Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]OCCOC.C([Zn]CC)C.ICI.[CH:15](/[C:19]1=[CH:20][N:21]([C:36]([CH3:39])([CH3:38])[CH3:37])[S:22]/[C:23]/1=[N:24]\[C:25](=[O:35])[C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])=[CH:16]/[CH2:17][CH3:18]>C(Cl)Cl>[C:36]([N:21]1[CH:20]=[C:19]([CH:15]2[CH2:1][CH:16]2[CH2:17][CH3:18])/[C:23](=[N:24]/[C:25](=[O:35])[C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[O:33][CH3:34])/[S:22]1)([CH3:38])([CH3:37])[CH3:39]
Reactant: COCCOC
Reactant: CC/C=C\c1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Agent: CC[Zn]CC
Solvent: ClCCl
Solvent: ICI
Product: CCC1CC1c1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
To a solution of CH2Cl2 (10 mL) and 1,2-dimethoxyethane (95 mg, 1.06 mmol) at −10° C. was added diethylzinc (130 mg, 1.06 mmol). To this solution was added dropwise diiodomethane (565 mg, 2.1 mmol). After the addition was complete, the resulting clear solution was stirred for 10 min at −10° C. A solution of Example 25B (200 mg, 0.53 mmol) was added to the reaction mixture, which was allowed to warm to room temperature and stir overnight. The reaction was quenched with NH4Cl then acetone and extracted with EtOAc (2×). The organics were combined, dried (MgSO4), filtered and solvent evaporated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 159 mg (77%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 0.59 (q, J=5.52 Hz, 1 H) 0.92 (t, J=7.36, 6.44 Hz, 3 H) 0.94-1.14 (m, 2 H) 1.16-1.29 (m, 2 H) 1.65 (s, 9 H) 2.11-2.33 (m, 1 H) 3.91 (s, 3 H) 6.91 (d, J=8.90 Hz, 1 H) 7.33 (dd, J=8.90, 2.76 Hz, 1 H) 7.81 (s, 1 H) 8.08 (d, J=2.76 Hz, 1 H); MS (DCI/NH4+) m/z 393 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[C:23](Cl)[N:22]=1.C1(C)C=CC=CC=1>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([F:29])([F:30])[F:28])=[C:21]([Cl:20])[N:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)c(Cl)n2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a suspension of tert-butyl-1-piperazine carboxylate (27.0 g, 145 mmol) and K2CO3 (40.0 g, 290 mmol) in DMSO (200 mL) were 2,6-dichloro-3-trifluoromethylpyridine (29.1 g, 135 mmol) and toluene (50 mL) added. The thick slurry was stirred at 80° C. for two hours, followed by addition of toluene (0.5 L) and water (1 L). The phases were separated and the organic phase was washed twice with water. The solvent from the dried (MgSO4) organic phase was evaporated at reduced pressure. The solid residue was recrystallized from EtOAc/heptane to give white crystals (37 g). The filtrate from the recrystallization was concentrated and the residue chromatographed on a column of silica with hexane/EtOAc (90:10) to give further 6.0 g of product (total yield 85%). Purity 99% (HPLC); mp 125° C. Anal. (C15H19ClF3N3O2) C, H, N.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)C>[C:33]1([NH:39][C:40]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=3)[N:3]=2)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1cc(Br)nc(Oc2cccc(OC(F)(F)F)c2)c1
Reactant: O=C=Nc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc(Oc2cccc(OC(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
1.0 g (0.0027 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethoxy)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. The obtained solution was cooled in a dry ice-acetone bath in an argon atmosphere and mixed with 2.6 ml of a 1.6M-hexane solution of BuLi (0.0027×1.5 mol), followed by stirring for about 10 minutes. After 0.74 g (0.0027×2.3 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about 45 minutes. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The obtained fraction was concentrated and then subjected to precipitation using hexane, thereby obtaining an aimed product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:22]=3)[CH:16]=[C:4]2[N:3]=1.O.[NH2:30][NH2:31].O1[CH2:37][CH2:36]OCC1>>[CH3:4][C:16]1[CH:15]=[C:17]([CH:22]=[CH:36][CH:37]=1)[CH:18]=[N:30][NH:31][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:18]=[N:19][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:22]=3)[CH:16]=[C:4]2[N:3]=1
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3ccc(N4CCOCC4)nc3)cc2n1
Reactant: C1COCCO1
Solvent: O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccc(N5CCOCC5)nc4)cc3n2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
There was suspended, in 1,4-dioxane (3 mL), 5-chloro-7-morpholin-4-yl-2-(6-morpholin-4-yl-pyridin-3-yl)-pyrazolo[1,5-a]pyrimidine (28.9 mg, 0.0720 mM) and then hydrazine monohydrate (34.8 μL, 0.720 mM) was added to the suspension. After stirring this suspension at 60° C. overnight, it was stirred at 150° C. for 10 minutes under the irradiation with microwaves. Hydrazine monohydrate (40 μL, 0.82 mM) was added to this reaction liquid and then it was stirred at 150° C. for 15 minutes under the irradiation with microwaves. This reaction liquid was diluted with a saturated aqueous common salt solution and then extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting residue was suspended in ethanol (2 mL), then acetic acid (5.0 μL, 0.087 mM) and 3-methyl-benzaldehyde (8.5 μL, 0.072 mM) were added to the suspension and the mixture was stirred at room temperature for one hour. The solvent was distilled off from the reaction mixture, the resulting residue was purified by the reversed phase HPLC and then subjected to a desalting operation to thus give the title compound (14.3 mg, overall yield of these two steps: 40%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[NH2:11][NH2:12]>C(OCC)C.C1COCC1>[CH3:1][O:2][C:3](=[O:4])/[C:5](/[NH:11][NH2:12])=[CH:6]\[C:7]([O:9][CH3:10])=[O:8]
Reactant: NN
Reactant: COC(=O)C#CC(=O)OC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)/C=C(/NN)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of dimethylacetylene dicarboxylate (1.4 g, 9.9 mmol) in diethylether (40 mL) under argon was added a solution of hydrazine in THF (1 M, 10 mL) and the resulting mixture stirred at room temperature overnight. The precipitate was filtered off and dried to afford the title compound (597 mg, 35%) as a white solid. MS: m/e=175.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].C1(OC(=O)NC[C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)C=CC=CC=1.[CH3:36][N:37](C)[CH:38]=[O:39]>[Cl-].[Na+].O>[O:28]([C:25]1[CH:26]=[C:27]([CH:22]=[CH:23][CH:24]=1)[CH2:36][NH:37][C:38]([N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:39])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(NCc1ccc(Oc2ccccc2)cc1)Oc1ccccc1
Reactant: CN(C)C=O
Reactant: c1cnc2cc[nH]c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(NCc1cccc(Oc2ccccc2)c1)n1ccc2ncccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.7 %

