Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][NH2:11].[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][NH:11][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([I:12])[CH:14]=1
Reactant: NCCc1c(Cl)cccc1Cl
Reactant: O=Cc1cccc(I)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1cccc(Cl)c1CCNCc1cccc(I)c1
Reaction time: 1 h

Procedure:
2-(2,6-Dichlorophenyl)ethylamine (1.0 g) and 3-iodobenzaldehyde (1.2 g) were combined in dichloromethane (50 mL). After 1 hour, sodium triacetoxyborohydride (2.2 g) was added. After 3.5 hours, the reaction mixture was poured onto 1M aqueous sodium hydroxide (200 mL) and extracted twice with dichloromethane. The organics were combined, dried (sodium sulfate) and evaporated to give the subtitle product, as an oil (2.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH2:24][C:25]#[C:26][CH3:27]>>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:24][C:25]#[C:26][CH3:27])=[CH:3][CH:4]=1)[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH3:14]
Reactant: CCOC(=O)C(Sc1ccc(O)cc1)c1ccc(OC)cc1
Reactant: CC#CCBr
Product: CC#CCOc1ccc(SC(C(=O)OCC)c2ccc(OC)cc2)cc1
Yield: 96 %

Procedure:
Ethyl{[4-(2-butynyloxy)phenyl]sulfanyl}(4-methoxyphenyl)acetate was prepared according to the general method as outlined in example 1 (step 1), starting from ethyl [(4-hydroxyphenyl)sulfanyl](4-methoxyphenyl)acetate (15.82 g, 49.7 mmol) and 4-bromo-2-butyne (4.79 ml, 54.7 mmol); 17.66 g yellow oil. Yield 96%; MS(EI): 370.1 (M+H)+
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[CH2:38]([C:40]1[S:41][CH:42]=[C:43]([CH2:45][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:44]=1)[CH3:39].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:38]([C:40]1[S:41][CH:42]=[C:43](/[CH:45]=[CH:24]\[C:23]2[C:19]([O:18][CH2:17][C:16]3[CH:32]=[CH:33][C:13]([O:12][CH2:11][C:9]4[N:10]=[C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)[O:7][C:8]=4[CH3:36])=[C:14]([O:34][CH3:35])[CH:15]=3)=[N:20][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)[N:44]=1)[CH3:39]
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(/C=C\c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 20.4 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.60 g), [(2-ethyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.76 g), potassium carbonate (0.25 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give 4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-2-(2-furyl)-5-methyl-1,3-oxazole as colorless crystals (0.15 g, yield 21%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 132-133° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O)=O)C>C(O)C.C(O)(=O)C.[Fe]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([N:7]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:14][C:4](=[O:3])[CH2:6]2)=[O:27])=[CH:19][CH:20]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N2CC(=O)Nc3ccccc32)cc1
Temperature: 80 °C
Yield: 16.2 %

Procedure:
A mixture of N-ethoxycarbonylmethyl-N-(4-nitrobenzoyl)-2-nitroaniline (500 mg) and iron powder (374 mg) in a mixture of ethanol (10 ml) and acetic acid (1 ml) was heated at 80° C. for 3 hours and the solution was cooled to ambient temperature. The mixture was filtered through celite and the filtrate was evaporated in vacuo. The residue was dissolved in chloroform (20 ml) and the solution was neutralized with aqueous sodium hydrogen carbonate. The solution was filtered through celite and the organic filtrate was washed with brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give a crude oil. The oil was purified by silica gel column (10 g, 2% methanol in chloroform) to give 4-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoxalin-2-one (58 mg) as a pale yellow powder.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH2:2]([N:6]1[C:10]([CH3:11])=[CH:9][S:8]/[C:7]/1=[CH:12]\[C:19]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:20])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)csc1C
