Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].CO[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:16]1([O:24]C)[C:17](=[CH:20][CH:21]=[CH:22][CH:23]=1)[O:18]C.Cl.N1C=CC=CC=1>ClCCl>[OH:18][C:17]1[CH:20]=[C:21]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:22]=[CH:23][C:16]=1[OH:24]
Reactant: COC(=O)CCCC(=O)O
Reactant: COc1ccccc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)CCCC(=O)c1ccc(O)c(O)c1

Procedure:
Under the conditions of example 3A, 28.8g of aluminum chloride in 320 ml of dichloromethane is reacted with 11.9g of glutaric acid monomethyl ester chloride and 10g of veratrole, worked up and chromatographed. The thus obtained crude product is further reacted under the conditions of example 3A with 270g of pyridinehydrochloride and worked up. 5.6g of 5-(3,4-dihydroxyphenyl)- 5-oxo-pentanoic acid of melting point 210°-215° C. is obtained as crude product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:15][C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:17]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:15][C@@H:16]1[CH2:17][N:18]([C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH2:19][CH2:20][N:21]1[C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)c1ccnc(Cl)n1
Reactant: C[C@@H]1CN(c2ccc(S(C)(=O)=O)cc2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc(S(C)(=O)=O)cc2)CCN1c1nccc(C(=O)OC(C)(C)C)n1
Temperature: 100 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
Tert-butyl 2-chloropyrimidine-4-carboxylate (70 mg, 0.326 mmol) and (R)-3-methyl-1-(4-(methylsulfonyl)phenyl)piperazine (166 mg, 0.652 mmol) were dissolved in acetonitrile (2 ml), followed by addition of N,N-diisopropylethylamine (0.11 ml, 0.652 mmol), and then the resulting liquid was stirred at 100° C. under nitrogen stream for 24 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (50% EtOAc/Hexanes), to obtain 120 mg of pale yellow solid (85%).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](COC)n1cc(Br)nc(Br)c1=O
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Product: CC[C@H](COC)n1cc(Br)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 150-152° C.; 1H NMR (300 MHz, CDCl3): δ 7.18 (d, J=2.2 Hz, 1 H), 7.12 (s, 1 H), 7.10 (d, J=1.8 Hz, 1H), 4.95-4.90 (m, 1 H), 4.34 (t, J=8.1 Hz, 2 H), 3.67 (dd, J=10.6, 5.8 Hz, 1 H), 3.55 (dd, J=10.6, 3.5 Hz, 1H), 3.35 (s, 3 H), 3.12 (t, J=8.1 Hz, 2 H), 1.92-1.72 (m, 2 H), 0.93 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2BrCl2 (M+H)+: 446.0038; found m/z 446.0008.
Reaction SMILES: C([O:8][C:9](=[O:24])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])C1C=CC=CC=1.CO>O.[Pd]>[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:24])=[O:8])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCCCCCCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
To a solution of N-octanoyl-L-proline benzyl ester (7.04 g) in 1% water-containing methanol (70 ml) was added 10% Pd-C (0.71 g), and the mixutre was stirred under hydrogen atmosphere at room temperature for 1.5 hours. After the catalyst was filtered off, the filtrate was concentrated to give 5.08 g of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:47])([CH3:46])[CH2:9]/[CH:10]=[CH:11]/[C:12](=[O:45])[N:13]([C@@H:15]([C:27](=[O:44])[N:28]([C@H:30]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:31][NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH3:29])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[CH3:14])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:47])([CH3:46])[CH2:9]/[CH:10]=[CH:11]/[C:12]([N:13]([C@@H:15]([C:27](=[O:44])[N:28]([C@H:30]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:31][NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH3:29])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[CH3:14])=[O:45]
Reactant: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)N)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
(3E)-4-(N-((1R)-1-(N-((1R)-1-Benzyl-2-(methylsulfonylamino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamic acid tert-butyl ester (729 mg, 1.07 mmol) was dissolved in dichloromethane (3 ml). The solution was cooled to 0° C. Trifluoroacetic acid (3 ml) was added. The reaction mixture was stirred for 15 min at 0° C. The solvents were removed in vacuo at 20° C. The residue was dissolved in dichloromethane (100 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (60 g), using dichloromethanelmethanol/25% aqueous ammonia as eluent, to give 440 mg of the title compound as free base.
