Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].CO.[Cl-].[CH2:6]([N:10]1[C:14]2[C:15](=[O:20])[N:16]([CH3:19])[N:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:21]1[CH:26]=[CH:25][N+:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)[C:7]#[C:8][CH3:9].Cl>O>[CH2:6]([N:10]1[C:14]2[C:15](=[O:20])[N:16]([CH3:19])[N:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:23][CH:22]=1)[C:7]#[C:8][CH3:9]
Reactant: CC#CCn1c(-c2cc[n+](Cc3ccc(OC)cc3)cc2)nc2cnn(C)c(=O)c21
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC#CCn1c(C2=CCN(Cc3ccc(OC)cc3)CC2)nc2cnn(C)c(=O)c21
Reaction time: 1 h
Yield: 59.4 %

Procedure:
0.020 g of sodium borohydride was added to a 5 ml methanol solution of 0.060 g of 4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]-1-(4-methoxybenzyl)pyridinium chloride, and the mixture was stirred for one hour. 15 ml of water and 0.1 ml of 5N hydrochloric acid were added to the solution to quench the reducing agent. Then, the solution was made alkaline with 1 ml of 5N sodium hydroxide, and extracted with 30 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.033 g of the title compound was obtained from the fraction eluted with methanol-ethyl acetate (1:19).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>O.C1(C)C=CC=CC=1.C(OCC)C.C1COCC1>[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([B:29]([OH:34])[OH:30])=[CH:3][CH:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccc(-c2ccccc2)c2ccccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: OB(O)c1ccc(-c2ccccc2)c2ccccc12
Temperature: -20 °C
Yield: 57.5 %

Procedure:
Under an argon gas atmosphere, a mixture of 121.0 g (427.3 mmol) of 1-bromo-4-phenylnaphthalene, 1.2L of dehydrated THF and 1.2L of dehydrated diethylether was cooled down to −20 degrees C., and added with 360 ml (562 mmol) of hexane solution of 1.56M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for one hour at −20 degree C. The reaction mixture was further cooled down to −60 degrees C., and added with 241.1 g (1.28 mol) of triisopropyl borate in drops. The reaction mixture was subsequently warmed up to room temperature, and stirred for 16 hours at room temperature. The reaction mixture was further added with solution of hydrochloric acid to be stirred for one hour at room temperature. After the reaction, the reaction mixture was further added with toluene, so that aqueous phase thereof was eliminated. After organic phase thereof was cleansed with water and dried with magnesium sulfate, the solvent was distilled away under reduced pressure. By recrystallizing the obtained solid by hexane, 61.0 g of 4-phenylnaphthalene-1-boronic acid was obtained at an yield of 58%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](O)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][N:60]1[C:64]([NH2:65])=[CH:63][C:62]([CH3:66])=[N:61]1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:65][C:64]3[N:60]([CH3:59])[N:61]=[C:62]([CH3:66])[CH:63]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Reactant: Cc1cc(N)n(C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)n(C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
In a 100 mL round-bottomed flask, To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol) and HATU (201 mg, 0.527 mmol) in DMF (3 mL) was added Hunig's base (0.15 mL, 0.88 mmol), and the mixture was stirred at room temperature for 15 minutes. 1,3-Dimethyl-1H-pyrazol-5-amine (59 mg, 0.53 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed the reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (190 mg) as a yellow solid. LC-MS (ES) m/z=435 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[C:8](=[N:11]\[S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/[CH2:9][F:10])[C:5]([F:18])=[C:4]([Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:3]=1.C1COCC1.[Cl-].[C:32]([O:36][C:37](=[O:40])[CH2:38][Zn+])([CH3:35])([CH3:34])[CH3:33]>C([O-])(O)=O.[Na+].O>[Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:11][S@@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])([CH2:9][F:10])[CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:40])[C:5]([F:18])=[C:4]([Si:19]([CH2:20][CH3:21])([CH2:22][CH3:23])[CH2:24][CH3:25])[CH:3]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(/C(CF)=N\[S@](=O)C(C)(C)C)c1F
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)nc([C@](CF)(CC(=O)OC(C)(C)C)N[S@](=O)C(C)(C)C)c1F
Temperature: 0 °C

