Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:12]=[C:13]([CH3:19])[N:14]([CH:16]([F:18])[F:17])[CH:15]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:15]1[N:14]([CH:16]([F:17])[F:18])[C:13]([CH3:19])=[N:12][C:11]=1[C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Cl:3]
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)cn1C(F)F
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(Br)n1C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
Bromine (0.54 g, 3.1 mmol), in 7 ml of methylene chloride, was added dropwise to a solution of 0.9 g (3.2 mmol) of 4-(2,4-dichlorophenyl)-1-difluoromethyl-2-methylimidazole stirring in 35 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight. Another 0.3 g of bromine, in 5 ml of methylene chloride, were added and the reaction stirred overnight. Methylene chloride (250 ml) and saturated sodium bicarbonate (200 ml) were added and the organic layer separated and washed with saturated sodium bicarbonate and brine followed by drying over magnesium sulfate. Evaporating in vacuo gave a red oil residue. Flash chromatography on silica gel (20:1-10:1-5:1-3:1 hexane/ethyl acetate) afforded 0.7 g of 5-bromo-4-(2,4-dichlorophenyl)-1-difluoromethyl-2-methylimidazole as a white solid (m.p. 81°-83° C.). NMR (CDCl3, 200 MHz) δ: 2.65 (s, 3H), 7.20 (t, 1H), 7.27-7.40 (m, 2H), 7.52 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:48])[CH2:10][C:9]2[N:8](COCC[Si](C)(C)C)[N:7]=[C:6]([C:19]3[N:20](COCC[Si](C)(C)C)[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([N:28]([CH3:39])[C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O>[CH3:1][C:2]1([CH3:48])[CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([N:28]([CH3:39])[C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1
Reactant: CN(C(=O)OCc1ccccc1)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)c1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1
Temperature: 90 °C
Yield: 88.4 %

Procedure:
A solution of benzyl N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylcarbamate (13 g, 19 mmol) obtained in Example 1, Step 6, in N,N-dimethylformamide (102 ml) was added to tetrabutylammonium fluoride (93 ml, 93 mmol) concentrated in advance under reduced pressure, and then ethylenediamine (19 ml) was added. The mixture was stirred with heating at 90° C. for 7 hr. After cooling, water and ethyl acetate were added, and the organic layer was separated. Then, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with water, 10% aqueous citric acid solution and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (7.2 g, yield 91%).
Reaction SMILES: [SH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8])=[O:4].Cl[CH2:15][C:16]([OH:18])=[O:17].[I-].[K+].Cl.[Cl-].[Na+]>C(=O)([O-])[O-].[K+].[K+]>[C:16]([CH2:15][S:8][CH2:7][C@@H:6]([C:9]([OH:11])=[O:10])[NH:5][C:3](=[O:4])[C:2]([S:1][CH2:6][C:9]([OH:11])=[O:10])([CH3:13])[CH3:12])([OH:18])=[O:17]
Reactant: O=C(O)CCl
Reactant: CC(C)(S)C(=O)N[C@@H](CS)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Product: CC(C)(SCC(=O)O)C(=O)N[C@@H](CSCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 194.5 %

Procedure:
N-(2-Mercapto-2-methylpropanoyl)-L-cysteine (11.2 g, 0.05 mol) is dissolved in 1 M potassium carbonate and monochloroacetic acid (11.3 g, 0.12 mol) and potassium iodide (1.0 g) are added. The mixture is stirred overnight at room temperature under a nitrogen atmosphere and acidified with 6 N hydrochloric acid. Sodium chloride is added and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried and concentrated to dryness to yield 16.5 g (97.2%) of S-carboxymethyl-N-(2-carboxymethylthio-2-methylpropanoyl)-L-cysteine.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[CH3:16][O:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[O:35].[Cl-].[NH4+]>C1COCC1>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2([OH:35])[C:23]1[C:18]([O:17][CH3:16])=[N:19][CH:20]=[CH:21][N:22]=1