Reactant: O=C(Cl)C1CCCCC1
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCN1C(C)=CS/C1=C\C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added cyclohexanecarbonyl chloride (23.5 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3 H) 1.09-1.44 (m, 7 H) 1.51-1.70 (m, 3 H) 1.69-1.88 (m, 4 H) 2.21-2.36 (m, 4 H) 3.95-4.01 (m, 2 H) 5.79-5.91 (m, 1 H) 6.57-6.73 (m, 1 H) MS (ESI) positive ion 280 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5]1.I[CH3:12]>C1COCC1>[CH3:12][O:3][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5]1
Reactant: CI
Reactant: COC(=O)C1(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(OC)CC1
Reaction time: 0.25 h

Procedure:
NaH (738 mg, 18.44 mmol; 60% dispersion in oil) was added to a solution of methyl 1-hydroxycyclopropanecarboxylate (1.83 g, 14.18 mmol) in anhydrous THF (15 mL) cooled on an ice bath. The mixture was stirred for 15 minutes then iodomethane (3.22 g, 1.42 mL, 22.69 mmol) was added slowly, and the resulting mixture stirred at ambient temperature for 18 hours. The reaction mixture was quenched with ammonium chloride and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water, dried over MgSO4, and filtered. The filtrate was evaporated under reduced pressure to give methyl 1-methoxycyclopropanecarboxylate. An aqueous 6N NaOH solution (4 mL) was added to a solution of methyl 1-methoxycyclopropanecarboxylate (1.08 g, 8.3 mmol) in anhydrous THF (5 mL). The mixture was stirred at room temperature for 18 hours, then acidified with aqueous 6N HCl and extracted with EtOAc (3×15 mL). The combined organic layer was dried over MgSO4, filtered and concentrated to give 1-methoxycyclopropanecarboxylic acid (892 mg, 54% yield) as an oil. 1H NMR (400 MHz, (CD3)2SO) δ 12.40 (br s, 1H), 3.30 (s, 3H), 1.15-1.10 (m, 2H), 1.08-1.04 (m, 2H).
Reaction SMILES: N1C2C(=CC=CC=2)CC1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([C:28]([NH2:30])=[O:29])=[CH:27][C:21]=3[N:20]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH:32]1S(C1C=CC(C=O)=CC=1)(=O)=O.C(NS(C1C=CC(C=O)=CC=1)(=O)=O)C1C=CC=CC=1>>[N:31]1([S:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([C:28]([NH2:30])=[O:29])=[CH:27][C:21]=4[N:20]=3)=[CH:15][CH:14]=2)(=[O:11])=[O:12])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(S(=O)(=O)C4Cc5ccccc5N4)cc3)nc2c1
Reactant: O=Cc1ccc(S(=O)(=O)C2Cc3ccccc3N2)cc1
Agent: O=Cc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Product: NC(=O)c1ccc2[nH]c(-c3ccc(S(=O)(=O)N4CCc5ccccc54)cc3)nc2c1

Procedure:
2-[4-(2,3-Dihydro-indole-2-sulfonyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide. This compound was prepared as described in Example 46 substituting 4-(2,3-dihydro-indole-2-sulfonyl)-benzaldehyde (202 mg, 0.703 mmol) for N-benzyl-4-formyl-benzenesulfonamide in Step B. The title compound was obtained as a beige powder, 130 mg (44%). HPLC (Method C): Rt=4.80. MS (ESI): mass calculated for C22H18N4O3S, 418.5; m/z found, 419.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 8.36 (d, J=8.2 Hz, 2H), 8.22 (s, 1H), 8.04 (m, 3H), 7.84 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.20 (m, 2H), 7.01 (m, 1H), 4.01 (t, J=8.2 Hz, 2H), 2.94 (t, J=8.1 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][C:28]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:34][CH2:33][C:28]4([CH2:27][O:26][CH3:25])[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCC1(CN)CCCC1
Product: COCC1(CNC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CCCC1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (1-(methoxymethyl)cyclopentyl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26-1.38 (m, 2H) 1.38-1.59 (m, 6H) 2.37 (s, 3H) 3.13 (s, 2H) 3.21 (s, 3H) 3.26 (d, J=6.32 Hz, 2H) 7.59 (dd, J=7.83, 1.52 Hz, 1H) 7.66 (s, 1H) 7.73 (d, J=8.08 Hz, 1H) 8.09 (s, 1H) 8.33 (s, 2H) 8.42 (t, J=6.06 Hz, 1H) 8.82 (t, J=1.52 Hz, 1H) 12.56-13.49 (m, 1H). MS m/z [M+H]+ 446.2.