Procedure:
To a 1000 mL 3-neck round-bottomed flask equipped with an addition funnel and internal temperature probe was added (R,E)-N-(1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (43.3 g, 95 mmol) and THF (400 mL). The mixture was cooled to 0° C. and 2-tert-butoxy-2-oxoethylzinc chloride (Rieke Metals; 458 mL, 229 mmol, 0.5 M in diethyl ether) was added dropwise over 1 h keeping the internal temperature under 3° C. After the addition the ice bath was allowed to melt and warm to rt overnight. The reaction mixture was diluted with sat NaHCO3 (200 mL) and water (200 mL) and extracted with EtOAc (3×200 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 25% EtOAc/hexane, 1500 g RediSep column) afforded:
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](O)[CH3:12].S(=O)(=O)(O)O>ClCCl>[CH2:11]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([SH:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: O=C(O)c1ccc(S)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(S)cc1

Procedure:
Ethyl-4-mercaptobenzoate was prepared by treating 4-mercaptobenzoic acid (1.50 g, 9.73 mmol) with ethanol (97 mL) in the presence of catalytic concentrated sulfuric acid under a nitrogen atmosphere. The reaction was heated at reflux for three hours. The volume of the reaction was reduced to 10 mL under reduced pressure and then partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined organic solutions were washed with water (75 mL) and saturated aqueous sodium bicarbonate (2×75 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide an oil. The oil was dissolved in dichloromethane (100 mL), and the resulting solution was extracted with saturated aqueous sodium carbonate (3×100 mL). The combined extracts were washed with dichloromethane (3×50 mL) and then treated with concentrated hydrochloric acid to adjust to pH 7. The solution was then extracted with dichloromethane (3×100 mL), and the combined extracts were washed with water (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.23 g of ethyl-4-mercaptobenzoate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:17])[C:14]([CH3:16])([CH3:15])[C:5]=3[C:4]=2[CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:17])[C:14]([CH3:15])([CH3:16])[C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(C(F)(F)F)nc2)C1(C)C

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-1,1,2-trimethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH3:23])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:22][CH3:23]
Reactant: CCCOc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCOc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 7.2 %

Procedure:
A mixture of methyl thiosalicylate (0.24 g, 1.4 mmol), 2-cyano-6-propoxypyridine (0.23 g, 1.4 mmol), triethylamine (0.30 ml, 2.1 mmol) and toluene (20 ml) was refluxed for 48 hrs as described in Example 1. The reaction mixture was concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (5:1, v/v) and recrystallized from hexane-ethyl acetate to give the titled compound (0.03 g, 7%) as crystals.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][C:19]([F:22])([F:21])[F:20])[CH2:7][NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:2]=S.[NH2:23][C:24]1[C:31]([NH2:32])=[CH:30][C:27]([C:28]#[N:29])=[C:26]([N:33]2[CH2:38][CH2:37][CH2:36][CH:35]([C:39]([F:42])([F:41])[F:40])[CH2:34]2)[CH:25]=1.CN(C=O)C.C(Cl)CCl>C(Cl)(Cl)Cl.O>[C:28]([C:27]1[C:26]([N:33]2[CH2:38][CH2:37][CH2:36][CH:35]([C:39]([F:42])([F:40])[F:41])[CH2:34]2)=[CH:25][C:24]2[NH:23][C:2]([NH:1][C:4]3[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=3[O:18][C:19]([F:22])([F:21])[F:20])[CH2:7][NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:32][C:31]=2[CH:30]=1)#[N:29]
Reactant: N#Cc1cc(N)c(N)cc1N1CCCC(C(F)(F)F)C1
Reactant: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)c(N=C=S)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)c(Nc2nc3cc(C#N)c(N4CCCC(C(F)(F)F)C4)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-(3-isothiocyanato-4-trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide (135 mg, 0.406 mmol), 4,5-diamino-2-(3-trifluoromethyl-piperidin-1-yl)benzonitrile (115 mg, 0.406 mmol) and DMF (2 mL) was stirred at rt for 4 h. EDC (101 mg, 0.527 mmol) was added and mixture was stirred at rt overnight. The mixture was treated with water and extracted with Et2O. Concentration and purification by column chromatography gave an oil. The oil was treated with CHCl3 and the precipitate was collected by filtration.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:10][CH2:9][C@@H:7](O)[CH2:6]1)=[N+:2]=[N-:3].C([O-])(=[S:13])C.[K+].C(#N)C>C(OCC)(=O)C.CCCCCC>[N:1]([CH2:4][C@@H:5]1[O:10][CH2:9][C@H:7]([SH:13])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC([O-])=S
Reactant: [N-]=[N+]=NC[C@H]1C[C@H](O)CO1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: [N-]=[N+]=NC[C@H]1C[C@@H](S)CO1

