Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[C:20]3[CH:26]=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:33]([O:37][C:38]([N:40]1[C:44]([CH3:46])([CH3:45])[CH2:43][CH2:42][C@H:41]1[C@H:47]([C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=1)[C:48](O)=[O:49])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:57][C:54]1[CH:53]=[CH:52][C:51]([C@@H:47]([C@H:41]2[N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[C:44]([CH3:46])([CH3:45])[CH2:43][CH2:42]2)[C:48](=[O:49])[N:30]2[CH2:29][CH2:28][N:27]([C:19]3[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:23][N:22]=[C:21]4[NH:24][N:25]=[CH:26][C:20]=34)[CH2:32][CH2:31]2)=[CH:56][CH:55]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Cl)cc2)CCC1(C)C
Reactant: c1ccc(-c2cnc3[nH]ncc3c2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2CCN(c3c(-c4ccccc4)cnc4[nH]ncc34)CC2)c2ccc(Cl)cc2)CCC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
DIEA (0.0475 mL, 0.273 mmol) was added to a solution of 5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.030 g, 0.0681 mmol, See Example 1), (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (0.0251 g, 0.0681 mmol, see Example D) and TBTU (0.0263 g, 0.0818 mmol) in DCM (1 mL) and stirred at room temperature for 16 hours. The mixture was directly loaded onto a silica column and purified by chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 5-((S)-1-(4-chlorophenyl)-2-oxo-2-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)ethyl)-2,2-dimethylpyrrolidine-1-carboxylate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-2-((S)-5,5-dimethylpyrrolidin-2-yl)-1-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)ethanone (0.019, 46%). MS APCI (+) m/z 529.3 detected.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][C:18]([CH2:30][CH2:31][OH:32])([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1.Cl>C(Cl)Cl.O>[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([S:58]([O:32][CH2:31][CH2:30][C:18]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[O:19][CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:4]=3)[CH2:17]2)(=[O:60])=[O:59])=[CH:54][CH:53]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCOC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC2(c3ccc(Cl)c(Cl)c3)CN(C(=O)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCO2)cc1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of 2-[4-{[3,5-bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol obtained in Reference Example 2 (2.3 g, 4.3 mmol) in methylene chloride (23 ml) were added dimethylaminopyridine (0.05 g, 0.43 mmol) and triethylamine (0.9 ml, 6.5 mmol) under a nitrogen stream, the resulting mixture was cooled to 0-5° C., and then a solution of 4-methylbenzenesulfonyl chloride (1.1 g, 5.6 mmol) in methylene chloride (7 ml) was further added dropwise at below 10° C. After stirring at room temperature for 8 hours, water (23 ml) and concentrated hydrochloric acid (1 ml) were added to the reaction mixture, and the resulting mixture was partitioned. The separated organic layer was washed with water (30 ml) and evaporated to dryness. The residue obtained was purified by chromatography on a silica gel column and then crystallized from a mixed solvent of toluene (3.2 ml) and methylcyclohexane (32 ml) under ice-cooling to afford the title compound [1.9 g, yield: 63.9%] as a colorless crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[CH2:7][N:8]([C:18](=[O:46])[C@H:19]([CH3:45])[NH:20][C@H:21]([C:42]([OH:44])=[O:43])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28][CH2:27]1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6](=[O:47])[CH2:7][N:8]([C:18](=[O:46])[C@H:19]([CH3:45])[NH:20][C@H:21]([C:42]([OH:44])=[O:43])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H](N[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: [Pd]
Solvent: CO
Product: C[C@H](N[C@@H](CCCCC1CCNCC1)C(=O)O)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
In 20 ml of methanol is dissolved 0.5 g of N-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-carboxypentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester, and a catalytic reduction is carried out at ambient temperature and under atmospheric pressure using 10% palladium-carbon (50% wet., 0.5 g) as a catalyst. After stirring at room temperature for 4 hours, the catalyst is filtered off, and the filtrate is concentrated under reduced pressure to give 0.28 g of N-[N-[(S)-5-(4-piperidyl)-1-carboxypentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Oc1ccc(-c2cc3ccc(O)cc3s2)cc1
Product: O=C(Oc1ccc(-c2cc3ccc(OC(=O)c4ccccc4)cc3s2)cc1)c1ccccc1