Reactant: COc1cnccn1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nccnc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
n-BuLi (26 mmol, 16.3 mL of a 1.6M solution in hexanes) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (26 mmol, 4.4 mL) in THF (150 mL) at 0° C. After stirring for 30 min at 0° C., the solution was cooled to −78° C. and a solution of 2-methoxypyrazine (20 mmol, 1.93 mL) in THF (30 mL) was added dropwise. After stirring at −78° C. for 15 min, a suspension of 5-chloroisatin (10 mmol, 1.82 g) in THF (50 mL) was added. The reaction mixture was stirred at 0° C. for 2 h, then saturated ammonium chloride solution was added. The mixture was extracted three times with ethyl acetate, and the collected extracts were washed with saturated brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by crystallization from diethyl ether yielded 1.14 g of the required intermediate.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:15])([F:14])[C:5]([F:13])([F:12])[C:6](F)([F:10])[CH2:7][CH2:8]I>O1CCCC1>[F:10][C:6]([C:5]([F:13])([F:12])[C:4]([F:15])([F:14])[F:3])=[CH:7][CH2:8][NH:2][CH3:1]
Reactant: FC(F)(F)C(F)(F)C(F)(F)CCI
Reactant: CN
Solvent: C1CCOC1
Product: CNCC=C(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.55 g of methylamine is condensed in a solution of 2.6 ml of 1,1,1,2,2,3,3 heptafluor-5-iodo-pentane in 20 ml of anhydrous tetrahydrofuran at −40° C., and it is stirred overnight at room temperature in a pressurized reactor. After the pressurized reactor was opened at −30° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. Then, the reaction solution is mixed with diethyl ether, washed with saturated common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 1.26 g of (3,4,4,5,5,5-hexafluoro-pent-2-enyl)-methyl-amine is obtained as a crude product.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([Cl:7])[N:6]=1.C[Sn](C)(C)[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:13]=1.[Cl-].[Li+].CO>O1CCOCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:7][C:5]1[N:6]=[C:2]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:13]=2)[S:3][C:4]=1[CH:8]=[O:9]
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)Nc1cc(-c2nc(Cl)c(C=O)s2)ccn1
Temperature: 110 °C
Yield: 45.6 %

Procedure:
2,4-Dichloro-5-thiazolecarboxaldehyde (2.50 g, 0.0137 mol), N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (4.93 g, 0.0165 mot), lithium chloride (1.75 g, 0.0412 mol), copper(I) iodide (0.785 g, 0.00412 mol), tetrakis(triphenylphosphine)palladium(0) (0.794 g, 0.000687 mol) were combined in dioxane (200 mL) under an atmosphere of Argon. The solution was heated at 110° C. for 2 hr. TLC indicated complete conversion. Mixture was cooled to rt and MeOH (100 mL) was added until almost all solids dissolved. Suspension was filtered through celite and the filtrate was evaporated. Water (100 mL) was added and the solids were collected by filtration, washed with water and hexane and dried in vacuum at 40° C. to give 1.76 g of amorphous solid (46%). LCMS: (FA) ES+ 282, 284. 1H NMR (400 MHz, d6-DMSO) 10.83 (s, 1H), 10.02 (s, 1H), 8.70 (s, 1H), 8.51 (dd, J=5.20, 0.67 Hz, 1H), 7.68 (dd, J=5.20, 1.67 Hz, 1H), 2.13 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:28][C@H:27]([CH2:29]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C=O)C.O>[N:41]([CH2:29][C@@H:27]1[CH2:28][C@H:25]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)[N:9]=2)[CH2:26]1)=[N+:42]=[N-:43]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3nc(-c4cccc(OCc5ccccc5)c4)c4c(N)nccn43)C2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1C[C@@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of cis-toluene-4-sulfonic acid 3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutylmethyl ester (100 mg, 0.18 mmol) in DMF (2 