Procedure:
The title compound is prepared by the procedure of Example 111 using 2.22 gof product from Example 116, 1.01 g of potassium thioacetate and 25 ml of acetonitrile to give 0.90 g of the desired product after chromatography (silica gel: 30% ethyl acetate/hexane). IR(neat): 2100 and 1692 cm-1.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[NH:48]1[CH:52]=[CH:51][C:50]([CH2:53][NH2:54])=[N:49]1>>[NH:48]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:41]([C:39]2[S:40][C:36]([N:33]3[CH2:34][CH2:35][N:31]([CH2:30][C:29]4[CH:46]=[CH:47][C:26]([F:25])=[CH:27][CH:28]=4)[C:32]3=[O:45])=[CH:37][C:38]=2[CH3:44])=[O:42])=[N:49]1
Reactant: NCc1cc[nH]n1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cc[nH]n1
Yield: 72 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1H-pyrazol-3-yl)methanamine, the title compound was obtained as a colorless solid in 72% yield: 1H NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 7.30-7.23 (m, 2H), 7.07-6.98 (m, 2H), 6.46 (t, J=5.0 Hz, 1H), 6.28 (s, 1H), 6.09 (s, 1H), 5.70 (br s, 1H), 4.60 (d, J=5.0 Hz, 2H), 4.43 (s, 2H), 3.83-3.74 (m, 2H), 3.47-3.39 (m, 2H), 2.48 (s, 3H); MS (ES+) m/z 436.2 (M+23).
Reaction SMILES: BrC[C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:14]([OH:20])(=[O:19])[CH2:15][C:16]([OH:18])=[O:17].C(C(CC)C(N)=O)C.[O-]CC.[Na+]>>[C:14]([OH:20])(=[O:19])[CH2:15][C:16]([OH:18])=[O:17].[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:3][C:4]1=[O:13]
Reactant: O=c1[nH]c2ccccc2cc1CBr
Agent: CCC(CC)C(N)=O
Agent: CC[O-]
Agent: O=C(O)CC(=O)O
Product: O=c1ccc2ccccc2[nH]1

Procedure:
bromomethyl carbostyril (2) is reacted with diethylacetamide malonate (3) in the presence of a base such as sodium ethoxide to give carbostyril malonate compound (4);
Reaction SMILES: [CH3:1][C:2]1[N:37]=[C:5]2[N:6]([CH2:33][C:34](=O)[CH3:35])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Cl.[NH2:39][O:40][CH:41]([CH3:43])[CH3:42].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH3:1][C:2]1[N:37]=[C:5]2[N:6]([CH2:33]/[C:34](=[N:39]/[O:40][CH:41]([CH3:43])[CH3:42])/[CH3:35])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:18][CH:19]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(C)=O)c2nc(C)nn12
Reactant: CC(C)ON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(C)=N/OC(C)C)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
A mixture of 2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.4 g), 2-(aminooxy)propane hydrochloride (1.8 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.2 g, 36%).
Reaction SMILES: [OH-].[Na+].CO[C:5](=[O:27])[C:6]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:7]=1.Cl.[NH2:29][C:30]1[S:31][CH:32]=[C:33]([CH3:35])[N:34]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CO.C(Cl)Cl.C(OC(=O)C)C>[CH:13]([O:12][C:10]1[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)[CH:7]=[C:6]([CH:11]=1)[C:5]([NH:29][C:30]1[S:31][CH:32]=[C:33]([CH3:35])[N:34]=1)=[O:27])([CH3:15])[CH3:14]
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(OC(C)C)c1
Reactant: Cc1csc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1csc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)C)c2)n1
Reaction time: 8 h

Procedure:
After adding 0.28 ml (0.56 mmol) of aqueous 2N sodium hydroxide to a solution of 41.0 mg (0.11 mmol) of the obtained sulfone compound in methanol (1.0 ml), the reaction mixture was stirred overnight. Aqueous 2N hydrochloric acid was added to the reaction mixture, extraction was performed with acetic acid ethyl ester, and the organic layer was washed with brine, dried and concentrated under reduced pressure to obtain a crude carboxyl compound. After adding 5.90 mg (0.51 mol) of 2-amino-4-methylthiazole, 9.30 mg (0.068 mmol) of 1-hydroxybenzotriazole hydrate and 13.0 mg (0.068 mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to a solution of 12.0 mg (0.034 mmol) of the obtained carboxyl compound in methylene chloride (0.5 ml), the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=1:1) to obtain the title compound as a white solid. The analysis data for the compound obtained in Production Example 1 are shown below.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[N+:11]([O-])([OH:13])=[O:12]>CC(O)=O>[N+:11]([C:7]1[CH:8]=[C:1]([O:9][CH3:10])[C:2]([O:3][CH3:4])=[CH:5][CH:6]=1)([O-:13])=[O:12]
Reactant: COc1ccccc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])cc1OC