Procedure:
2-(4-Hydroxyphenyl)-6-hydroxybenzo[b]thiophene and benzoyl chloride were converted to the title compound by the procedure of Example 3 to yield a white crystalline solid. mp 216° C.-218° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]2[N:17]=[C:16]([N:18]3[C@@H:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][O:20][C:19]3=[O:26])[CH:15]=[CH:14][N:13]=2)[CH3:10])=[CH:5][CH:4]=1.CS([Cl:31])(=O)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:31][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]2[N:17]=[C:16]([N:18]3[C@@H:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][O:20][C:19]3=[O:26])[CH:15]=[CH:14][N:13]=2)[CH3:10])=[CH:5][CH:4]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CO)cc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CCl)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-3-(2-((S)-1-(4-(hydroxymethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (71 mg, 0.2 mmol) in DCM (2 mL) was added methanesulfonyl chloride (27 mg, 0.24 mmol) and DIPEA (0.070 mL, 0.4 mmol). The solution was stirred for 16 h at room temperature then washed with water and brine. After separation, the organic phase was dried over Na2SO4, filtered and concentrated. The crude product was used to next step without further purification.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][N:55]([CH2:62][CH2:63]O)[C:56]1[CH:61]=[CH:60][N:59]=[N:58][CH:57]=1.Cl>C(Cl)Cl.C(Cl)Cl.CO>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:63][CH2:62][N:55]([CH3:54])[C:56]4[CH:61]=[CH:60][N:59]=[N:58][CH:57]=4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: CN(CCO)c1ccnnc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN(C)c1ccnnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (128 mg, 0.4 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (314 mg, 1.2 mmol) and 2-(N-methyl-N-(pyridazin-4-yl)amino)ethanol (80 mg, 0.52 mmol) in methylene chloride (5 ml) and the mixture stirred for 2 hours at ambient temperature. The solvent was removed by evaporation, the residue was triturated with ether and the resulting solid was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/methanol (9/1 followed by 8/2) to give a white solid. This solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (0.5 ml of a 4M solution) was added. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(pyridazin-4-yl)amino)ethoxy)quinazoline hydrochloride (110 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:15])([F:14])[C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[OH-].[K+].O.C(Cl)(=O)C([Cl:22])=O>C(O)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:15])([F:14])[C:9]([Cl:22])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)C(F)(F)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(Cl)C(F)(F)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
Ethyl 4-chlorophenyl-2,2-difluoroacetate (250 mg) and potassium hydroxide (300 mg) were mixed in 27 ml of ethanol and 2.4 ml of water and the reaction mixture was refluxed for four hours. The mixture was then acidified and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4 and the solvent was removed in vacuo to give a product which was dissolved in 410 mg of oxalyl chloride with catalytic amount of N,N-dimethylformamide. The mixture was stirred for two hours and excess oxalyl chloride was removed in vacuo to give 4-chlorophenyl-2,2-difluoroethanoyl chloride which was used as is for the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3[CH:18]=[C:17](I)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[CH2:27]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3[CH:18]=[C:17]([CH:27]=[CH:26][C:25]4[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: C=Cc1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCN1c2ncc(C=Cc3cccc(F)c3)cc2C(=O)N(C)c2ccc(Cl)nc21

Procedure:
By a procedure analogous to that described in Example 1h, 2-chloro-5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one was coupled with 3-fluorostyrene in the presence of bis(triphenylphosphine)palladium(II) chloride and triethylamine. The product was hydrogenated by a procedure analogous to that described in Example 15 to give 16 mg of the title compound, m.p. 130°-131° C. (ethyl acetate/hexanes).
Reaction SMILES: [C:1]1([C:7]2[C:18]3[CH2:17][C:16]([CH3:19])=[CH:15][C:14]=3[CH:13]=[C:12]3[C:8]=2[CH2:9][CH2:10][CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[Si:26]([CH:29]1[C:37]2[C:32](=[C:33]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[CH:44]([CH3:46])[CH3:45])([CH3:28])[CH3:27].[Cl-].[NH4+]>C(OCC)C.CCCCCC.[Cu](C#N)C#N>[CH3:27][Si:26]([CH3:28])([CH:11]1[C:12]2[C:8](=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:18]3[CH2:17][C:16]([CH3:19])=[CH:15][C:14]=3[CH:13]=2)[CH2:9][CH2:10]1)[CH:29]1[C:37]2[C:32](=[C:33]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[CH:44]([CH3:45])[CH3:46]
Reactant: CC(C)C1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)Cl
Reactant: CC1=Cc2cc3c(c(-c4ccccc4)c2C1)CCC3
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=Cc2cc3c(c(-c4ccccc4)c2C1)CCC3[Si](C)(C)C1C(C(C)C)=Cc2c(-c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.3 %