Procedure:
1H-Pyrrolo[3,2-b]pyridine described in Preparation Example S-4 (44 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (3 mL), sodium hydride (18 mg, 0.45 mmol, 60% in oil) was added thereto, followed by stirring at room temperature for 30 minutes. Next, (4-phenoxy-benzyl)-carbamic acid phenyl ester described in Preparation Example 75 (143 mg, 0.45 mmol) was added, and the solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into brine, which was then extracted with ethyl acetate, and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), and the title compound (11 mg, 0.032 mmol, 8.7%) was obtained.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[CH2:12][CH2:13][CH3:14]>>[CH2:12]([S:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH2:13][CH3:14]
Reactant: CCCI
Reactant: O=C(O)c1cccnc1S
Product: CCCSc1ncccc1C(=O)O
Yield: 96 %

Procedure:
2-Mercapto-nicotinic acid (1 g, 6.4 mmol) and 1-iodopropane were reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (1.22 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:20]=CC)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:6]2.O.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:33].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH:20]([C:4]1[C:3]([O:2][CH3:1])=[CH:11][C:10]([CH3:12])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[O:33]
Reactant: CC=Cc1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 5-methoxy-7-methyl-4-(prop-1-en-1-yl)-1H-indole-1-carboxylate (0.29 g, 0.97 mmol) was dissolved in dioxane (7.27 mL) and water (2.4 mL) and 2,6-lutidine (0.23 mL, 1.94 mmol) was added followed by osmium tetroxide (0.24 mL, 0.019 mmol) and sodium periodate (0.83 g, 3.88 mmol) at 0° C. The reaction was removed from the ice bath and let stir at room temperature for 1 hour. The reaction was diluted with methylene chloride and water. The organic layer was separated, dried over sodium sulfate and then concentrated. The resulting residue was absorbed onto silica and then purified by silica gel flash chromatography (0-50% ethyl acetate/heptanes) to provide the title compound. MS (ESI+) m/z 290.1 (M+H).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([F:25])[C:17]=1[F:26])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(C)C=CC=CC=1.O.C(O)C>[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:12]=[CH:11][C:5]([C:4]3[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=[CH:2][CH:3]=3)=[CH:4][CH:3]=2)=[C:18]([F:25])[C:17]=1[F:26])[CH3:14]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccc(-c2ccc(OCC)c(F)c2F)cc1
Temperature: 25 °C
Yield: 108.6 %

