Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12]([C:14]2[C:15]([OH:26])=[N:16][C:17]([C:20]3[N:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:18][CH:19]=2)=[O:13])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:27]([O:29][P:30]([O-:34])[O:31][CH2:32][CH3:33])[CH3:28].CCN(CC)CC>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>[OH:26][C:15]1[C:14]([C:12]([NH:11][C:8]([C:5]2[CH:6]=[CH:7][C:2]([P:30](=[O:34])([O:31][CH2:32][CH3:33])[O:29][CH2:27][CH3:28])=[CH:3][CH:4]=2)([CH3:10])[CH3:9])=[O:13])=[CH:19][N:18]=[C:17]([C:20]2[N:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:16]=1
Reactant: CC(C)(NC(=O)c1cnc(-c2cccnn2)nc1O)c1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1ccc(C(C)(C)NC(=O)c2cnc(-c3cccnn3)nc2O)cc1

Procedure:
A mixture of N-(2-(4-bromophenyl)propan-2-yl)-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (36-c, 200 mg, 0.484 mmol), diethylphosphite (195 mg, 1.45 mmol), Et3N (146 mg, 1.45 mmol) and Pd (PPh3)4 (0.1 g) in toluene (10 mL) was refluxed overnight. The reaction mixture was concentrated in vacuum. The residue was purified by pre-HPLC to afford the product 36-d, (3.0 mg). 1H NMR (300 MHz, DMSO) δ10.85 (s, 1H), 9.08 (s, 1H), 8.75 (d, J=8.4 Hz), 7.86 (m, 1H), 7.61-7.52 (m, 2H), 7.43-7.42 (m, 2H), 4.00-3.92 (m, 4H), 1.61 (s, 6H), 1.20 (t, J=6.9 Hz, 6H). LC-MS: (M+H)+ 472.
Reaction SMILES: I[CH3:2].[NH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[C:5]=1[N+:15]([O-:17])=[O:16].[H-].[Na+]>O1CCCC1>[CH3:14][C:6]1[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([NH:3][CH3:2])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(N)c([N+](=O)[O-])c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)OC)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
Iodomethane (125 uL, 2.0 mmol) was added to a mixture of the methyl 4-amino-2-methyl-3-nitrobenzoate (400 mg, 1.9 mmol) and sodium hydride (60% oil dispersion, 84 mg, 2.1 mmol) in tetrahydrofuran (10 mL) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extract was washed with water (2×30 mL), brine (30 mL), dried over sodium sulfate, filtered and concentrated, then purified by flash chromatography (25% ethyl acetate in hexanes) to give methyl 2-methyl-4-(methylamino)-3-nitrobenzoate (308 mg, 72% yield). 1H NMR (400 MHz, CDCl3): 7.94 (d, 1H), 6.63 (d, 1H), 5.68 (br, 1H), 3.86 (d, 2H), 2.58 (s, 3H); MS (EI) for C10H12N2O4: 225 (MH+).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:19]1([NH:25][C:26]([N:9]2[C:10]([S:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(Sc2cc(-c3ccccc3)n[nH]2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)n1nc(-c2ccccc2)cc1Sc1ccccc1
Yield: 70 %