Procedure:
To 12.3 g (50 mmol) of 4-phenyl-6-methyl-1,2,3,5-tetrahydro-s-indacene (2b) and 150 mg (1.5 mmol) of copper cyanide (I) in 450 ml of diethylether was added dropwise at −70° C. 23 ml (57 mmol) of 2.5 M of n-butyllithium in n-hexane. The solution was slowly warmed to room temperature and stirred for 3 hrs at room temperature. Then to the solution was added at −70° C. 16.4 g (50 mmol) of chloro-(2-i-propyl-4-phenyl-indenyl)-dimethylsilane and the solution was warmed to room temperature and stirred for 5 hrs. The resulting back slurry solution was poured into an aqueous ammonium chloride solution and the organic layer was washed with brine, dried over sodium sulfate and the solvents were evaporated to give 28 g of crude product. This was purified by column chromatography (800 g of silica gel, 101 Heptane:CH2Cl2=5:1). Yield: 9.5 g (35%)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][CH2:20][O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:25]([CH2:24][C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:30][CH2:29][CH2:28][C:27]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(Cl)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-chlorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as stating materials, the title compound was prepared.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:41][C:42]([F:48])([F:47])[C:43]([F:46])([F:45])[F:44])(=O)=O>CC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:41][C:42]([F:48])([F:47])[C:43]([F:46])([F:45])[F:44])=[C:3]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(c1cc([N+](=O)[O-])ccc1O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1cc([N+](=O)[O-])ccc1OCC(F)(F)C(F)(F)F)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 99 %

Procedure:
To a refluxing solution of 50 mg of (2-hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone in acetone (2 mL) containing potassium carbonate (35 mg) was added 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (54 mg) over 10 min. The reaction mixture was refluxed for 20 hours before being concentrated in vacuo and purified by column chromatography (SiO2, CH2Cl2/MeOH) to yield the title compound as a colorless solid (66 mg). MS (m/e): 569.0 (M+H+, 100%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:27]([CH2:37][OH:38])[CH2:26]1)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:39]1([C:45]2[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:27]([CH2:37][O:38][C:48]2[CH:49]=[CH:50][C:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:46][CH:47]=2)[CH2:26]1)=[O:23])=[O:19])([CH3:15])([CH3:14])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](COc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1
Reaction time: 17 h

Procedure:
Diethyl azodicarboxylate (158 mL) was added to a mixture of (2S,4R)-4-(N-tert-butoxycarbonylglycylamino)-2-hydroxymethyl-N-tert-butoxycarbonylpyrrolidine (A, 310 mg), 4-phenylphenol (148 mg), and triphenyl phosphine (229 mg) in tetrahydrofuran (10 mL) under argon at room temperature. After stirring at room Ad temperature for 17 hr, the mixture was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (chloroform:methanol=200:1, v/v) to afford title compound (431 mg): 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 18H), 2.01 (m, 1H), 2.38 (m, 1H), 3.21 (m, 1H), 3.72 (m, 1H), 3.77 (d, J=4.4 Hz, 2H), 3.99-4.25 (m, 3H), 4.68 (m, 1H), 5.49 (m, 1H), 6.85 (m, 1H), 6.97 (d, J=7.3 Hz, 2H), 7.29 (d, J=7.3 Hz, 1H), 7.40 (t, J=7.3 Hz, 2H), 7.48-7.63 (m, 4H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([F:23])=[C:11]([CH:22]=1)[CH2:12][C:13]1[C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=[CH:15][CH:14]=1>>[Cl:6][C:7]1[C:22]2[C:19](=[O:21])[C:18]3[CH:17]=[N:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:2])[C:11]=2[C:10]([F:23])=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: O=C(O)c1cnccc1Cc1cc(Cl)ccc1F
Product: O=C1c2ccncc2C(=O)c2c(Cl)ccc(F)c21
Temperature: 130 °C
Yield: 82 %