Procedure:
In SCHEME 5 veratrol (12) is selectively nitrated with 70% HNO3 in AcOH to give 4-nitroveratrol (21). Subsequent reaction of (21) with Buli and TMEDA in THF followed by trimethylborate and hydrochloric acid gives boronic acid (22). Boronic acid (22) is reacted under inert conditions with a brominated aromatic or heteroaromatic ester of generell type (15) under Suzuki-type basic conditions (Pd(PPh3)4 and aqueous sodium bicarbonate in dimethoxyethane) to a biaryl of type (23). Biaryl (23) is further hydrolized with aqueous lithium hydroxide in THF and MeOH or MeCN to give the corresponding carboxylic acid (24) which is converted to a building block of type (25) by reaction with oxalyl chloride in anhydrous dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][C:3]=1[C:10]1[O:14][C:13]([C:15]2[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23](=[O:25])[CH3:24])[CH:16]=2)=[CH:12][C:11]=1[C:26]1[N:30]=[CH:29][N:28]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:27]=1.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:4][C:3]=1[C:10]1[O:14][C:13]([C:15]2[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23](=[O:25])[CH3:24])[CH:16]=2)=[CH:12][C:11]=1[C:26]1[N:30]=[CH:29][N:28]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:38])[CH3:36])[N:27]=1
Reactant: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(-c3cc(C=O)ccc3Cl)o2)c(C)cn1
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(-c3cc(CN4CCCC4)ccc3Cl)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of N-{4-[5-(2-chloro-5-formylphenyl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (0.19 g, 0.34 mmol) in DCM (10 mL) was added pyrrolidine (0.14 mL, 1.68 mmol) and STAB (0.21 g, 1.01 mmol). The mixture was allowed to stir at rt overnight. The mixture was diluted with water and extracted with DCM. The organic solutions were combined, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-(4-{5-[2-chloro-5-(pyrrolidin-1-ylmethyl)phenyl]-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl}-5-methylpyridin-2-yl)acetamide (0.20 g, 100%). LCMS (FA): m/z=607.7 (M+H).
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH3:35])[CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:25])[O:23][C:19]=2[C:18](F)=[C:17]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:16]=1[CH3:43])#[N:14].C(N(CC)CC)C>[Cl-].[Na+].O>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH3:35])[CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:25])[O:23][C:19]=2[C:18]([N:9]2[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]2)=[C:17]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:16]=1[CH3:43])#[N:14]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)CCc3ccccc3)nc2c1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(=O)N(C)CCc3ccccc3)nc2c1C#N
Reaction time: 1.17 h

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (3 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (110 μl, 871 μmol) was added at 150° C. to a dimethyl sulfoxide (12 ml) solution of 4-cyano-7-fluoro-N,5-dimethyl-6-phenyl-N-(2-phenylethyl)-1,3-benzoxazole-2-carboxamide (I-120) (300 mg, 726 μmol) and triethylamine (132 μl, 944 μmol), followed by stirring at the same temperature for 70 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (20:1, v/v) gave a crude product of the entitled compound as a solid, and the solid was suspended and washed in diisopropyl ether to obtain the entitled compound (161 mg, 44%) as a pale yellow solid.
Reaction SMILES: [I:1][CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH:14]C=O)[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.Cl.C(=O)(O)[O-].[Na+]>CO.O.C(OCC)(=O)C>[I:1][CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CI)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CI)O2
Yield: 91.8 %

Procedure:
To a solution of N-[2,3-dihydro-2-(iodomethyl)-2,4,6,7-tetramethylbenzofuran-5-yl]formamide (6.5 g) in methanol (40 mL) was added conc. hydrochloric acid (10 mL). The mixture was refluxed for 1.5 hours under nitrogen atmosphere, and poured into a suspension of sodium bicarbonate (12 g) in water and ethyl acetate The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, treated with activated carbon, filtrated and evaporated in vacuo. The residue was crystallized from hexane to afford 5.5 g of the title compound. Yield 91%.