Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH2:3]1.ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CN(C=O)C>CCOC(C)=O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH2:3]1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCCC(O)C4)c3n2)c2ccc(Cl)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4CCCC(=O)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
A 25 mL round-bottom flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-cyclohexyl) amide (22 mg, 0.052 mmol) and dichloromethane (5 mL). Dess-Martin periodinane (34.0 mg, 0.08 mmol) was added in one portion to the reaction mixture. The reaction mixture was placed under Ar and stirred for 2 h at room temperature. DMF (1.5 mL) was added and the reaction mixture was stirred for an additional 18 h. The reaction mixture was diluted to 100 mL with EtOAc and washed with sat NaHCO3 (3×20 mL). The crude white precipitate was filtered and reserved. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a crude solid. The combined crude solids were triturated with EtOAc (1×20 mL) then purified by chromatography over SiO2 with MeOH/dichloromethane (gradient: 0%-5% MeOH) to afford 6 mg (27%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-oxo-cyclohexyl)-amide as a white solid. MS: [M+H]+=423, 1H NMR (300 MHz, DMSO-d6) δ: 12.89 (br. s., 1H), 9.09 (s, 1H), 8.47 (s, 1H), 8.42 (d, J=8.7 Hz, 1H), 8.16 (d, J=7.6 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.39 (dd, J=8.7, 1.9 Hz, 1H), 4.23-4.41 (m, 1H), 4.18 (s, 3H), 2.69-2.78 (m, 1H), 2.58 (d, J=10.2 Hz, 1H), 2.42 (dd, J=11.1, 5.9 Hz, 1H), 2.17-2.34 (m, 2H), 1.96-2.08 (m, 1H), 1.80-1.93 (m, 1H), 1.65-1.80 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:34])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:12][C:11]=2[N+:35]([O-:37])=[O:36])[C:7](=[O:38])[C:6]=1[CH2:39]Cl)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].C([NH:52][C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][CH:54]=1)(=O)C>CC(C)=O>[C:1]([C:5]1[O:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:34])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:12][C:11]=2[N+:35]([O-:37])=[O:36])[C:7](=[O:38])[C:6]=1[CH2:39][O:59][C:56]1[CH:57]=[CH:58][C:53]([NH2:52])=[CH:54][CH:55]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCNC(=O)c1ccc(-n2oc(C(C)(C)C)c(CCl)c2=O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCNC(=O)c1ccc(-n2oc(C(C)(C)C)c(COc3ccc(N)cc3)c2=O)c([N+](=O)[O-])c1
Yield: 79.4 %

Procedure:
5.8 g of 5-t-butyl-4-chloromethyl-2-(4-n-hexadecylcarbamoyl-2-nitrophenyl)-4-isooxazolin-3-one and 1.4 g of potassium carbonate were mixed with 40 ml of acetone, and thereto were added 0.4 g of sodium iodide and 0.4 ml of polyethylene glycol. Thereto, 1.7 g of 4-acetylaminophenol was further added, and the resulting mixture was heated under reflux for 5 hours. After the completion of the reaction, crystals were precipitated by addition of diluted hydrochloric acid, and then filtered off. To the crystals taken out were added 40 ml of ethanol and 20 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 4 hours. After cooling, crystals separated out on stirring. They were filtered off, and washed successively with acetonitrile and acetone. Yield: 5.5 g, Percent yield: 79.4%, Melting point: 220° C. or higher.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[O:11][CH:12]=[C:13]([CH3:15])[N:14]=1)=S.[N:16]#[C:17][NH2:18].[Pb]>>[C:17]([NH:18][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[O:11][CH:12]=[C:13]([CH3:15])[N:14]=1)#[N:16]
Reactant: N#CN
Reactant: CNC(=S)NCCCSc1nc(C)co1
Agent: [Pb]
Product: CNC(=NCCCSc1nc(C)co1)NC#N

Procedure:
