPLC to give (4-{3-[3-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-phenyl]-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 63 mg, 10.2%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:25]([O:27][CH2:28][CH3:29])=[CH2:26])CCC>C1(C)C=CC=CC=1.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>[CH2:28]([O:27][C:25]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1)=[CH2:26])[CH3:29]
Reactant: O=C(Nc1ccccc1)c1cn2cc(I)ccc2n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
To a suspension of 1 g of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 50 mL of toluene are added 159 mg of tetrakis(triphenylphosphine)palladium and 1.09 g of tributyl(1-ethoxyvinyl)tin. The reaction mixture is heated for 9 hours at 150° C. and then for 16 hours at 130° C., and concentrated to dryness. The residue is taken up in dichloromethane and washed with aqueous 10% potassium fluoride solution. The organic phase is dried and concentrated to dryness and the residue is chromatographed on a silica cartridge, eluting with a mixture of cyclohexane and ethyl acetate. The fractions containing the expected product are combined and evaporated to dryness under reduced pressure to give 0.52 g of 6-(1-ethoxyvinyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a beige-coloured solid.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:26])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][CH:7]=[CH:6][CH:5]=2.N1C=CC=CC=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>ClCCl>[C:33]([O:1][C:2]1[C:3](=[O:26])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:36])[CH2:34][CH3:35]
Reactant: C[Si](C)(C)CCCCCCCCCC1=C(O)C(=O)c2ccccc2C1=O
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)OC1=C(CCCCCCCCC[Si](C)(C)C)C(=O)c2ccccc2C1=O
Reaction time: 0.05 h

Procedure:
To a stirred solution of 2-hydroxy-3-(9-trimethylsilylnonyl)-1,4-naphthoquinone, Example 12, (100 mg, 0.27 mmol) in dry dichloromethane (10 ml) at room temperature was added pyridine (0.5 ml) and, after 3 minutes, propanoyl chloride (62 mg, 0.67 mmol). The reaction was stirred for 2 h before diluting with dichloromethane (50 ml), washing with water (2×30 ml), dilute hydrocholic acid (30 ml), saturated sodium chloride solution (30 ml) and dried (MgSO4). Filtration and evaporation of the solvent under reduced pressure and chromatography, eluent hexane/ether, gave 2-propanoyloxy-3-(9-trimethylsilylnonyl)-1,4-naphthoquinone (112 mg). m. pt. 41-43° C. NMR peaks at: 184.6, 178.2, 151.2, 139.8, 134.0, 133.7, 132.1, 130.9, 126.7, 126.5, 33.6, 29.7, 29.4, 29.4, 29.3, 29.3, 28.5, 24.3, 23.9, 16.7, -1.6; 171.6, 27.3, 9.1 (COCH2CH3).
Reaction SMILES: [OH:1][C:2]1[N:6]([CH:7]2[CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([CH:22]=[CH2:23])[C:13]=1[O:24][CH3:25])=[O:11].O=S(Cl)Cl.[CH3:30]S(C1C=CC(C(O)=O)=C(OC)C=1C=C)(=O)=O.C1(N2C=CC(=O)N2)CC1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.COCCOC>[CH3:30][O:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9]2)[N:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([CH:22]=[CH2:23])[C:13]=1[O:24][CH3:25])=[O:11]
Reactant: C=Cc1c(S(C)(=O)=O)ccc(C(=O)O)c1OC
Reactant: C=Cc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C3CC3)c2O)c1OC
Agent: O=C([O-])[O-]
Agent: O=c1ccn(C2CC2)[nH]1
Agent: [K+]
Solvent: COCCOC
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: C=Cc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C3CC3)c2OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Hydroxy-1-cyclopropyl-1H-pyrazol-4-yl-(4-methylsulfonyl-2-methoxy-3-vinylphenyl)methanone SOCl2 (1.2 g, 10 mmol) was added to a solution of 4-methylsulfonyl-2-methoxy-3-vinylbenzoic acid (1.6 g, 6 mmol) in toluene (60 ml), and the mixture was heated at reflux for 2 h. The mixture was then concentrated, and the product was added to a solution of N-cyclopropylpyrazolone (6 mmol), K2CO3 (1.6 g, 11.6 mmol) in DME (30 ml), and the mixture was stirred at RT overnight. The mixture was subsequently heated at reflux for 2 h and concentrated, and the residue was dissolved in H2O. The H2O phase was extracted 3× with CH2Cl2, and the combined organic phases were dried over MgSO4 and concentrated.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:11][CH2:10]2)[N:5]=[CH:4]1.[O:33]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34]1>>[ClH:1].[ClH:1].[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([NH:20][C:38]([C:35]4[CH:36]=[CH:37][O:33][CH:34]=4)=[O:39])[CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:11][CH2:10]2)[N:5]=[CH:4]1
Reactant: O=C(O)c1ccoc1
Reactant: Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2
Agent: Cl
Product: O=C(Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2)c1ccoc1