Reaction SMILES: S(Cl)(Cl)(=O)=[O:2].[Cl:6][C:7]1[CH:8]=[C:9]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]3[NH:28][C:27](=[O:29])[O:26][C:25]([CH3:31])([CH3:30])[C:24]=3[CH:32]=2)[CH:10]=[CH:11][C:12]=1[Cl:13]>C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[C:9]([S:14]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]3[NH:28][C:27](=[O:29])[O:26][C:25]([CH3:30])([CH3:31])[C:24]=3[CH:32]=2)=[O:2])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 1 gm (0.0085 mol) of sulfurylchloride in 5 ml of methylene chloride is added dropwise, at -70° C., to a solution of 3.2 gm (0.0075 mol) of 6-[4-(3,4-dichloro-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one in 50 ml of methylene chloride, under stirring, and after it has all been added, stirring is continued at -70° C. for 15 hours. After heating to ambient temperature, aqueous soda solution is added, under vigorous stirring, and the organic phase is separated from the aqueous phase, washed with water, and dried with sodium sulfate. The residue remaining after the methylene chloride has been distilled off is recrystallized from isopropanol/diisopropyl ether.
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[CH3:8][CH:9]([CH3:17])[CH2:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14].IC>O>[CH3:4][CH:12]([C:11](=[O:16])[CH2:10][CH:9]([CH3:17])[CH3:8])[C:13](=[O:15])[CH3:14]
Reactant: C1CCOC1
Reactant: CC(=O)CC(=O)CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(=O)C(C)C(=O)CC(C)C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To 0.1 mol sodium hydride was added 100 ml anhydrous tetrahydrofuran, then added slowly dropwise 0.1 mol 6-methyl-2,4-heptandione at room temperature. The reaction was stirred for 0.5 hours, then 0.12 mol iodomethane was added dropwise and the reaction was stirred at room temperature for further 10 hours. Upon completing the reaction, 20 ml water was added. The mixture was extracted with ethyl acetate. After removing the solvent, distillation under reduced pressure gave a cut fraction 88-9° C./1 kPa (165-166° C. at atmosphere pressure), and the yield was 94%.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]1)#[N:2].[C:16](O)([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)O
Reactant: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid (3.72 g, 17.44 mmol) is dissolved in 20 mL of dichloromethane, cooled to 0° C. and 0.2 g of 4-dimethylaminopyridine (DMAP) is added, followed by t-butyl alcohol and followed by 4.32 g of dicyclohexylcarbodiimide (DCC). This solution is allowed to slowly warm to room temperature over a 76.5-hour period. Thin layer chromotography (TLC) shows mainly product, and some slightly lower Rf by-products. The mixture is stirred one hour and 50 mL of dichloromethane is added and stirring continues five hours. An additional 100 mL of diethyl ether is added and the mixture filtered. The precipitate is washed with diethyl ether. The filtrate is concentrated to an oil. The crude product is chromatographed on silica gel eluting with 4:1 hexane:ethyl acetate. The eluate is concentrated to yield (±)-cis-1,1-dimethylethyl 6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.