Reaction of N-methyl-N'-[3-(4-methyl-2-oxazolyl)thiopropyl]thiourea with lead cyanamide by the procedure of Example 121 gives the title compound.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[N-:4]=[C:5]=[O:6].[C:7]1([CH2:13]C2C=CC=CC=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N(C=O)C1C=CC=CC=1>>[CH3:13][C:7]1[C:8]([N:4]=[C:5]=[O:6])=[CH:9][C:10]([N:1]=[C:2]=[O:3])=[CH:11][CH:12]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: [N-]=C=O
Agent: O=CNc1ccccc1
Product: Cc1ccc(N=C=O)cc1N=C=O

Procedure:
7 g of the addition compound described in Example 22, 1 g of a polysiloxane-polyalkylene glycol of Example 32 (foam stabilizer) and 200 g of a mixture of 70% by weight of crude diphenylmethane diisocyanate which had been prepared by aniline formaldehyde condensation followed by phosgenation, and 30% by weight of the distillation residue obtained from the preparation of tolylene diisocyanate were vigorously stirred together as described in Example 36. The isocyanate mixture has an isocyanate content of 29.1% and a viscosity of 1030 cP/25° C. This mixture was then heated to 150° C. for 30 minutes.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:13][NH:14][CH:15]=2)C=CC=CC=1.BrCCCC.N1C=CC=C(C2C(O)=CN(COCC[Si](C)(C)C)N=2)C=1>CCOCC.C(OCC)(=O)C>[CH2:9]([O:10][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][NH:14][CH:15]=1)[CH2:8][CH2:7][CH3:1]
Reactant: c1ccc(CCCOc2c[nH]nc2-c2cccnc2)cc1
Agent: C[Si](C)(C)CCOCn1cc(O)c(-c2cccnc2)n1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCBr
Product: CCCCOc1c[nH]nc1-c1cccnc1
Yield: 30 %

Procedure:
Compound 32C was prepared following the procedure as described for the synthesis of compound 32A (see Scheme 5) using 1-bromo-butane as the alkyl halogenide and 3-pyridin-3-yl-1-(2-trimethylsilanyl-1-ethoxymethyl)-1H-pyrazol-4-ol (30). Work-up and flash chromatography (ethyl acetate/diethyl ether 1/1) afforded compound 31C. Yield 30% (oil). 1H-NMR (major isomer is given, 400 MHz, CDCl3): δ 8.9 (d, J=2 Hz, 1H), 8.6 (dd, J=5 Hz, 2 Hz, 1H), 8.05 (dt, J=8 Hz, 2 Hz, 1H), 7.42 (s, 1H), 7.41-7.37 (m, 1H), 5.37 (s, 2H), 3.98 (t, J=7 Hz, 2H), 3.74-3.68 (m, 2H), 1.74-1.66 (m, 2H), 1.49-1.39 (m, 2H), 0.92 (t, J=7 Hz, 3H), 0.02 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.C(Cl)(=O)C(Cl)=O.[CH:39]1([NH2:42])[CH2:41][CH2:40]1.[OH-].[Na+].Cl>CN(C)C=O.CO.O1CCCC1>[CH:39]1([NH:42][C:19]([C:18]2[CH:22]=[CH:23][C:15]([C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:7]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[C:6]=3[C:4]([OH:3])=[O:5])=[CH:16][CH:17]=2)=[O:20])[CH2:41][CH2:40]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1c(-c2ccc(C(=O)O)cc2)c2ccccc2n1Cc1cccc(OC)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc(Cn2c(C(=O)O)c(-c3ccc(C(=O)NC4CC4)cc3)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a 25 mL round-bottomed flask at rt was charged with 4-{2-(ethoxycarbonyl)-1-[(3-methoxyphenyl)methyl]indol-3-yl}benzoic acid (Example 98, 270 mg, 0.63 mmol), tetrahydrofuran (2 mL) and one drop of N,N-dimethylformamide. Oxalyl chloride (240 mg, 0.16 mL, 1.89 mmol) was added to the above mixture dropwise. After 1 hour, the reaction mixture was concentrated and re-dissolved in tetrahydrofuran (2 mL) and cyclopropylamine (359 mg, 6.3 mmol) was added. After 10 minutes at rt, aqueous sodium hydroxide (3 N) was added to the reaction mixture and enough methanol was added to make the mixture one phase. The resulting solution was refluxed for 1 hour before it was cooled to rt and acidified with hydrochloric acid (1N) and extracted with ethyl acetate (25 mL). The organic layer was washed with water, brine and dried over anydrous sodium sulfate. The solution was concentrated in vacuo to give a white solid which was triturated with diethyl ether to provide 3-[4-(N-cyclopropylcarbamoyl)phenyl]-1-[(3-methoxyphenyl)methyl]indole-2-carboxylic acid as a white solid (142 mg, 51%): mp 237° C.; MS (electrospray, MH+) calcd for C27H25N2O4 441, found 441; 