Reaction SMILES: [C-:1]#[N:2].[K+].C1OCCOCCOCCOCCOCCOC1.O[CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:35]=[CH:36][CH:37]=1)[O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C(P(CCCC)CCCC)CCC>C(#N)C.CCOCC.C(Cl)(Cl)(Cl)Cl>[C:1]([CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:35]=[CH:36][CH:37]=1)[O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)COc1cccc(CCCO)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)COc1cccc(CCCC#N)c1
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
A mixture of potassium cyanide (1.16 g), 18-crown-6 (236 mg) and acetonitrile (18 ml) was stirred for 15 min under an atmosphere of argon. A mixture of methyl 3-(3-hydroxypropyl)phenoxyacetate (2.0 g) and tributylphosphine (1.99 g) in acetonitrile (10 ml) was added to the reaction mixture, followed by the dropwise addition of a solution of carbon tetrachloride (0.95 ml) in an acetonitrile (10 ml) with cooling in ice bath. The mixture was stirred overnight at room temperature. The mixture was diluted with ether, and washed with aqueous 10% citric acid. After the addition of carbon tetrachloride (10 ml), the mixture was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=9:1) to give the title compound (1.47 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[SH:11].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([S:11][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([Cl:8])[C:2]=1[Cl:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(S)c(Cl)c1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(SCc2ccccc2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
A solution of 6.23 g of 2,3-dichloro-4-methoxythiophenol in 60 ml of sieve-dried dimethylformamide is added to 0.75 g of sodium hydride over a period of 2-3 minutes. After stirring at room temperature for 20 minutes, the yellowish solution is treated with 5.10 g of benzyl bromide at a rate so that the temperature does not rise above 40°. Stirring is continued for an additional 30 minutes. The cloudy mixture is poured onto 200 g of crushed ice with caution and the white precipitate is collected on a filter after 1 hour at 10° C. The air-dried product is recrystallized from acetone-hexane to give 7.8 g of 4-benzylthio-2,3-dichloroanisole as white needles, mp 116°-117° C.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:22][C:23]1[CH:24]=[C:25]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])[CH:26]=[CH:27][CH:28]=1.Cl.C(N=C=N)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[O:30])[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:24]=4)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of the (4-adamantan-1-yl-phenoxy)-acetic acid (143 mg, 0.5 mmol) and (3-amino-phenyl)phenyl-methanone (148 mg, 0.75 mmol) in DMF (5.0 mL) were added 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (144.0 mg, 0.75 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (101 mg, 0.75 mmol), and N,N-diisopropylethylamine (DIPEA) (0.13 ml, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. Purification by silica gel column chromatography (n-Hexane:EtOAc:MeOH=12:3:1) gave 2-(4-Adamantan-1-yl-phenoxy)-N-(3-benzoyl-phenyl)-acetamide as a white solid (173.1 mg, 74.3% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH:12]=[O:13].Br[CH2:15][C:16]([NH2:18])=[O:17].C(N=P(N(C)C)(N(C)C)N(C)C)(C)(C)C.Cl>O.CN(C=O)C>[CH:12]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][CH2:15][C:16]([NH2:18])=[O:17])[CH:3]=2)[N:7]([CH3:11])[CH:6]=1)=[O:13]
Reactant: NC(=O)CBr
Reactant: Cn1cc(C=O)c2cc(O)ccc21
Agent: CN(C)P(=NC(C)(C)C)(N(C)C)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C=O)c2cc(OCC(N)=O)ccc21
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