Reaction SMILES: CO[C:3](=[O:44])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:34][C:35]2[CH:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][C:36]=2[F:43])[CH:13]2[CH2:18][CH2:17][N:16]([C@H:19]([CH3:33])[CH2:20][CH2:21][NH:22][C:23]([C:25]3[C:26]([CH3:32])=[N:27][CH:28]=[N:29][C:30]=3[CH3:31])=[O:24])[CH2:15][CH2:14]2)=[CH:8][CH:7]=1.[NH3:45]>CO>[C:3]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH2:34][C:35]2[CH:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][C:36]=2[F:43])[CH:13]2[CH2:18][CH2:17][N:16]([C@H:19]([CH3:33])[CH2:20][CH2:21][NH:22][C:23]([C:25]3[C:30]([CH3:31])=[N:29][CH:28]=[N:27][C:26]=3[CH3:32])=[O:24])[CH2:15][CH2:14]2)=[CH:10][CH:11]=1)(=[O:44])[NH2:45]
Reactant: COC(=O)COc1ccc(N(Cc2cc(C#N)ccc2F)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Reactant: N
Solvent: CO
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc(OCC(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
COMPOUND 237 (74 mg, 0.12 mmol) was dissolved in MeOH (15 mL) and NH3(g) was passed through the solution for 10 minutes. The mixture was stirred at room temperature for 1 h then concentrated to give COMPOUND 239 as a yellow foam (72 mg, 100%). 1H NMR (CDCl3) δ 0.92-1.25 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.59 (m, 1H), 1.71-1.82 (m, 3H), 2.17 (m, 1H), 2.50 (s, 6H), 2.55 (m, 1H), 2.75-2.90 (m, 3H), 3.31-3.46 (m, 2H), 3.83 (m, 1H), 3.97 (s, 2H), 4.41 (s, 2H), 5.60 (br s, 1H), 6.60 (d, 2H, J=9.0 Hz), 6.76 (d, 2H, J=9.0 Hz), 7.17 (m, 1H), 7.52 (m, 2H), 8.23 (m, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 13.42, 21.92, 29.40, 30.42, 31.08, 39.81, 42.94, 43.79, 51.92, 58.25, 59.94, 67.83, 108.52, 115.69, 116.49, 116.80, 117.52, 118.34, 129.01, 129.21, 130.68, 132.73, 132.86, 133.32, 133.39, 142.87, 150.71, 157.58, 161.04, 162.97, 164.43, 166.40, 171.31. ES-MS m/z 588 (M+H). Anal. Calcd. for C32H38N7FO3.1.2CH4O: C, 63.69; H, 6.89; N, 15.66; F, 3.03. Found: C, 63.77; H, 6.68; N, 15.53; F, 2.87.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:23][C:12]2=[CH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH2:32][CH:33]([NH2:35])[CH3:34].C(N(CC)C(C)C)(C)C>C(O)CCC>[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH2:32][CH:33]([NH:35][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:23][C:12]2=[CH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1)[CH3:34]
Reactant: CN1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Reactant: CC(N)Cc1cc(F)ccc1F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C)C3=O
Yield: 61.3 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.44 g, 1.34 mmol), 1-(2,5-difluorophenyl)propan-2-amine (0.27 g, 1.61 mmol), n-butanol (30 mL) and N,N-diisopropylethylamine (5 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a brown solid product, 0.38 g, 61.3% yield. MS: 461.9 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 13.40 (s, 1H), 11.31 (s, 1H), 10.92 (d, 1H, J=8.0 Hz), 8.13 (s, 1H), 8.00 (s, 1H), 7.42-7.37 (m, 2H), 7.20-7.18 (m, 1H), 7.09-7.04 (m, 1H), 6.18 (d, 1H, J=8.0 Hz), 4.19-4.14 (m, 1H), 3.06 (s, 3H), 3.04-2.98 (m, 2H), 1.33 (d, 3H, J=6.0 Hz).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH2:12][C:13]([NH2:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCOC(C)=O>CN1CCCC1=O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:11]=[C:10]([CH2:12][C:13]([NH2:15])=[O:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:19][CH2:18]1
Reactant: NC(=O)Cc1nc(Cl)nc2ccccc12
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN1CCN(c2nc(CC(N)=O)c3ccccc3n2)CC1
Temperature: 50 °C

Procedure:
2-(2-chloro-quinazolin-4-yl)-acetamide (221 mg, 1.0 mmol) is dissolved in 1-methyl-2-pyrrolidinone (2.0 mL) and N-methylpiperazine (555 μL, 5.0 eq.) is added. The mixture is heated 45 min. at 50° C. AcOEt is added and the suspension is filtered to afford 2-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-acetamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][C:13]([O:15]CC)=[O:14])=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)Cc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN(C(=O)Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