Procedure:
Fuming sulfuric acid (30% SO3 ; 0.31 mL) is added to 4-(5-chloro-2-fluorobenzyl)nicotinic acid of Preparative Example 19. The dark mixture is heated quickly to 130° C. for 10 min in a flask fitted with a cotton filled drying tube. After cooling to room temperature, the reaction mixture is quenched with ice (3 g) and extracted with methylene chloride (4×7 mL). The combined extracts are dried with Na2SO4 and the solvent is removed by roto-evaporation to yield 9-chloro-6-fluorobenzo[g]isoquinoline-5,10-dione as a yellow solid (0.045 g; 82% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C[N:14](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:14])=[O:12]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of substituted indole-2-carboxylic acid (1e: 1 mmol) in dry DMF (4 mL) were added HATU (1.5 eq.) and the desired amine (R6—NH2: 1.2 eq.) followed by DIPEA (5.0 eq.) at 0° C. The resulting mixture was stirred at room temperature for 12 h to 24 h. To the reaction mixture water (10 mL) was added and stirred for 10 minutes. The resultant solid was collected by filtration, washed with water, hexane and dried. In some instances reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compounds were purified by column chromatography over silica gel (100-200 mesh) or CombiFlash® purification system (Teledyne Isco) using appropriate mixtures of ethyl acetate and hexanes/petroleum ether or preparative HPLC to obtain the desired product indole-2-carboxamide (I).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](O)(=[O:11])[CH3:10]>>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:11])[CH3:10]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(=O)O
Product: CC(=O)N1CCC[C@H]1C(=O)O
Temperature: 150 °C
Yield: 82.5 %

Procedure:
Proline (1 g, 8.68 mmol) and acetic acid (20 mL) were mixed together and heated at 150° C. in a microwave for two hours. The excess acetic acid was removed using a rotary evaporator. The residue was stirred in MTBE at ambient temperature until a solid precipitated. The mixture was filtered and the solid was washed with MTBE. The solid was dried in a vacuum oven at 60° C. The product was obtained as a white solid (1.12 g, 82.5%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.77-1.95 (m, 4H), 1.97 (s, 2H), 2.0-2.19 (m, 1H), 3.35 (dt, 1H), 3.41-3.58 (m, 2H), 4.19 (dd, 1H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C@@:8]12[C:24](=O)[CH2:23][CH2:22][C@H:21]1[C@H:20]1[C@@H:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=3[CH2:18][CH2:19]1)[CH2:10][CH2:9]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:24]1[CH2:23][CH2:22][C@H:9]2[C@H:10]3[C@H:11]([CH2:20][CH2:21][C@:8]12[CH3:7])[C:12]1[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=1[CH2:18][CH2:19]3
Reactant: CC(C)(C)[O-]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a suspension of methyl triphenylphosphonium bromide (8.93 g, 25.0 mmol) in THF (120 mL) was added potassium tert-butoxide (2.69 g, 24 mmol) and stirred for 30 min at room temperature. The reaction mixture was added estrone (18, 2.70 g, 10 mmol), stirred for 19 h at room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl at 0° C. and extracted with EtOAc. The combined organic layers were washed with H2O, then with saturated aqueous NaCl, and dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (5:1→3:1, v/v) to afford 2.24 g of 19 (84% yield), m.p. 135°-136° C.
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[C:3]1=O.C([SiH](CC)CC)C.C(OCC)(=O)C.O>FC(F)(F)C(O)=O>[CH3:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[CH2:3]1
Reactant: COC(=O)C1(C)CCc2c(OC)cccc2C1=O
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(C)CCc2c(cccc2OC)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 211.9 %

Procedure:
To a solution of 2-methyl-2-methoxycarbonyl-5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene (2.0 g) in trifluoroacetic acid (20 ml) was added triethylsilane (2.0 ml) at room temperature. After being stirred for 6 hours at room temperature, the solution was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N--HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 2-methyl-2-methoxycarbonyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (4.0 g).