5-Hydroxy-1-methyl-1H-indole-3-carbaldehyde (I-2) (0.5 g, 2.86 mmol), 2-Bromo-acetamide (0.43 g, 3.1 mmol), and N′″-tert-butyl-N,N,N′,N′,N″,N″-hexamethyl-phosphorimidic triamide (2.18 mL, 8.6 mmol) were dissolved into anh. DMF (3 mL) in a seal tube. The resulting solution was then sealed and heated at 120° C. (monitored by LCMS). The reaction completed after 3.5 h. The mixture was cooled to room temperature, added 20 mL of water, and 6 N HCl to pH 2-3. The mixture was then extracted with ethyl acetate (20 mL×6). The organic layers were combined, washed with brine (10 mL×2), dried over Mg2SO4, filtered and dried under reduced pressure to give the title compound as 0.5 g orange powder (crude yield: 76%, used without further purification). LCMS (2-85% ACN/H2O in 7 min): M+ 233.1 (100%); 95% purity (at 220 nM).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([N:18]=[C:19]=[S:20])=[O:17])=[CH:14][CH:13]=1>CCOCC>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:16](=[O:17])[C:15]1[CH:21]=[CH:22][C:12]([CH3:11])=[CH:13][CH:14]=1)=[O:5]
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Reactant: NC(=O)c1ccccc1N
Solvent: CCOCC
Product: Cc1ccc(C(=O)NC(=S)Nc2ccccc2C(N)=O)cc1
Reaction time: 48 h
Yield: 98.2 %

Procedure:
To a stirred mixture of 5.4 g of 2-aminobenzamide and 200 ml of ether was added dropwise, a solution of 7.5 g of 4-methylbenzoyl isothiocyanate in 100 ml of ether over 30 minutes. After 48 hours, the solid was collected, giving 12.2 g of the desired product as grey crystals, mp 208°-210° C. (dec.).
Reaction SMILES: [SH:1][CH:2]([CH3:10])[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>FC(F)(F)C(O)=O>[C:17]([S:1][CH:2]([CH3:10])[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(S)C(=O)NCC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(SC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of alpha-mercaptopropionyl glycine (50 g; 0.307 moles) in 300 ml of trifluoroacetic acid, were added 79.9 g (0.307 moles) of triphenylcarbinol. The thus obtained solution was kept under stirring at room temperature for 15 minutes. The excess of trifluoroacetic acid was removed by evaporation and the residue taken up with ether. Filtration yielded a white solid, which was then washed with ether and dried in vacuo to constant weight.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[NH2:21])=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[Cl-].C([O:33][C:34](=O)[C:35](O)=[O:36])C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:12]3[C:13](=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[NH:21][C:34](=[O:33])[C:35]2=[O:36])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2ccc([N+](=O)[O-])cc2N)cc1
Reactant: CCOC(=O)C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-n2c(=O)c(=O)[nH]c3cc([N+](=O)[O-])ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
At a bath temperature of +40° C., under argon and with exclusion of moisture, 582 mg (2.3 mmol) of 4-(2-amino-4-nitrophenylamino)benzoic acid ethyl ester is combined with 488 mg (4.8 mmol) of triethylamine in 27 ml of dry tetrahydrofuran. A solution of 659 mg (4.8 mmol) of oxalic acid ethyl ester chloride and 8 ml of dry tetrahydrofuran is added dropwise to this batch and stirred for 2 hours at room temperature. The mixture is then combined with 0.2 ml of triethylamine and 0.1 ml of oxalic acid ethyl ester chloride, and agitated for one hour at room temperature. The batch is filtered, and the filtrate is concentrated and distributed in water/ethyl acetate. The organic phase is concentrated. The residue is refluxed for 2 hours at the bath temperature in 25 ml of 1N hydrochloric acid and 25 ml of ethanol. The thus-precipitated product is suctioned off, washed with water, and dried, yielding 220 mg of 4-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)benzoic acid ethyl ester (further processed without purification).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].N#N.I[CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+].[CH3:22][C:23](C)=O>>[CH2:22]([O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH3:15])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:23]
