Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH2:32]([NH:39][CH2:40][CH2:41][C:42]#[N:43])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:32]([N:39]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH2:40][CH2:41][C:42]#[N:43])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: N#CCCNCc1ccccc1
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(CCC#N)Cc2ccccc2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 3-benzylamino-propionitrile (73 μL, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 592 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([OH:9])=[O:8].Cl.[CH2:12](O)[CH3:13]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([O:9][CH2:12][CH3:13])=[O:8]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(=O)c1cccs1
Temperature: 25 °C

Procedure:
Thiophene-2-glyoxylic acid (2 g, 12.8 mmol) was added to anhydrous ethanol (100 ml) which was saturated with HCl by bubbling HCl gas for 2 min. The resulting mixture was stirred at room temperature. overnight. TLC showed the reaction was complete. Solvent was removed and the residue was purified by chromatography over silica gel eluting with ethyl acetate/hexane 10:90 to give ethyl thiophene-2-glyoxylate (1.5 g).
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.[CH3:48][N:49]1[C:53]([CH2:54][NH2:55])=[CH:52][N:51]=[CH:50]1>>[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]([NH:55][CH2:54][C:53]4[N:49]([CH3:48])[CH:50]=[N:51][CH:52]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cn1cncc1CN
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)NCc1cncn1C
Yield: 75 %

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 (1-methyl-1H-imidazol-5-yl)methanamine, the title compound was obtained as a colorless solid in 75% yield: 1H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 7.30-7.22 (m, 2H), 7.08-6.98 (m, 3H), 6.08 (s, 1H), 5.86 (t, J=5.0 Hz, 1H), 4.59 (d, J=5.0 Hz, 2H), 4.42 (s, 2H), 3.84-3.75 (m, 2H), 3.65 (s, 3H), 3.49-3.40 (m, 2H), 2.48 (s, 3H); MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[CH3:37][S:38]([NH:41][CH2:42][CH2:43]N1CCCCC1)(=[O:40])=[O:39]>>[ClH:11].[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:31]2[CH2:36][CH2:35][CH:34]([CH2:43][CH2:42][NH:41][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:33][CH2:32]2)=[C:7]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=2)[CH:6]=1
Reactant: CS(=O)(=O)NCCN1CCCCC1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Reactant: C1CCNCC1
Product: COc1cc(COc2cc(N)c(Cl)cc2C(=O)CCCCN2CCC(CCNS(C)(=O)=O)CC2)cc(OC)c1
Product: Cl

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy) phenyl]-5-chloropentan-1-one and piperidine with 4[2-(methylsulfonyl)aminoethylpiperidine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy) phenyl]-5-{4-[2-(methylsulfonyl)aminoethyl]-piperidin-1-yl}pentan-1-one hydrochloride, m.p. 205°-206° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.CCCCCC.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][C:27]=1[CH3:34]>C1COCC1.O>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([CH:30]([C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[C:27]([CH3:34])[CH:28]=2)[OH:31])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: COc1ccc(C=O)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOc1cc(C(O)c2ccc(OC)c(C)c2)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-bromo-2-ethoxy-1-methoxy-benzene (1.7 g, 7.4 mmol) in THF (20 mL) was added a solution of n-butyllitium in hexane (2.8 mL, 2.5 N, 7.0 mmol) at −78° C. and kept for 20 min. To the mixture was added 4-methoxy-3-methyl-benzaldehyde (1.0 g, 90% pure, 6.0 mmol) at −78° C. After 18 h, water (30 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with HCl (0.5 N, 50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent gave (3-ethoxy-4-methoxy-phenyl)-(4-methoxy-3-methyl-phenyl)-methanol as a solid (2.0 g, 100% crude yield). The sample was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1F)([O-:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccccc2[N+](=O)[O-])C1
Temperature: 110 °C
Yield: 60.4 %