Procedure:
12.6 parts of 3-phenyl-5-phenylthiopyrazole, 100 parts of toluene and 6 parts of phenyl isocyanate are stirred for 12 hours at 20° C. After the toluene has been distilled off, there is obtained 13 parts (70% of theory) of 1-(phenylcarbamoyl)-3-phenyl-5-phenylthiopyrazole; m.p.: 138° to 139.5° C (recrystallized from acetonitrile).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]([CH3:15])([C:12](Cl)=[O:13])[C:9](Cl)=[O:10].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH2:24][NH:25][OH:26]>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH2:24][N:25]1[C:9](=[O:10])[C:8]([CH3:15])([CH3:7])[C:12](=[O:13])[O:26]1
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Reactant: ONCc1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)C(=O)ON(Cc2ccc(Cl)cc2Cl)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
Seventy-five ml of methylene chloride and 9.6 ml (0.12 mole) of pyridine were placed in a flask under argon and cooled to 0° C. To this solution 8.4 grams (0.05 mole) dimethylmalonylchloride in 20 ml methylene chloride was added dropwise with stirring. This mixture was cooled to -70° C. and 9.6 g (0.05 mole) of N-(2,4-dichlorophenylmethyl)hydroxylamine (Intermediate E) was added in a single portion, and the temperature rose to 35° C. Stirring was continued for two hours at -10° C., and at ambient temperature for about 18 hours. The reaction mixture was washed with 2 N hydrochloric acid and saturated aqueous sodium chloride solution, and the methylene chloride layer was dried over sodium sulfate, which was removed by filtration. The filtrate was evaporated under reduced pressure and the resulting viscous liquid was subjected to column chromatography on silica gel. Elution was accomplished with 25% ethyl acetate in hexane. Cuts 3-11 were combined and solvent was removed under reduced pressure, yielding a light orange viscous liquid. This solidified as 6.5 grams of product (45% yield); mp 68°-69.5° C. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].Br[CH2:28][CH2:29][C:30]#[N:31]>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:28][CH2:29][C:30]#[N:31])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: N#CCCBr
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCC#N)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 and 3-bromopropionitrile using an analogous procedure to that outlined in the preparation of Compound 205.1H NMR (400 MHz, MeOD) δ ppm 1.28 (d, J=14.65 Hz, 2 H) 1.28 (s, 2 H) 2.30 (s, 3 H) 3.10 (t, J=6.69 Hz, 2 H) 5.12 (t, J=6.82 Hz, 2 H) 7.00-7.05 (m, 2 H) 7.53 (dd, J=2.02, 0.76 Hz, 1 H) 7.81 (t, J=7.45 Hz, 1 H) 7.92 (ddd, J=7.89, 1.45, 1.26 Hz, 1 H) 8.02 (dt, J=7.83, 1.52 Hz, 1 H) 8.10 (t, J=1.89 Hz, 1 H) 8.26 (d, J=2.02 Hz, 1 H) [M+H] calc'd for C23H21N3O3S, 421; found, 421.
Reaction SMILES: [Na].[CH2:2]([N:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH:3]([CH3:5])[CH3:4].Br[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:2]([N:6]=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:13]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(C)CN=Cc1ccc(O)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=NCC(C)C)cc1
Reaction time: 10 h
Yield: 62 %

Procedure:
(a) To 100 ml of absolute ethanol is added 0.80 g of sodium, and 5.5 g of 4-(N-isobutylformimidoyl)phenol is added to the solution. Subsequently, 6.78 g of ethyl 2-bromo-2-methylpropionate is further added. The mixture is refluxed under heating and with stirring for 10 hours. After distilling off the ethanol from the reaction mixture, water is added to the residue, which is then extracted three times with benzene. The extract is washed with water twice and dried, and the solvent is removed therefrom to give 5.61 g of ethyl 2-[4-(N-isobutylformimidoyl)phenoxy]-2-methylpropionate in the form of a pale orange oil.
Reaction SMILES: O.[N:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:15]([OH:17])=[O:16])=[N+:3]=[N-:4].O[N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25]>CN(C=O)C>[N:2]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:15]([O:17][N:19]1[C:23](=[O:24])[CH2:22][CH2:21][C:20]1=[O:25])=[O:16])=[N+:3]=[N-:4]
Reactant: O=C1CCC(=O)N1O
Reactant: [N-]=[N+]=Nc1c(C(=O)O)cnc2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1c(C(=O)ON2C(=O)CCC2=O)cnc2ccccc12
Reaction time: 0.5 h