1H NMR (DMSO-d6) δ 13.1 (br s, 1H), 8.48 (d, J=4.0 Hz, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.1 Hz, 1H), 7.30-7.37 (m, 1H), 7.12-7.22 (m, 2H), 6.79 (dd, J=8.2, 2.5 Hz, 1H), 6.69 (dd, 1H), 6.62 (d, J=7.6 Hz, 1H), 5.83 (s, 2H), 3.68 (s, 3H), 2.85-2.89 (m, 1H), 0.56-0.64 (m, 2H), 0.65-0.75 (m, 2H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1cncn1C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cncn4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 18 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 5-ethynyl-1-methyl-1H-imidazole (Aldrich) in the same manner as Example 15. ESI MS m/z 538 [C26H31N7O4S+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.C(N(CC)CC)C.Cl[CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28].O>C1(C)C=CC=CC=1.CN(C)C=O.ClCCl>[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12
Reactant: Cc1nccn2c(C3CCNCC3)nc(Br)c12
Reactant: CN(C)C(=O)CCl
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1nccn2c(C3CCN(CC(=O)N(C)C)CC3)nc(Br)c12
Yield: 58.8 %

Procedure:
To 1-bromo-8-methyl-3-(piperidin-4-yl)imidazo[1,5-a]pyrazine (0.447 mmol, 132 mg) in toluene (1 ml) and N,N-dimethylformamide (1 ml) were added triethylamine (0.894 mmol, 0.125 ml) and 2-chloro-N,N-dimethylacetamide (0.447 mmol, 0.046 ml). After stirring at room temperature for two hours water and dichloromethane were added, mixture was put on a phase separation filter and concentrated in vacuo. Purification by column chromatography (silica gel; dichloromethane with gradient 0 to 20% methanol) gave 2-(4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)piperidin-1-yl)-N,N-dimethylacetamide (100 mg).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[CH:23][C:22]=3[O:34][CH3:35])=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl.C([O:43]CC)C.CCCCCC>CC(C)=O>[CH3:35][O:34][C:22]1[CH:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:25]=[CH:26][C:21]=1[C:19]([N:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][N:14]2[C:5]([C:3]([OH:4])=[O:43])=[CH:6][CH:7]=[C:8]2[CH2:9]1)=[O:20]
Reactant: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: CCOCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trichloro-1-{10-[(3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step E (1.6 g, 2.9 mmol) in acetone (20 mL) was added 2.5 N sodium hydroxide (2.3 mL, 5.8 mmol). After stirring overnight, the reaction was acidified with 2 N hydrochloric acid (3.2 mL, 6.4 mmol) then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Trituration with diethyl ether/hexane provided 1.2 g of desired product as an off-white solid, m.p. 201–204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9](Cl)[N:8]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].N12CCCN=C1CCCCC2.O>C(O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:9]2[CH:10]=[N:11][CH:12]=[C:7]([NH:6][CH2:5][C:4]3[CH:14]=[CH:15][CH:16]=[C:2]([Cl:1])[CH:3]=3)[N:8]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cccc(CNc2cncc(Cl)n2)c1
Solvent: CCO
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(NCc3cccc(Cl)c3)n2)CC1
Temperature: 25 °C

Procedure:
A mixture of (3-chloro-benzyl)-(6-chloro-pyrazin-2-yl)-amine (I-2a) (71.0 mg, 0.28 mmol), piperazine-1-carboxylic acid tert-butyl ester (260.2 mg, 1.40 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (208.9 μL, 1.40 mmol) in 1.0 mL of ethanol was refluxed for 18 h under nitrogen. The reaction was then cooled to ambient temperature and poured into 20 mL of water. This was extracted 2×30 mL of ethyl acetate and the combined organic extracts were washed with 3×15 mL water followed by 15 mL of brine. The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo to a yellow residue that was chromatographed (prep. TLC, 1:1 hexane:ethyl acetate) to give the title compound (I-2b) as a white solid, 13.5 mg.