Procedure:
A mixture of 3(R)-amino-piperidine-1-carboxylic acid tert-butyl ester (137 mg, 0.69 mmol) and 2-nitrofluorobenzene (102 mg, 0.72 mmol), K2CO3 (100 mg) was heated at 110° C. for 12 hr. The mixture was diluted with CH2Cl2, filtered and concentrated. The residue was purified by chromatography (5% EtOAc in hexane) to give a yellow oil (134 mg, 61%).1H-NMR (300 MHz, CDCl3) δ 8.20 (d, J=8.55 Hz, 1H, NH), 8.10 (d, J=7.20 Hz, 1H), 7.48 (t, 1H), 7.01 (d, J=8.30 Hz, 1H), 6.70 (t, 1H), 4.00 (broad, 1H), 3.75 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 2.10 (m, 1H), 1.82-1.60 (m, 3H), 1.43 (s, 9H) ppm; IR (film) 3357, 2967, 2935, 2858, 1692, 1620, 1572, 15508, 1423, 1372, 1266, 1230, 1154 cm−1; LRMS (calculated for C6H23N2O4) 321, found 321.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22]C)=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(NC(=O)C(C)C)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C(=O)Nc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)ccc1Cl
Yield: 57.6 %

Procedure:
A mixture of methyl 2-(4-chloro-3-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (216 mg, 0.52 mmol) in methanol (8 mL) and 4.2 mL of aqueous solution of sodium hydroxide (1 M, 4.2 mmol) was stirred at reflux for 2 h. Thin layer chromatography indicated that the starting material was consumed completely. Methanol was removed under reduced pressure and the residue was acidified to pH=6 with 1 M hydrochloric acid solution. The precipitated white solid were collected by filtration and dissolved in Ethyl acetate, dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford 120 mg of 2-(4-chloro-3-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. LC-MS(M+1)=383.
Reaction SMILES: C[Li].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:16]2[CH:17]=[C:18]([C:21]#N)[CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:23])[CH:12]([CH3:24])[N:11]=1.Cl.[OH-:26].[Na+].[CH3:28]COCC>O1CCCC1>[C:21]([C:18]1[CH:19]=[CH:20][C:15]2[NH:14][C:13](=[O:23])[CH:12]([CH3:24])[N:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[F:3])[C:16]=2[CH:17]=1)(=[O:26])[CH3:28]
Reactant: CCOCC
Reactant: [OH-]
Reactant: CC1N=C(c2ccccc2F)c2cc(C#N)ccc2NC1=O
Agent: Cl
Agent: [Li]C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(c1ccccc1F)=NC(C)C(=O)N2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
110 ml of a 2 N solution of methyl lithium in ether are added dropwise to a solution, stirred at -70° under argon, of 12.81 g (43.68 mmol) of 5-(o-fluorophenyl)-2,3-dihydro-3-methyl-2-oxo-1H-1,4-benzodiazepine-7-carbonitrile in 500 ml of tetrahydrofuran. After 21 hours at -70°, 440 ml of 2 N hydrochloric acid are added thereto at -70° and, after warming to room temperature, the mixture is neutralised with 135 ml of 3 N sodium hydroxide. After separating the aqueous phase, the organic phase is evaporated at 40° in vacuo, the residue is taken up in methylene chloride and the organic phase is washed with the aqueous phase separated above. The methylene chloride solution is washed with water, dried and evaporated. The residue yields, from methylene chloride/cyclohexane, 7-acetyl-5-(o-fluorophenyl)-1,3-dihydro-3-methyl-2H-1,4-benzodiazepin-2-one of melting point 203°.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][C:13]2([CH2:17]OS(C)(=O)=O)[CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[Na+].[I-:26]>CC(=O)CC>[I:26][CH2:17][C:13]1([CH2:12][C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: CS(=O)(=O)OCC1(CC#Cc2ccc(OC(F)(F)F)cc2)CCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: FC(F)(F)Oc1ccc(C#CCC2(CI)CCC2)cc1
Temperature: 90 °C
Yield: 87.3 %