mL) was charged with sodium azide (35 mg, 0.54 mmol), the resulting mixture was stirred at rt overnight. The mixture was diluted with water (5 mL), then extracted with ethyl acetate (3×10 mL), the combined organic phases were washed with water (2×10 mL) and brine (10 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with 100% ethyl acetate), yielding the title compound as a white solid; LC-MS (ES, Pos.): m/z 426 [MH+]; 1H NMR (CDCl3, 400 MHz) δ 2.36-2.44 (m, 2H), 2.63-2.79 (m, 3H), 3.37 (d, J=6.7 Hz, 2H), 3.69 (m, 1H), 5.14 (s, 4H, —OCH2— and —NH2), 7.02-7.05 (m, 2H), 7.10 (d, J=5.0 Hz, 1H), 7.25-7.45 (m, 8H).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][CH:21]=[CH:22][Sn](CCCC)(CCCC)CCCC)[CH3:19]>CN(C=O)C.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>[CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[CH:19]=[CH:18][O:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: Ic1ncnc2c1ncn2Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC=Cc1ncnc2c1ncn2Cc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 9-benzyl-6-iodopurine (7) (1.00 g, 2.8 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.208 g, 0.02 mmol) and ethoxyvinyl(tributyl)tin (2.07 g, 3.8 mmol) in dry DMF (4 mL) was heated under N2 at 100° C. for 6 h. TLC indicated completion of reaction. DMF was distilled off under reduced pressure and the resulting residue was redissolved in EtOAc (50 mL) and filtered through a pad of celite. The solvent (EtOAc) was distilled off and the residue obtained purified by flash chromatography. Yield 0.393 g, (47%). Mp 114-115° C. 1H NMR (CDCl3): δ 1.55 (t, 3H, CH3, J=7.5 Hz), 4.13 (q, 2H, CH2, J=13.7 Hz), 4.99 (d, 1H, CH, J=3 Hz), 5.48 (s, 2H, benzylic CH2), 6.16 (d, 1H, CH, J=3 Hz), 7.30-7.38 (m, 5H, Ar—H), 8.09 (s, 1H, purine C8—H), 9.07 (s, 1H, purine C2—H). 13C NMR (CDCl3): δ14.3, 47.3, 63.7, 94.7, 127.8, 127.8, 128.6, 129.1, 129.2, 130.3, 135.0, 144.4, 152.1, 152.3, 152.4, 155.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5](Cl)=[O:6].[C:15]1([N:21]2[C:25]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:24](=[O:31])[NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([N:28]1[CH2:27][CH2:26][C:25]2([N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][NH:23][C:24]2=[O:31])[CH2:30][CH2:29]1)=[O:6]
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Product: O=C(c1cc(F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1

Procedure:
The title compound, MS: m/e=422.3 (M+H+), was prepared in accordance with the general method of example 1 from 3-fluoro-5-(trifluoromethyl)benzoyl chloride and 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C(=O)(O)[O-].[Na+].Cl[C:15]([O:17][CH3:18])=[O:16].Cl>C(OCC)C.O>[OH:4][C@H:3]([CH3:5])[C@H:2]([NH:1][C:15]([O:17][CH3:18])=[O:16])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)Cl
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.1 %

Procedure:
L-Threonine (0.50 g, 4.2 mmol) and sodium bicarbonate (1.13 g, 13.4 mmol) were dissolved into water (20 mL) then cooled in an ice bath. Methyl chloroformate (0.36 mL, 4.62 mmol) was dissolved in diethyl ether (2 mL) and added dropwise with vigorous stirring. The solution was stirred at ambient temperature for 5 hours then adjusted to pH 3 with concentrated hydrochloric acid and extracted into ethyl acetate. The organic solution was dried over sodium sulfate, filtered, and concentrated to give 0.12 g of the title compound as a waxy solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]([NH2:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>CN1C(=O)CCC1.C([O-])(O)=O.[Na+]>[ClH:1].[Cl:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]([NH:11][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccncc1
Reactant: Nc1csc2c(Cl)cccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Clc1cccc2c(Nc3ccncc3)csc12
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