Procedure:
4-Azido-3-quinolinic acid monohydrate (2.3 g; 0.01 M) was suspended at ambient temperatures in dry DMF (25 ml). N-hydroxysuccinimide (1.2 g; 0.01 M) was added and the resulting mixture cooled to 0°-5° C. N,N-dicyclohexylcarbodi-imide (2.3 g; 0.11 M) was added and the mixture stirred at 0°-5° C. for 1/2 hr. then at ambient temperatures for 4 days. The insoluble material was removed by filtration and the filtrate evaporated to dryness in vacuo. The residual solid was recrystallized from iso-propyl alcohol as a light-brown, crystalline solid, 2.5 g. (80%), m.p. 173°-5° C. (dec.)(Found: C, 53.71; H, 2.80; N, 22.47%. C14H9N5O4 requires: C, 54.02; H, 2.89; N, 22.47%), νmax (KBr), 2120, 1790, 1760, 1730, 1490, 1390, 1370, 1202, 890, 780, 640cm-1, δ[(CD3)2SO] 2.9(s)(CH2CH2), 7.57-8.4(m), 9.18(s) (aromatic protons), m/e 311(M+)
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]([NH2:7])=[NH:6].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=2)[C:12]([Cl:26])=[CH:11][N:10]=1.O>CS(C)=O>[Cl:26][C:12]1[C:13]2[C:18](=[CH:17][C:16]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[C:9]([NH:6][C:5]([NH2:7])=[NH:4])=[N:10][CH:11]=1
Reactant: N=C(N)N
Reactant: Clc1cnc(Cl)c2cc(Sc3ccccc3)ccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N=C(N)Nc1ncc(Cl)c2ccc(Sc3ccccc3)cc12
Temperature: 80 °C
Yield: 66.7 %

Procedure:
NaH (13.6 mg, 80% dispersion by wt in mineral oil, 0.45 mmol) was added in one portion to a solution of guanidine hydrochloride (44 mg, 0.46 mmol) in DMSO (2 mL) and the mixture was heated at 80° C. under N2 for 10 min. 1,4-Dichloro-7-(phenylsulfanyl)isoquinoline (60 mg, 0.195 mmol) was added and the mixture heated at 80° C. for 1 h. The cooled mixture was poured into water (20 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was extracted with hexanes-i-Pr2O and this organic solution was decanted, and then stirred with a solution of HCl in Et2O to give a precipitate. The white solid was collected by filtration and dried in vacuo to give 4-chloro-1-guanidino-7-(phenylsulphanyl)isoquinoline (51 mg, 0.13 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[C:7]([CH3:13])=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=2[O:3]1.[CH3:15][O:16]C(Cl)Cl>ClCCl>[CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[C:7]([CH3:13])=[C:8]([CH3:12])[C:9]([CH3:11])=[C:10]([CH:15]=[O:16])[C:4]=2[O:3]1
Reactant: Cc1cc2c(c(C)c1C)CC(C)(C)O2
Reactant: COC(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C)c(C=O)c2c(c1C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 22 g of the 2,3-dihydro-2,2,4,5,6-pentamethylbenzofuran in 150 ml of absolute dichloromethane was added 12.8 ml of titanium chloride(IV) and 15.8 ml of a α,α-dichloromethyl methyl ether at 0° C. With stirring at room temperature for 1 hour, the reaction mixture was quenched with 300 ml of water and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford 20 g of 2,3-dihydro-2,2,4,5,6-pentamethylbenzofuran-7-carboxaldehyde as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([Cl:19])[C:17]=1[CH3:18])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([Cl:19])[C:17]=1[CH3:18])[C:12]([Cl:22])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(Cl)cc(C(=O)O)cc1OCc1ccccc1
Solvent: CC#N
Product: Cc1c(Cl)cc(C(=O)Cl)cc1OCc1ccccc1