Procedure:
To a solution of 0.78 g (2.15 mmol) methanesulfonic acid 1-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyl]-cyclobutylmethyl ester in 30 ml 2-butanone was added 0.65 g (4.30 mmol) NaI. The mixture was heated for 9 h at 90° C. The solvent was evaporated and the residue suspended in dichloromethane, ether was added and the suspension was filtrated. Evaporation of the organic phase gave 0.74 g of the title compound as dark brown oil.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9](Br)=[CH:8][CH:7]=[CH:6][C:5]=12.C([O:13][B:14](OCC)[O:15]CC)C.[Li]CCCC.[Cl-].[NH4+]>O1CCCC1.CCCCC>[N:1]1[O:2][N:3]=[C:4]2[C:9]([B:14]([OH:15])[OH:13])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Brc1cccc2nonc12
Reactant: CCOB(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: OB(O)c1cccc2nonc12
Reaction time: 0.08 h
Yield: 32 %

Procedure:
To a solution of 4-benzo[c]furazanyl bromide (4 g, 0.020 mol) in tetrahydrofurane (80 ml) and n-pentane (20 ml) is added triethylborate (3.8 ml, 0.022 mol) and N,N,N,N-tetraethylendiamine (3 ml, 0.02 mol). Then, n-BuLi (8.8 ml, 2.5N in hexane, 0.022 mol) is added dropwise at -100° C. and the solution is stirred for 5 minutes more. The reaction mixture is poured into an aqueous solution of saturated ammonium chloride and the water phase is extracted with ethyl acetate. The organic solvent is removed and the crude product is taken up in dichloromethan/n-hexane (5:6). The suspension is filtered to yield the title compound (1.05 g) which is used without further purification.
Reaction SMILES: CO[C:3]1[N:8]=[N:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O>>[Cl:14][C:3]1[N:8]=[N:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)nn1
Reactant: O=S(Cl)Cl
Product: O=C(O)c1ccc(Cl)nn1
Temperature: 25 °C
Yield: 100 %

Procedure:
Potassium dichromate (3.3 g, 11.2 mmol) was added in portions to a solution of 3-Chloro-6-methyl-pyridazine (1.2 g, 9.3 mmol) in H2SO4 (10 ml). After addition the mixture is stirred at 50° C. on. The reaction was pored on ice and the mixture was extracted three times with diethyl ether. The combined organic phases were dried and concentrated to give the title compound (840 mg, 57%). LC-MS (M++1): 159 and 161 (3:1). Step 2: 6-Chloro-pyridazine-3-carboxylic acid methyl ester: A solution of 6-chloro-pyridazine-3-carboxylic acid (700 mg, 4.53 mmol) in thionyl chloride (15 ml) was refluxed for 3 h. The reaction was cooled to ambient temperature and evaporated to dryness. Sodium methoxide (244 mg, 4.53 mmol) in MeOH (20 ml) was added to the residue and the solution was stirred on at room temperature (rt). H2O was added and the mixture was extracted three times with DCM. The combined organic phases were dried and concentrated. Flashchromatography (SiO2, Heptane/EtOAc 1:1) afforded 560 mg (72%) of the title compound. 1H NMR (CDCl3), δ (ppm): 4.09 (s, 3 H), 7.69 (d, 1 H), 8.18 (d, 1 H).LC-MS (M++1): 173 and 175 (3:1). Step 3: 6-Methoxy-pyridazine-3-carboxylic acid methyl ester: A solution of 6-chloro-pyridazine-3-carboxylic acid methyl ester in NaOMe in MeOH (1M, 10 ml) was refluxed on. H2O was added and the mixture was extracted three times with DCM to give organic phase I. The combined organic phases I were dried and concentrated to give the title compound (40 mg, 10%). The water phase was acidified with concentrated hydrochloric acid and extracted three times with DCM to give organic phase II. The combined organic phases II were dried and concentrated to give 6-methoxy-pyridazine-3-carboxylic acid (LC-MS (M++1): 155) (230 mg, 65%). A solution of 6-methoxy-pyridazine-3-carboxylic acid in thionyl chloride (6 ml) was refluxed for 3 h. The reaction was cooled to ambient temperature and evaporated to dryness. MeOH (10 ml) was added to the residue and the solution was stirred on at rt. Saturated NaHCO3 (aq) was added and the mixture was extracted three times with DCM. The combined organic phases were dried and concentrated to give the title compound (253 mg, 100%). LC-MS (M++1): 169. Step 4: 4-Ethyl-5-(6-methoxy-pyridazin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thione: NaOMe (86 mg, 1.6 mmol) was added to a solution of 6-methoxy-pyridazine-3-carboxylic acid methyl ester (210 mg, 1.25 mmol) and 4-ethyl-3-thiosemicarbazide (190 mg, 1.6 mmol) in MeOH (6 ml) and the mixture was heated to 70° C. at 72 h. The reaction was cooled to ambient temperature and evaporated to dryness. H2O (10 ml) was added to the residue and the mixture was acidified with concentrated hydrochloric acid and the title compound 35 mg (12%) was collected by filtration. LC-MS (M++1): 238.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](C)=[CH:3]1.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1C.CNC1C=CC=CC=1.C(O)C(O)C.C=CC>>[CH3:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][NH:2]2.[CH3:1][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[CH:14][NH:13]2)=[CH:17][CH:18]=1
Reactant: Cc1cc2ccccc2n1C
Reactant: Cc1cn(C)c2ccccc12
Solvent: C=CC
Solvent: CNc1ccccc1
Solvent: CC(O)CO
Product: Cc1ccc2cc[nH]c2c1
Product: Cc1cccc2[nH]ccc12