Procedure:
Ethyl 4-iodobenzoate (1) (25.0 g), 4-ethoxy-2,3-difluorophenylboronic acid (2) (20.1 g), potassium carbonate (25.0 g), Pd/C (0.25 g), toluene (100 ml), ethanol (100 ml) and water (100 ml) were added to a reaction vessel under an atmosphere of nitrogen, and heated to reflux for 2 hours. After the reaction solution had been cooled to 25° C., it was poured into water (500 ml) and toluene (500 ml), and mixed with them. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography using silica gel as a stationary phase powder and toluene as an eluent. The product was further purified by recrystallization from ethanol and dried to give ethyl 4-ethoxy-2,3-difluoro-4′-biphenylbenzoate (3) (18.8 g). The yield based on the compound (1) was 67.9%.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10](Cl)[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20]([OH:24])[CH2:21][CH2:22][OH:23]>>[NH2:2][C:3]1[N:11]=[C:10]([O:23][CH2:22][CH2:21][CH2:20][OH:24])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCCO
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na]
Product: Nc1nc(OCCCO)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 51 %

Procedure:
Sodium (80 mg, 3.5 mmol) in 3 ml of 1,3-propanediol was added 6-amino-9-benzyl-2-chloropurine (235 mg, 0.90 mmol). The mixture was heated at 100° C. for 3 hours. The reaction mixture was concentrated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and the solvent was removed. The residue was purified with silica gel chromatography (3% methanol/chloroform) to give the subject compound (137 mg, yield 51%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16](OCC)=[O:17])[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O>[CH3:1][N:2]([CH3:21])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][OH:17])[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: CCOC(=O)c1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C1CCc2[nH]c3ccc(CO)cc3c2C1
Reaction time: 1 h

Procedure:
A solution of 12.8 g. of 3-(dimethylamino)-6-ethoxycarbonyl-1,2,3,4-tetrahydrocarbazole (Example 43) in 350 ml. of dry tetrahydrofuran was added dropwise to a refluxing solution of 3.5 g. of lithium aluminum hydride in 100 ml. of dry tetrahydrofuran and refluxing was continued for one hour after completion of the addition. Ethyl acetate was added followed by water, the mixture was filtered, and the filtrate was evaporated to dryness to give, after recrystallization from ethyl alcohol, 6.4 g. of 3-(dimethylamino)-6-hydroxymethyl1,2,3,4-tetrahydrocarbazole, m.p. 195°-197° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C:9](=[O:12])[CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.C[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)CN.C(N(C(C)C)CC)(C)C>CS(C)=O>[OH:23][C:24]1[CH:25]=[CH:26][C:29]([C:2]2[N:7]=[C:6]3[N:8]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[C:9](=[O:12])[CH2:10][NH:11][C:5]3=[N:4][CH:3]=2)=[CH:30][CH:31]=1
Reactant: COc1cccc(CN)c1
Reactant: COc1cccc(CN2C(=O)CNc3ncc(Br)nc32)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cccc(CN2C(=O)CNc3ncc(-c4ccc(O)cc4)nc32)c1
Yield: 20 %

Procedure:
7-Bromo-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. Methyl 2-(3,5-dibromopyrazin-2-ylamino) acetate (0.58 g, 1.8 mmol), 3-methoxybenzylamine (227 μL, 1.8 mmol), diisopropylethylamine (1 mL), and dimethylsulfoxide (1 mL) were heated to 100° C. for 3 d under nitrogen. The reaction was extracted with ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered and concentrated. The residue was purified on silica gel column (0-100% ethyl acetate in hexanes) to give the title compound (124 mg, 20% yield) as a pink solid. MS (ESI) m/z 349.0 [M+1]+.
Reaction SMILES: [CH:1]([O-:5])([O-])[O:2][CH3:3].[CH3:6]C1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C([C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:30][C:29]=2[CH:37]=1)=O>CO>[CH3:6][O:5][CH:1]([O:2][CH3:3])[C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:30][C:29]=2[CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: COC([O-])[O-]
Reactant: COC(=O)c1cc2cc(C=O)ccc2o1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)c1cc2cc(C(OC)OC)ccc2o1
Reaction time: 8 h