Procedure:
350 mg 3-benzyloxy-5-chloro-4-methyl-benzoic acid in 10 ml acetonitrile are combined with 0.60 ml thionylchloride and gently refluxed for 15 minutes. Then the reaction mixture is evaporated down and evaporated again with toluene. The acid chloride is further reacted without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
A mixture of 27.4 g (125.6 mmol) of 2-bromo-5-nitrophenol, 26 g (188.4 mmol) potassium carbonate, and 250 mL DMF were stirred 15 min at room temperature. 16.4 mL (138 mmol) of benzyl bromide was added in one portion to the reaction mixture and the mixture was heated to 90° C. TLC analysis indicated complete reaction, so the reaction mixture was cooled to 5° C. in an ice/water bath, filtered and concentrated. 300 mL water was added to the reaction mixture and the black precipitate was filtered and air dried. The crude product was taken up in dichloromethane and purified over silica eluting with 35% hexanes in dichloromethane, to give 2-bromo-5-nitro-O-benzylphenol 35.5 g (115.2 mmol, 91.7%) as an ivory solid. 1H NMR (400 MHz) CDCl3 7.78 (s, 1H), 7.72 (s, 2H), 7.46-7.48 (m, 2H), 7.38-7.42 (m, 2H), 7.32-7.35 (1H), 5.23 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14](Br)=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=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>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][C:23]=2[Cl:25])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ncc1Br
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cc(N)ncc1-c1ccc(Cl)cc1Cl
Temperature: 150 °C
Yield: 58.8 %

Procedure:
In a sealed tube, a mixture of (2-amino-5-bromo-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (4.48 g, 14.8 mmol, prepared according to Example 1, Step 1.3), 2,4-dichloro-benzeneboronic acid (4.24 g, 22.2 mmol), Pd(PPh3)4 (855 mg, 0.74 mmol) and Na2CO3 (2.0 M solution in water, 26 mL, 52.0 mmol) in DME (50 mL) was heated at 150° C. for 17 min in a microwave oven. The reaction mixture was cooled to RT, diluted in AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→100% TBME) to yield the title compound (3.2 g, 8.7 mmol, 59%) as a white solid. MS: 368 [M−1]+; HPLC: AtRet=1.69.
Reaction SMILES: [Cl:1][C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C.[CH2:47]([Si:49]([C:54]#[CH:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH3:48]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[C:48]#[C:47][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51]
Reactant: C#C[Si](CC)(CC)CC
Reactant: C[Si](C)(C)CCOCn1c(Cl)c(I)c2c(=O)[nH]ncc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC[Si](C#Cc1c(Cl)n(COCC[Si](C)(C)C)c2cn[nH]c(=O)c12)(CC)CC
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To 61 mg (0.14 mmol) of 2-chloro-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 30-(b) were added 5 mg of bis(triphenylphosphine)palladium dichloride, 4 mg of cuprous iodide, 8 mg of triphenylphosphine, 1 ml of diisopropylamine, 0.04 ml of triethylsilylacetylene and 0.4 ml of N,N-dimethylformamide, the mixture was degassed under reduced pressure and replaced with argon, and the mixture was stirred at 80° C. for 1.5 hours. After completion of the reaction, toluene was added to the reaction mixture, and the mixture was washed successively with 5% aqueous sodium hydrogen sulfite solution, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. The organic layer after separation was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:3→1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 47 mg of the title compound as a yellowish solid. (Yield: 75%)
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:35])=[C:16]([N:22](S(CCC)(=O)=O)[S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2.[CH3:36][O:37][CH2:38][CH2:39][OH:40].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:35][C:15]1[C:14]([C:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([O:40][CH2:39][CH2:38][O:37][CH3:36])=[N:11]3)=[O:13])=[C:19]([F:20])[C:18]([F:21])=[CH:17][C:16]=1[NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24]
Reactant: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F)S(=O)(=O)CCC
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(OCCOC)nc3c2)c1F
Temperature: 90 °C
Reaction time: 7.5 h
Yield: 0.6 %