Procedure:
The indoles prepared by the above-mentioned method of the present invention include, for example, indole, 1-methylindole, 1-ethylindole, 1-phenylindole, 1-benzylindole, 3-methylindole, 4-methylindole, 5-methylindole, 6-methylindole, 7-methylindole, 1,2-dimethylindole, 1,3-dimethylindole, 1,4-dimethylindole, 1,5-dimethylindole, 1,6-dimethylindole, 1,7-dimethylindole, 3,4-dimethylindole, 3,5-dimethylindole, 3,6-dimethylindole, 3,7-dimethylindole, 1-ethyl-2-methylindole, 1-ethyl-3-methylindole, 1-ethyl-4-methylindole, 1-ethyl-5-methylindole, 1-ethyl-6-methylindole, 1-ethyl-7-methylindole, 1,3-diethylindole, 1,3,7-trimethylindole, 1,3,4-trimethylindole, 1,3,5-trimethylindole, 1,3,6-trimethylindole, 1,2,5-trimethylindole, 1-ethyl-2,5-dimethylindole, 1-ethyl-3,5-dimethylindole, 1-ethyl-3,6-dimethylindole, 1-ethyl-3,7-dimethylindole, 1-benzyl-3-methylindole, 1-methyl-5-methoxyindole, 1,3-dimethyl-5-methoxyindole, 1-benzyl-5-methoxyindole and the like. Concomitantly, two kinds of indoles may be obtained depending on the starting compounds used. For example, 1,3-dimethylindole and 1,2-dimethylindole are obtained by using N-methylaniline and propylene glycol (or propylene (oxide) as the starting compounds. On the other hand, 4-methylindole and 6-methylindole are obtained by using m-toluidine and ethylene glycol as the starting compounds.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17]([O:19][C:20]([C:22]1[O:23][C:24]([CH2:27]Cl)=[CH:25][CH:26]=1)=[O:21])[CH3:18]>CN(C)C=O>[CH2:17]([O:19][C:20]([C:22]1[O:23][C:24]([CH2:27][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[CH:25][CH:26]=1)=[O:21])[CH3:18]
Reactant: Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(COc2ccc(-c3ccc(C)cc3)cc2)o1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 83.9 %