Procedure:
Methyl orthoformate (1.0 g) and polymer-bound PPTS (1.0 g) were added to a solution of methyl 5-formylbenzofuran-2-carboxylate (15 g) in MeOH (100 ml), and after allowing the mixture to stand at room temperature for 8 hours, the reaction solution was filtered and the mother liquor was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=9/1) to obtain methyl 5-(dimethoxymethyl)benzofuran-2-carboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]2[CH2:60][CH:59]2[NH2:61])=[CH:54][CH:53]=1.C(N(CC)CC)C>ClCCCl>[Cl:51][C:52]1[CH:53]=[CH:54][C:55]([CH:58]2[CH2:60][CH:59]2[NH:61][C:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:22][CH:21]=2)=[O:19])=[CH:56][CH:57]=1
Reactant: NC1CC1c1ccc(Cl)cc1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CC4c4ccc(Cl)cc4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A mixture of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 2) (0.041 g, 0.116 mmol), 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.0245 g, 0.128 mmol), 1-hydroxybenzotriazole monohydrate (0.0195 g, 0.128 mmol), and 1,2-dichloroethane (1 ml) was stirred at room temp for 0.5 hours. A mixture of 2-(4-chlorophenyl)cyclopropanamine hydrochloride (0.0261 g, 0.128 mmol) and triethylamine (0.0809 ml, 0.580 mmol) in 1,2-dichloroethane (1 ml) was added to the activated acid mixture. The mixture was stirred at ambient temperature for 1 hour. The crude mixture was directly purified on silica gel (EtOAc in hexanes gradient) to provide 50.7 mg of the title compound as a thin film (87%).
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[N+:15]([O-])=O)[C:4]([NH2:6])=[O:5])#[N:2]>[Fe]>[Cl:14][C:12]1[CH:13]=[C:8]2[C:9](=[CH:10][CH:11]=1)[N:15]=[C:1]([NH2:2])[C:3]([C:4]([NH2:6])=[O:5])=[CH:7]2
Reactant: N#CC(=Cc1cc(Cl)ccc1[N+](=O)[O-])C(N)=O
Agent: [Fe]
Product: NC(=O)c1cc2cc(Cl)ccc2nc1N

Procedure:
Following the procedure of Example IV B, α-cyano-β-(2-nitro-5-chlorophenyl)acrylamide (51.0 g., 0.2 mole) is treated with iron powder (56 g., 1.0 mole) to provide 19 g. (43%) of the title carboxamide derivative. M.P. 250°-251° C. when recrystallized from ethanol.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:21]([F:24])([F:23])[F:22])=[CH:11][C:12]([N+:18]([O-])=O)=[C:13]([CH2:15][C:16]#N)[CH:14]=1)C1C=CC=CC=1.O.C(O)(=O)C>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][C:10]=1[C:21]([F:24])([F:23])[F:22])[NH:18][CH:16]=[CH:15]2
Reactant: N#CCc1cc(OCc2ccccc2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Oc1cc2cc[nH]c2cc1C(F)(F)F
Yield: 84.4 %

Procedure:
5-Benzyloxy-2-nitro-4-(trifluoromethyl)phenylacetonitrile (2.22 g, 6.6 mmol) was dissolved in ethanol (45 ml), water (5 ml) and acetic acid (0.32 ml) then hydrogenated with 10% palladium on carbon at 1 atmosphere pressure for 2 hours. The catalyst was filtered off and filtrate evaporated to give 5-hydroxy-6-trifluoromethylindole (1.12 g, 84%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>C1(C)C=CC=CC=1.Cl>[CH2:23]([S:25]([O:15][C:6]1[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:27])=[O:26])[CH3:24]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Oc1ccc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
8.04 g (0.0389 mol) of 2,4-di-tert-butylphenol and 4.13 g (0.0408 mol) of triethylamine were dissolved in 15 mL of toluene followed by dropping in 5.01 g (0.0389 mol) of ethanesulfonyl chloride over the course of 30 minutes at 10° C. Following completion of dropping, the mixture was stirred for 2 hours at 25° C. and the 2,4-di-tert-butylphenol was confirmed to no longer be present. The reaction liquid was placed in 3% aqueous hydrochloric acid solution and following separation of the organic layer, was washed once with saturated aqueous NaHCO3 solution and twice with saturated brine followed by drying with MgSO4 and concentrating. The resulting crude crystals were purified by crystallization with n-heptane to obtain 8.14 g (yield: 70%) of 2,4-di-tert-butylphenyl ethanesulfonate (white crystals, melting point: 76° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.[OH-].[Na+]>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C=CC(=O)O)cc1OC
Temperature: 80 °C

Procedure:
3,4-Dimethoxybenzaldehyde (25 g, 0.15 mol), malonic acid (32.87 g, 0.31 mol) and piperidine (1 mL) were dissolved in pyridine (100 mL) under stirring. The reaction mixture was heated at 80° C. for 3 h, after which the temperature was further increased to 120° C. and maintained at this temperature for 3 h. The reaction mixture was cooled, diluted with water (70 mL) and pH of the solution was adjusted to 9 by addition of 10% aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (3×150 mL). The pH of the aqueous layer was adjusted to 2 by addition of aqueous HCl (1:1) and the resulting solid was filtered and dried to afford the title compound.