To a solution of 7-chloro-3-aminobenzo[b]thiophene (47.82 g, 325 mmole) in NMP (300 mL) was added 4-chloropyridine hydrochloride (50.78 g) and the reaction mixture was placed in a 130° C. oil bath. After stirring for 5 minutes, the reaction mixture was cooled, diluted with a saturated solution of NaHCO3, and extracted with ethyl acetate. The biphasic mixture was thick with precipitates which were removed by filtration over Celite. The organic layer was separated, washed with water, dried (MgSO4), and concentrated. Trituration of the resulting solid with diethyl ether/pentane yielded 28.95 g of product as a green solid. TLC revealed that the precipitates filtered in the initial extraction contained product. Flash chromatography (silica gel) and trituration of the resulting solid with diethyl ether/pentane yielded 11.32 g of an off-white solid. A 2.0 g portion of this material was dissolved in 40 mL of hot methanol allowed to stand for a half hour, filtered to remove orange precipitates. Ethereal hydrogen chloride was added to the filtrate. The hydrochloride salt was then filtered, washed with diethyl ether, and dried under high vacuum, P2O5, and refluxing xylenes to yield 1.89 g of a beige crystalline solid, mp 305° C. (dec.).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:23]([CH3:29])=[CH:24][CH:25]=[CH:26][C:27]=2[CH3:28])[C:15]2[O:14][CH:13]([CH2:12][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CN1CCCC1)C2

Procedure:
The title compound was prepared (0.094 g, 73%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and pyrrolidine (0.48 g, 6.76 mmol). mp 245-247° C.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[OH:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[Li+].[OH-].O.Cl>C1COCC1>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[OH:31])=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2O)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)O)c2F)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[5-(3-fluorophenyl)-2-hydroxy-3-methyl-phenyl]methylamino]phenoxy]acetate (90 mg, 0.20 mmol, 1.0 eq) in THF (3 mL) was added a solution of LiOH (2M aqueous solution, 3 mL, 6 mmol, 30 eq). The reaction was stirred at room temperature for 3 h. Water was added and the mixture acidified to pH 4-5 with diluted HCl then extracted with EtOAc. The combined organic extracts were washed with water and brine, dried and evaporated in vacuo to give the title compound (as a white solid (73 mg, 86%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11](Br)=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)=[O:4].Br[C:20]1C=CC2C3C(=CC=CC=3)CC=2C=1>>[Cl:1][CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([CH3:20])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Reactant: O=C(CCl)c1ccc2c(c1)Cc1cc(Br)ccc1-2
Product: Cc1ccc2c(c1)Cc1cc(C(=O)CCl)ccc1-2

Procedure:
Following the same procedure, 2-(chloroacetyl)-7-bromofluorene was prepared from 2-bromofluorene.
Reaction SMILES: [CH3:1][N:2]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:3](=[O:27])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH:22]=[CH:23][C:24]([OH:26])=O)=[CH:6]1.C(Cl)(=O)C(Cl)=O.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[CH3:1][N:2]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:3](=[O:27])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH:22]=[CH:23][C:24]([N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:26])=[CH:6]1
Reactant: C1CCNC1