Procedure:
Example 63 was prepared as a yellow solid from Example 26 and 3-furoic acid as described for Example 62.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH2:10][NH:11][C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27](Br)[CH:26]=3)[CH3:24])[C:15]=2[CH3:32])=[O:13])[C:4](=[O:9])[N:5]=[C:6]([CH3:8])[CH:7]=1.Cl[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][N:35]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][N:35]=3)[CH:26]=2)[CH3:24])[C:15]=1[CH3:32])=[O:13]
Reactant: Clc1ccncn1
Reactant: CC1=CC(C)=NC(=O)C1CNC(=O)c1c(C)n(C(C)c2cccc(Br)c2)c2ccccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3cccc(-c4ccncn4)c3)c3ccccc23)c(=O)[nH]1
Temperature: 25 °C
Yield: 32 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 1-[1-(3-Bromo-phenyl)-ethyl]-2-methyl-1H-indole-3-carboxylic acid (4,6-dimethyl-2-oxo-2,3-dihydro-pyridin-3-ylmethyl)-amide (Step 8) (20 mg, 0.04 mmol), 4-Chloro-pyrimidine (6.95 mg, 0.06 mmol), potassium carbonate (10.9 mg, 0.08 mmol), 1,1′-Bis(diphenylphosphino)ferrocene palladium dichloride (44 mg, 0.06 mmol) and 1,4-dixoane/H2O (4:1, 8 mL). The mixture was purged and placed under N2 and stirred heated to reflux with stirring overnight. The reaction was then allowed to cool to rt and the mixture was concentrated in vacuo. The resulting residue was purified by preparative-HPLC (Column: YMC-Actus Triart C18150*30 mm*5 um; Mobile phase A: water with 0.1% HCl solution; Mobile phase B: MeCN; column temperature: 30° C.; Gradient: 35-65% B). The collected fractions were combined and lyophilized to afford the title compound (6.3 mg, yield 35%) LCMS (M+H+) m/z: calc'd 491.23. found 492.0; 1H NMR (400 MHz, MeOD-d4) δ 9.2 (s, 1H), 8.85-8.54 (d, 2H), 8.14-8.06 (m, 2H), 7.78-7.72 (m, 1H), 7.58-7.54 (t, 1H), 7.44-7.42 (d, 1H), 7.15-7.12 (d, 1H), 7.04-7.01 (t, 2H), 7.01-6.79 (t, 1H), 6.8 (s, 1H), 6.14-6.12 (t, 1H), 4.88 (m, 2H), 4.67 (s, 1H), 2.73 (s, 3H), 2.6 (s, 3H), 2.47 (s, 3H), 2.08-2.07 (d, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:14]([F:15])=[C:13]([F:16])[C:10](C#N)=[C:9]([F:17])[C:8]=1[F:18].NC1C(F)=C(F)C(F)=C(F)C=1C#N>>[F:15][C:14]1[C:13]([F:16])=[CH:10][C:9]([F:17])=[C:8]([F:18])[C:7]=1[NH2:6]
Reactant: N#Cc1c(F)c(F)c(N)c(F)c1F
Agent: N#Cc1c(N)c(F)c(F)c(F)c1F
Agent: O=S(=O)(O)O
Product: Nc1c(F)c(F)cc(F)c1F
Temperature: 140 °C

Procedure:
2,3,5,6-Tetrafluoroaniline was produced from 4-amino-2,3,5,6-tetrafluorobenzonitrile. To be specific, in a 200 ml four-neck flask provided with a stirrer, a thermometer, a dropping funnel, and a water separating tube, 100 g of 60% sulfuric acid was placed and heated to 140° C. To the hot sulfuric acid, 36 g of the raw material, 4-amino-2,3,5,6-tetrafluorobenzonitrile (having a purity of 94% and containing 6% of 2-amino-3,4,5,6-tetrafluorobenzonitrile as an impurity) was added dropwise at a rate of 6 g/hr. The 2,3,5,6-tetrafluoroaniline which was formed by the reaction was expelled by azeotropy with water, guided into the water dropping tube, and separated from the water. The reaction was continued for six hours while the reaction vessel was supplied with the same amount of water as expelled by distillation. After the completion of the reaction, the conversion ratio of the raw material determined by gas chromatography was found to be 96 mol %. When the 2,3,5,6-tetrafluoroaniline expelled by distillation was analyzed, the purity was found to be 95.3% and the yield to be 82.5%.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]([O:9][CH:10]=[CH2:11])(=[O:8])[CH3:7].CO>[O-]S(C(F)(F)F)(=O)=O.[Ag+].O>[C:6]([O:9][CH:10]=[CH:11][CH2:4][CH:3]([CH3:5])[CH:2]=[CH2:1])(=[O:8])[CH3:7]
Reactant: C=CC(=C)C
Reactant: C=COC(C)=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: CO
Product: C=CC(C)CC=COC(C)=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 6 %

Procedure:
4 mg (0.016 mmol) of (η6-benzene)ruthenium (II) dichloride, 15 mg (0.058 mmol) of silver triflate and 11.2 mg (0.052 mmol) of N-2-aminoethyl-p-toluenesulfonamide were placed in a sealed tube, which was then charged with 2 ml (20 mmol) of isoprene, 2 ml (22 mmol) of vinyl acetate and 2 ml of methanol. The mixture was heated with stirring at 100° C. for 6 hours in an argon atmosphere. The reaction mixture was poured into water and the organic layer was concentrated to obtain 0.17 g (yield: 6% based on isoprene) of a co-dimer (4-methylhexa-1,5-dien-1-yl acetate) (Purity: 75%, regioisomer: 17%, cyclic dimer of dienes: 8%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[CH3:15][Li].[Cl-].[NH4+]>C(OCC)C>[C:12]([C:6]1[O:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)(=[O:14])[CH3:15]
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)c1cc(C(C)C)c(C(C)C)o1
Reaction time: 0.75 h
Yield: 83.4 %

Procedure:
A solution of 4,5-diisopropylfuran-2-carboxylic acid (196 mg, 1.00 mmol) in diethyl ether (6 ml) was cooled to −18° C., and added dropwise with methyllithium (1.2 M in Et2O, 2.5 ml, 3 mmol), and the mixture was stirred for 45 minutes. The reaction mixture was added with saturated aqueous ammonium chloride, and the mixture was extracted with diethyl ether. The reaction mixture was treated in a conventional manner, and then the resultant was purified by silica gel chromatography [hexane-ethyl acetate (7:1)] to obtain the title compound (162 mg, 84%) as colorless oil.