A solution of ethyl N-(4-chloro-phenylacetyl)-N-phenylglycinate (0.4 g) and 5M NaOH (2.4 ml) in EtOH (12 ml) was refluxed for 2 h. After cooling to rt the mixture was poured into water (30 ml), acidified to pH 2 with 10% HCl and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (20 ml), dried over MgSO4, and evaporated. The crude was purified by flash chromatography on silica gel (hexane/ethyl acetate 3:2+3% formic acid) to afford N-((4-chlorophenylacetyl)-N-phenylglycine (0.1 g) as colourless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([CH:18]=[O:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([Mg]Cl)[CH2:22][CH3:23]>C1COCC1>[CH2:1]([O:8][C:9]1[C:17]([CH:18]([OH:19])[CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc2c(OCc3ccccc3)c(C=O)ccc21
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(O)c1ccc2c(ccn2C)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-(benzyloxy)-1-methyl-1H-indole-5-carbaldehyde (4.57 g, 17.22 mmol) in THF (60 mL) at −78° C. was slowly added a solution of n-PrMgCl (2M Et2O, 13.00 mL, 26 mmol). The mixture was stirred at this temperature for 15 min and then allowed to warm to 0° C. After 1 h the reaction was quenched with NH4Cl (aqueous saturated, 50 mL) and the product was extracted with EtOAc (3×100 mL). The combined organics were washed with NaCl (aqueous saturated, 100 mL) and dried over Na2SO4. The solvents were concentrated to yield 1-(4-(benzyloxy)-1-methyl-1H-indol-5-yl)butan-1-ol as an oil which was used directly in the next step without purification.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:25])[C:18](=O)[NH:19]2.FC1C=C2C(=CC=1)NC(=O)C2=O>>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:25])[C:18]1[N:19]2[C:7](=[O:8])[C:6]2[C:5](=[CH:4][CH:3]=[CH:2][CH:13]=2)[N:11]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Agent: O=C1Nc2ccc(F)cc2C1=O
Product: O=C1c2c(Cl)cccc2-n2c1nc1ccccc1c2=O
Yield: 16 %

Procedure:
Using the procedure in Example 12 and substituting isatoic anhydride for 5-chloroisatoic anhydride and 4-chloroisatin for 5-fluoroisatin gave the title compound in 16% yield: mp 294°-295.7° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H) 8.33 (d, 1H) 7.97 (d, 2H) 7.81-7.90 (m, 1H) 7.72-7.80 (m, 1H) 7.52 (d, 1H); MS (M+H)+ 283.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][CH:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[C:33](=[O:46])[N:34]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:35](=[O:38])[NH:36][N:37]=2)=[O:31])=[CH:25][C:24]=1[F:47].[CH2:48](Br)[C:49]#[CH:50].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][CH:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[C:33](=[O:46])[N:34]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:35](=[O:38])[N:36]([CH2:50][C:49]#[CH:48])[N:37]=2)=[O:31])=[CH:25][C:24]=1[F:47]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4n[nH]c(=O)n(-c5ccc(F)cc5)c4=O)cc3F)c2cc1OC
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C#CCn1nc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)c(=O)n(-c2ccc(F)cc2)c1=O
Yield: 21.8 %

Procedure:
A mixture of example 107 (25 mg, 0.046 mmol), propargyl bromide (10 uL, 0.1 mmol), and potassium carbonate (10 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) was stirred at rt 18 h. The mixture was filtered, solvent was removed and the product was purified by reverse phase HPLC to give an off-white solid (7 mg, 30%). LCMS m/z=586 (M+1); 1H NMR (DMSO) δ: 10.99 (s, 1H), 8.71 (d, 1H, J=6.1 Hz), 8.0 (dd, 1H, J=2.3, 12.7 Hz), 7.68 (s, 1H), 7.65-7.58 (m, 2H), 7.4 (s, 1H), 7.37-7.35 (m, 4H), 6.84 (d, 1H, J=5.8 Hz), 4.88 (d, 2H, J=2.3 Hz), 4.01 (2 s, 6H), 3.53 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].[F-].[K+].[Br:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1F>CS(C)=O.C(OCC)(=O)C>[Br:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9]