Reactant: CN(CCc1ccccc1)C(=O)Cn1cc(C=CC(=O)O)c2cc(OCc3ccccc3)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(CCc1ccccc1)C(=O)Cn1cc(C=CC(=O)N2CCCC2)c2cc(OCc3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 0.63 g (1.34 mmol) of N-methyl-N-phenethyl-2-(5-benzyloxy-3-(2-carboxyvinyl)indol-1-yl]-acetamide in 15 ml of methylene chloride, cooled to 0° C. with an external ice bath, is added dropwise 0.26 ml (3.02 mmol) of oxalyl chloride, followed immediately with 3 drops of N,N-dimethylformamide. The mixture is stirred in an ice bath for 30 minutes and then for 1 hour with the cooling bath removed. The reaction mixture is then concentrated in vacuo. The residue obtained is dissolved in 10 ml of methylene chloride and this solution is added dropwise to a mixture of 0.11 ml (1.34 mmol) of pyrrolidine, 0.24 ml of pyridine and 15 ml of methylene chloride with stirring at 0° C. (ice bath). The resulting reaction mixture is stirred at room temperature for several hours and quenched with saturated aqueous NH4Cl solution. Ethyl acetate and water are added and the layers separated. The organic layer is washed with 1N aqueous HCl solution and water, dried over magnesium sulfate and concentrated in vacuo. The residue is triturated in hot ethyl acetate to give N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-(1-pyrrolidinecarbonyl)-vinyl)indol-1-yl]acetamide (m.p. 185°-187° C.).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([OH:21])=O)=[O:5].[CH:30]([NH2:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:14])([CH3:15])[C:9]=2[C:8]=1[C:19]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:21])=[O:5]
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Reactant: CC(C)N
Product: CC(C)NC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 45A and commercially available isopropylamine by the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.08 (d, J=6.4 Hz, 6H), 1.44 (s, 6H), 1.47 (s, 6H), 3.89-4.00 (m, 1H), 7.66-7.80 (m, 3H), 7.91 (d, J=7.8 Hz, 1H), 11.51 (br s, 1H). MS (ESI+) m/z 473 (M+H)+. Anal. calcd. for C22H24F4N2O3S: C, 55.92; H, 5.12; N, 5.93. Found: C, 56.03; H, 5.26; N, 5.89.
Reaction SMILES: C(N(CC)C1C=CC=CC=1)C.[C:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([S:21](O)(=[O:23])=[O:22])[CH:20]=1)(=[O:14])[CH3:13].CN(C)C=O.S(Cl)([Cl:33])=O>C(Cl)(Cl)Cl.O>[C:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([S:21]([Cl:33])(=[O:23])=[O:22])[CH:20]=1)(=[O:14])[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)c1ccc(C)c(S(=O)(=O)O)c1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)c1ccccc1
Product: CC(=O)c1ccc(C)c(S(=O)(=O)Cl)c1
Reaction time: 1 h
Yield: 87.4 %

Procedure:
363 Grams (1.0M) of N,N-diethylaniline salt of 5-acetyl-2-methylbenzenesulfonic acid was dissolved in 934 g of chloroform, to this solution was added a mixture of 80.3 g (1.1M) of N,N-dimethylformamide with 130.9 g (1.1M) of thionyl chloride at a temperature of 2°-3° C., and the whole mixture was stirred at the same temperature for 1 hour. 1,500 Grams of water was added to this reaction mixture, the chloroform layer was separated and washed 3 times with 500 g of water. The chloroform layer was concentrated to obtain 203.1 g (0.874M) of 5-acetyl-2-methylbenzenesulfonyl chloride. The yield was 87.4% on the basis of N,N-diethylaniline salt of 5-acetyl-2-methylbenzenesulfonate.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17]C[CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.N1C=C(B(O)O)C=NC=1>>[CH:14]([N:13]([C@H:11]1[CH2:10][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:26]4[CH:27]=[N:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:12]1)[CH3:17])([CH3:18])[CH3:15]
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: COc1ccc(-c2ccc3nc([C@H]4C[C@H](N(C)C(C)C)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 52A for the product of Example 1E and substituting 6-methoxypyridine-3-boronic acid for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.00 (d, J=8.48 Hz, 1H) 7.87 (d, J=1.70 Hz, 1H) 7.68 (dd, J=9.16, 2.71 Hz, 1H) 7.49 (dd, J=8.48, 1.70 Hz, 1H) 7.39-7.44 (m, 1H) 6.70 (d, J=9.49 Hz, 1H) 3.75-3.88 (m, 1H) 3.65 (s, 3H) 3.56-3.63 (m, 1H) 3.00-3.16 (m, 1H) 2.66-2.80 (m, 2H) 2.52-2.65 (m, 2H) 2.18 (s, 3H) 1.05 (d, J=6.44 Hz, 6H). MS: (M+H)+=368.