Procedure:
4′-Methyl-biphenyl-4-ol (Intermediate 5; 2.0 g, 10.9 mmol) was added to a suspension of sodium hydride (60% dispersion; 384 mg, 9.6 mmol) in N,N-dimethylformamide (30 mL) and the mixture was stirred at −5° C. for 20 min. A solution of 5-(chloro-methyl)-furan-2-carboxylic acid ethyl ester (1.6 g, 8.5 mmol) in N,N-dimethylformamide (60 mL) was added and the reaction mixture was stirred overnight at room temperature. The solvents were evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with water and brine, dried (sodium sulfate), filtered, evaporated, and chromatographed, eluting with 0-50% methylene chloride/hexanes to give 5-(4′-methyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid ethyl ester (2.4 g, 84%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)=O.[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21].CCN(CC)CC>ClCCl>[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(methylsulfonyl)benzoic acid 1 (1.0 g, 5 mmol) in 50 mL of dichloromethane was added thionyl chloride (5 mL). The mixture was stirred at ambient temperature for 18 hours. After removal of all solvent, the residue was dissolved in 50 mL of dichloromethane. To the solution was added o-chloroaniline (0.766 g, 6 mmol) followed by 1.4 mL of Et3N. The mixture was stirred at ambient temperature for 2 hours. After washing with 1N HCl and water, the organic layer was concentrated to give N-(2-chlorophenyl)-4-(methylsulfonyl)benzamide 3 as a solid. Yield: 1.18 g, 76%.
Reaction SMILES: C([O-])(O)=O.[Na+].C(#[N:8])C.[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[C:15](Cl)=[O:16])([O-:11])=[O:10]>O>[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[C:15]([NH2:8])=[O:16])([O-:11])=[O:10]
Reactant: CC#N
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5 mg (14 μm) of the L-malic salt was dissolved in a mixture of 1 ml H2O, 3.5 mg (3 meq) NaHCO3, and 1 ml acetonitrile. 3.2 mg (14 μm) 3,5-dinitrobenzoyl chloride was added and the reaction stirred for 16 hr at room temperature. After 5 ml H2O was added, the reaction was vacuum filtered and washed with H2O (2×1 ml portions), cold isopropanol (2×1 ml portions) and diethyl ether (2×2 ml) to isolate 2.5 mg of the 3,5-dinitrobenzamide (85 area % by gradient reverse phase HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.OO.C(OCC)(=O)C.[CH:29]([NH2:31])=[O:30]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:29]([NH2:31])=[O:30])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(COc2cccnc2)cc1
Reactant: NC=O
Agent: O=S(=O)(O)O
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1ccc(OCc2ccc(Cl)cc2)cn1
Reaction time: 8 h

Procedure:
To 3-(4-chlorobenzyloxy)pyridine (2.19 g, 10 mmol) in formamide (10 ml) at 10° is slowly added conc. sulfuric acid. The reaction is then cooled to 5°, and FeSO4.7H2O (4.16 g, 15 mmol), finely powdered, and hydrogen peroxide (1.7 ml of 30% solution, 0.51 g of H2O2, 15 mmol) are added simultaneously over 10 minutes, with rapid stirring and cooling to 12°-18°. After addition is complete, the reaction is allowed to sit at RT overnight. Ethyl acetate and water are added to the reaction slurry. The layers are separated, and the aqueous phase is extracted with ethyl acetate (3×). The combined organic layers are washed with water and with brine and are dried over calcium sulfate. The residue is taken up in ether, leaving an oily residue. The oily residue is then taken up in chloroform, washed with sat. sodium carbonate, with water and with brine and purified by preparative thin layer chromatography (developing with 50% ethyl acetate/hexane and 0.05% ammonium hydroxide). The second band is collected, yielding 5-(4-chlorobenzyloxy)pyridine-2-carboxamide.