Reaction SMILES: [CH2:1]=O.[Cl:3][C:4]1[C:5]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([NH2:30])=[O:29])[C:21]=3[CH:20]=2)=[N:6][C:7]([NH:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[N:8][CH:9]=1.[BH4-].[Na+].[ClH:33]>CO.ClCCl>[ClH:3].[ClH:33].[Cl:3][C:4]1[C:5]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([NH2:30])=[O:29])[C:21]=3[CH:20]=2)=[N:6][C:7]([NH:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:1])[CH2:15][CH2:14]2)=[N:8][CH:9]=1
Reactant: C=O
Reactant: NC(=O)c1cccc2sc(-c3nc(NCCC4CCNCC4)ncc3Cl)cc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Aqueous formaldehyde (37.4% or 13.5 M, 0.134 mL, 1.80 mmol) is added to a stirred solution of 2-[5-chloro-2-(2-piperidin-4-ylethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid amide (150 mg, 0.361 mmol) in CH3OH (15 mL) and dichloromethane (15 mL) at room temperature to form a light suspension. The mixture is allowed to stir for 90 minutes. The mixture is cooled to 0° C. before it is treated with powdered sodium borohydride (68.1 mg, 1.80 mmol). The mixture is stirred at 0° C. for 1 hour, then allowed to slowly warm up to room temperature to form a clear solution. After concentration, the crude product is subject to chromatographic purification on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane 4-12%, to give the desired methylated product as a yellowish solid. The free base is dissolved in CH3OH (20 mL) and dichloromethane (20 mL) then treated with 12 N HCl (0.30 mL) to form a yellow solution. After concentration and vacuum drying at 60° C., the title compound is obtained as a yellow solid (174 mg, 95% yield). ES+(m/z) 430 (35Cl) and 432 (37Cl) [M(free base)+H].
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].[BH4-].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)Cl>[I:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[CH2:8][OH:9]
Reactant: Cc1cccc(C(=O)O)c1I
Agent: [Al+3]
Agent: [BH4-]
Agent: [H-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cccc(CO)c1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.6 %

Procedure:
Thionyl chloride (6 mL) was added over 1 min to a 0° C. solution of 2-iodo-3-methyl benzoic acid (3.0 g, 11.4 mmol) in DCM (10 mL). The solution was stirred for 24 h at rt and the volatile components were removed in vacuo. A portion of the crude acid chloride (955 mg) was dissolved in THF (15 mL) and NaBH4 (380 mg, 10 mmol) was added. After stirring for 90 min, multiple spots were evident by TLC analysis. The reaction mixture was cooled to −78° C. and solid LiAlH4 (300 mg, 7.91 mmol) was added. The reaction was stirred for 30 min, after which TLC analysis showed one major spot. The reaction was quenched by addition of EtOAc (10 mL) and was slowly poured into a vigorously stirred solution of HCl (1M, 30 mL). EtOAc (70 mL) was added, the layers were separated, and the organic layer was washed with NaHCO3 (3×15 mL), water (15 mL), brine (40 mL), and was dried over sodium sulfate. Removal of the solvent in vacuo yielded the title compound (752 mg, 89%) as a thick oil which was used without further purification. 1H-NMR (CDCl3): δ 7.27 (m, 2H), 7.20 (m, 2H), 4.74 (m, 2H), 2.50 (s, 3H), 2.0 (br s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br-].[O:14]1CCO[CH:15]1[CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC.Cl>ClCCl.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:19][CH:15]=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc2ncccc2c1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=CC=Cc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A mixture of 6-quinolinecarboxaldehyde (1.58 g, 10.05 mmol, prepared as described in U.S. Pat. No. 5,559,256), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (6.45 g, 15.02 mmol), and TDA-1 (3.20 mL, 10.00 mmol) in dichloromethane (50 mL) and sat. aq. K2CO3 (50 mL) was heated to reflux for 5 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. THF (25 mL) and 10% HCl (25 mL) were added and the mixture was stirred for 1 h at rt. The reaction mixture was cooled to 0° C., made basic with 10% NaOH, and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. Chromatography (SiO2, 1:1 hexane/ethyl acetate+0.2% triethylamine) provided a yellow solid that was partioned between ethyl acetate (20 mL) and 10% HCl (15 mL). The aqueous layer was washed with ethyl acetate (2×20 mL) and then made basic with 10% NaOH. The precipitated solids were collected by filtration, washed with water, and dried in vacuo to give 1.20 g (65%) of the title compound as a light yellow solid. MS 184 (M+H)+.