Procedure:
To a solution of N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N-(propylsulfonyl)propane-1-sulfonamide (50 mg, 9.6 mmol, 1.0 eq.) in DMF (2 mL) was added 2-methoxyethanol (17.5 mg, 24 mmol, 2.5 eq.) and Cs2CO3 (87 mg, 24 mmol, 2.0 eq.). The resulting mixture was stirred at 90° C. for 7.5 h, then cooled, washed with water and extracted with EA (20 mL×3). The combined organic phase was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) to afford N-(2,4,5-trifluoro-3-(3-(2-methoxyethoxy)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide (28 mg, 61%). LRMS (M+H+) m/z calculated 484.1, found 483.9. 1H NMR (DMSO-d6, 400 MHz) δ10.12 (s, 1 H), 8.81 (s, 1 H), 8.26 (s, 1 H), 8.22 (d, 1 H), 8.15 (d, 1 H), 7.79 (m, 1 H), 4.58 (brs, 2 H), 3.75 (brs, 2 H), 3.33 (s, 3 H), 3.23 (m, 2 H), 1.75 (m, 2 H), 0.97 (s, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][S:8][C:9]2[C:19]3[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14][C:13]=3[CH:12]=[CH:11][C:10]=2[Cl:27])[S:5][CH:6]=1.[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:23]([O:22][C:20]([N:16]1[CH2:17][CH2:18][C:19]2[C:9]([S:8][CH2:7][C:4]3[S:5][CH:6]=[C:2]([C:28]#[N:29])[CH:3]=3)=[C:10]([Cl:27])[CH:11]=[CH:12][C:13]=2[CH2:14][CH2:15]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3cc(Br)cs3)c2CC1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3cc(C#N)cs3)c2CC1
Temperature: 120 °C
Yield: 52 %

Procedure:
Degas a stirred solution of 6-(4-bromothiophen-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (183 mg, 0.37 mmol), zinc cyanide (50 mg, 0.42 mmol) and tetrakistriphenylphosphine palladium(0) (30 mg, 0.026 mmol) in dry DMF. Purge with dry nitrogen, and heat at 120° C. for 6 h. Dilute with water, extract three times with EtOAc, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(4-cyanothiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (85 mg, 52%). MS (APCI+) m/z: 335 (M+H−Boc)+. Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (APCI+) m/z: 335 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.[CH3:29][CH:30]1[CH2:32][O:31]1>C1(C)C=CC=CC=1>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[CH2:29][CH:30]([OH:31])[CH3:32]
Reactant: CN(C)CCc1sc2ccccc2c1Br
Reactant: CC1CO1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(O)Cc1c(CCN(C)C)sc2ccccc12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 17.5 %

Procedure:
A solution of [2-(3-bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (285 mg, 1 mmol) and TMEDA (181 uL, 1.2 mmol) in toluene (12 mL) was cooled to −78° C. n-BuLi (750 uL, 1.2 mmol, 1.6M in hexanes) was added and the reaction was stirred at −78° C. for 45 min. 2-Methyl-oxirane (280 uL, 4 mmol) was added at −78° C. and the reaction was allowed to slowly reach room temperature, while being stirred overnight. The reaction was quenched with NH4Cl, pH was adjusted with sat. NaHCO3 until pH ˜9, followed by an extraction with EtOAc (4×). The combined organic layers were washed with brine, dried (MgSO4) and concentrated. Silica gel column chromatography (eluent: dichloromethane with gradient up to dichloromethane/MeOH=97/3) afforded 46 mg of 1-[2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-propan-2-ol (Compound 23-1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.C([O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][C:34]([C:38](O)=[O:39])=[CH:35][CH:36]=3)[C:31]([CH3:41])=[C:30]2[CH3:42])=[CH:24][CH:23]=1)=[O:15])(C)(C)C>>[CH3:42][C:30]1[N:29]([CH2:28][C:25]2[CH:26]=[CH:27][C:22]([C:17]3[C:16]([C:14]([OH:15])=[O:13])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:23][CH:24]=2)[C:37]2[C:32]([C:31]=1[CH3:41])=[CH:33][C:34]([C:38](=[O:39])[NH:8][CH2:7][C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[CH:35][CH:36]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)o1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 5-methyl-2-furanylmethylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 493 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[C:11]([C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1)#[N:12]>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[N:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[C:11]#[N:12])[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1cnc(N2CCNCC2)c(C#N)c1
Reactant: O=C(O)c1ccc(Br)nc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C#N)c1
Yield: 79.2 %

Procedure:
Using 6-bromonicotinic acid (303 mg) and 4-(3-cyano-5-methylpyridin-2-yl)piperazine (303 mg) described in Preparation Example 107 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (458 mg) was obtained.