Reactant: O=Cc1cc(O)ccc1O
Reactant: CC(C)=O
Reactant: CCI
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(OCC)c(C=O)c1
Temperature: 25 °C

Procedure:
A suspension of 9.66 g (70 mmol) 2,5-dihydroxybenzaldehyde N2, 32.75 g (210 mmol) iodoethane, 24.19 g (175 mmol) K2CO3 in 350 ml acetone was heated to reflux for 18 hours under nitrogen. The solvent was evaporated and the residue was dissolved in 300 ml CHCl3 and 300 ml water. The organic phase was washed with 2×300 ml 2.5% Na2CO3 and 300 ml saturated NaCl and dried over Na2SO4. The solvent was evaporated and the residue (13.5 g) purified with a silica gel column (silica gel 100, CHCl3/cyclohexane: 1/1, v/v), affording 8.61 g light yellow oil, which crystallized after cooling to room temperature (yield. 63%).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([F:28])[C:19]=1[CH:20]=O>O1CCCC1.C(OCC)(=O)C>[F:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([F:28])[C:19]=1/[CH:20]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc(F)c(C=O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1c(F)cc(OC)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
A solution of ethyl diethylphosphonoacetate (2.34 g, 10.4 mmol) and sodium hydride (60% in oil, 0.38 g, 9.50 mmol) in tetrahydrofuran (40 mL) was stirred under ice-cooling for 10 min. 2,6-Difluoro-4-methoxybenzaldehyde (1.5 g, 8.71 mmol) was added to the solution, and the mixture was stirred for 4 hr while raising the temperature to room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (1.1 g, yield 52%) as colorless needle crystals. MS: m/z 243 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[I-].[Na+].C(N(C(C)C)[CH:18]([CH3:20])[CH3:19])C.C(Br)C=C>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8])[CH:18]=[CH2:19]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: CC(C)=O
Product: C=CCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 25 g (150 mmol) 5-hydroxy-2-nitro-benzaldehyde and 44.8 g (299 mmol) sodium iodide in 400 ml acetone are added 51.2 ml (299 mmol) N-ethyldiisopropylamine and 25.3 ml (299 mmol) allyl bromide. After stirring for 18 h at r.t. the reaction mixture is filtered and the solvent is evaporated. Extraction of the residue with 1 M aqueous hydrochloric acid/dichloromethane followed by chromatography (hexane/ethyl acetate) yields 5-allyloxy-2-nitro-benzaldehyde.
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:11])[CH:10]=1.[F:12][C:13]([F:19])([F:18])[S:14]([OH:17])(=[O:16])=[O:15]>N1C=CC=CC=1>[F:12][C:13]([F:19])([F:18])[S:14]([O-:17])(=[O:16])=[O:15].[F:12][N+:7]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:5]([Cl:4])[CH:6]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Clc1cncc(Cl)c1
Solvent: c1ccncc1
Solvent: CC#N
Product: F[n+]1cc(Cl)cc(Cl)c1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: -20 °C
Yield: 180.7 %

Procedure:
To 40 ml of acetonitrile were added 3.087 g (20.860 mmol ) of 3,5-dichloropyridine and 3.039 g (20.250 mmol ) of trifluoromethanesulfonic acid (i.e., the amount pyridine compound was 1.03 times that of trifluoromethanesulfonic acid in a molar ratio), and the mixture was cooled to -20° C. The following procedures were conducted as in Example 1, and 5.774 g (18.3 mmol) of N-fluoro-3, 5-dichloropyridinium trifluoromethanesulfonate were obtained with a yield of 90.0%.