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.C([O:16][C:17](=[O:19])[CH3:18])(=O)C>B(F)(F)F.CCOCC>[C:4]([O:12][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][C:1](=[O:12])[CH3:2])=[CH:3][C:2]=1[O:16][C:17](=[O:19])[CH3:18])(=[O:11])[CH3:3]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)Oc1cc(OC(C)=O)c2ccccc2c1OC(C)=O
Temperature: 25 °C

Procedure:
A solution of 1,4-naphthoquinone (79 g) in acetic anhydride (200 mL) and boron trifluoride etherate (10 mL) was heated overnight, then cooled to room temperature to give 1,2,4-triacetyloxynaphthalene, m.p. 136°-137° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:10]1[O:12][C@@H:11]1[CH2:13]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.O>CN(C)C=O>[C:1]1([O:7][CH2:13][C@@H:11]2[O:12][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(OC[C@H]2CO2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of phenol (336 mg) in anhydrous N,N-dimethylformamide (16 mL) was added sodium hydride (60% in mineral oil, 190 mg). The mixture was stirred for 1 h and (2S)-(+)-glycidyl 3-nitrobenzene sulfonate (1.0 g) in N,N-dimethylformamide (5 mL) was added. The mixture was heated to 60° C. and stirred for 30 min. The reaction was allowed to cool to room temperature, water (100 mL) was added and the mixture was extracted with 2:1 hexane:ethyl acetate (2 times 40 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to supply the crude product. Purification by silica gel chromatography (eluting with 10:1 hexane: ethyl acetate) afforded the title compound (474 mg) as a colorless oil.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.S(Cl)([Cl:16])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:16][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-n2nccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1ccc(-n2nccn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 50.58 g (289 mmol) of (4-[1,2,3]triazol-2-yl-phenyl)-methanol in 2000 ml of CH2Cl2, 31.59 ml (433 mmol) of thionyl chloride is added dropwise at 0–5° C. and the reaction mixture is allowed to warm to r.t. After stirring for 16 h, the reaction mixture is basified with sat. NaHCO3 at 0–5° C. and extracted with CH2Cl2. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6]2.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[C:7]([C:12]([OH:14])=[O:13])=[CH:6]2
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)n2c(C(=O)O)cc3cc(OC)ccc32)cc1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of commercially available 5-methoxyindole-2-carboxylic acid (6.69 g, 35 mmol) and triethylamine (10 mL, 71.7 mmol) in anhydrous CH2Cl2 (70 mL) containing catalytic amount of DMAP was added dropwise a solution of 4-methoxybenzoyl chloride (6.20 g, 36.34 mmol) in CH2Cl2 (15 mL) at 0° C. The reaction mixture was stirred at this temperature for 15 min and then at room temperature for 4 hours. The reaction mixture was washed successively with 5% aqueous KHSO4 solution (2×20 mL), brine (25 mL), dried over Na2SO4, and evaporated under reduced pressure to dryness. The solid residue was recrystallized from methanol to yield 5-methoxy-1-(4′-methoxybenzoyl)-1H-indole-2-carboxylic acid as a white solid (7.4 g, 65%): mp 185-187° C.; 1H NMR (DMSO-d6) δ 3.80 and 3.85 (each 3H, s, 2×OMe), 7.02 (1H, dd, J=2.5 Hz and J=9.0 Hz, ArH), 7.07 (2H, d, J=8.9 Hz, 2×ArH), 7.28 (1H, d, J=2.5 Hz, ArH), 7.33 (1H, s, ArH), 7.38 (1H, d, J=9.0 Hz, ArH), 7.59 (2H, d, J=8.9 Hz, 2×ArH), 13.2 (1H, brs, exchangeable, OH). Anal. Calcd. for C18H15NO5.0.1H2O: C, 65.73; H, 4.65; N, 4.25. Found: C, 65.77; H, 4.61; N, 4.24.