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OC(F)F)c(Oc2ccc([N+](=O)[O-])cc2Br)c1
Temperature: 110 °C
Reaction time: 5 h
Yield: 66 %

Procedure:
To a solution of 4-(difluoromethoxy)-3-hydroxy benzaldehyde (8.6 g, 0.046 mol) in dimethylsulphoxide (15 mL) was added potassium fluoride (5.36 g, 0.092 mol) at room temperature. Then it was refluxed to 100-120° C. To this 2-bromo-1-fluoro-4-nitrobenzene (20.3 g, 0.093 mol) in dimethylsulphoxide (10 mL) was added dropwise at 100-120° C. The heating was continued for 5 hours. The reaction mixture was poured into the crushed ice and stirred for 1 hour. Then the aqueous layer was decanted. The solid obtained was dissolved in ethyl acetate (500 mL). The organic layer was washed with water (3×200 mL). The organics were dried over sodium sulphate and filtered. The solvents were removed in vacuum to give the crude product. The product was purified by column chromatography by using gradient (0-2) % of ethyl acetate in hexane. The solid obtained was washed with hexane and dried. Yield—66%. 1H-NMR (DMSO-d6) δ: 7.06 (d, 1H), 7.23-7.41-7.59 (t, 1H), 7.67 (d, 1H), 7.82 (d, 1H), 7.96-7.98 (m, 1H), 8.20-8.23 (m, 1H), 8.61 (d, 1H), 9.97 (s, 1H); HPLC (purity): 99.5%; Mass calculated for C14H8BrF2NO5-388.1, observed—388.1; Rf—0.47 (Ethyl acetate:Hexane (3:7).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:15]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cccc(Cl)c1
Product: COC(=O)c1nc(C)sc1-c1cccc(Cl)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-chloro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.95 min; [M+H]+=268.0.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:47]=[CH:46][C:29]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45])=[CH:28][CH:27]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:48]([O:52][C:53](=[O:56])[CH2:54]Br)([CH3:51])([CH3:50])[CH3:49]>C1COCC1.CN(C=O)C.C1COCC1>[C:48]([O:52][C:53](=[O:56])[CH2:54][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:47][CH:46]=1)([CH3:51])([CH3:50])[CH3:49]
Reactant: OCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCOCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCOCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To an ice-cooled suspension of sodium hydride (180 mg, 4.5 mmol; 60% in mineral oil) in THF/DMF (5/1 mixed solution 7 ml), a solution of Compound 24 (817 mg, 1.28 mmol) in THF (6 ml) was gradually added; this was followed by stirring for 30 minutes. A solution of bromoacetic acid tert-butyl ester (1.0 g, 5.1 mmol) in THF (7 ml) was added thereto. After the ice bath was removed, stirring was further conducted at room temperature for 2 hours. Water was carefully added to stop the reaction, this was followed by extraction from ethyl acetate, and the combined organic phases were washed with saturated brine and dried with anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (ethyl acetate-ethyl acetate solution containing 5% methanol)) to yield Compound 25 (light-yellow oil 655 mg, 68%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:7]([O:9][CH3:10])=[O:8].Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([N:4]2[CH2:5][CH2:6][NH:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]2)=[N:13][CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: COC(=O)C1CNCCN1
Product: COC(=O)C1CN(c2ccc(C#N)cn2)CCN1
Yield: 35 %

Procedure:
This compound was synthesized from methyl piperazine-2-carboxylate and 6-chloronicotinonitrile as described for example 39 step 1 (90 mg, yield 35%). 1H NMR (400 MHz, MeOD) δ 8.42 (dd, J=2.4 Hz, 0.6 Hz, 1H), 7.76 (dd, J=9.0 Hz, 2.3 Hz, 1H), 6.90 (m, 1H), 4.39-4.35 (dd, J=13.2 Hz, 2.6 Hz, 1H), 3.95-3.90 (m, 1H), 3.76 (s, 3H), 3.63-3.60 (dd, J=8.4 Hz, 3.4 Hz, 1H), 3.52-3.47 (dd, J=13.1 Hz, 8.4 Hz, 1H), 3.45-3.39 (ddd, J=13.1 Hz, 9.3 Hz, 3.4 Hz, 1H), 3.13-3.08 (m, 1H), 2.86-2.79 (ddd, J=12.5 Hz, 9.1 Hz, 3.5 Hz, 1H).