Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Product: CCCCCCCCCCCCCC(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.111 g, 0.401 mmol) was reacted with N-(2-azidoethyl)tetradecanamide (0.130 g, 0.401 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-tetradecanamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.26 (s, 1H), δ 6.85 (s, 1H), δ 6.42 (s, 1H), δ 6.05 (s, 1H), δ 4.38 (s, 2H), δ 3.66 (s, 2H), δ 2.60 (s, 2H), δ 2.11 (s, 2H), δ 2.08 (t, 2H), δ 1.41 (m, 13H), δ 1.32 (s, 2H), δ 1.17 (s, 18H), δ 0.77 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 202.9, 174.3, 149.6, 148.3, 121.9, 100.1, 84.8, 49.5, 42.3, 39.5, 36.7, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 29.5, 29.3, 28.9, 28.1, 25.9, 25.6, 22.9, 14.3 ppm; HRMS (ESI) calcd for C31H55N7O3 (M+) 573.4366, found 573.4365, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)tetradecanamide hydrochloride (0.118 g, 87% yield). 1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), δ 6.53 (s, 1H), δ 4.71 (s, 2H), δ 3.75 (s, 2H), δ 2.89 (s, 2H), δ 2.54 (t, 2H), δ 2.17 (t, 2H), δ 1.80 (s, 2H), δ 1.69 (s, 2H), δ 1.54 (s, 2H), δ 1.48 (s, 2H), δ 1.28 (s, 20H), 0.88 (t, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 175.6, 161.8, 147.2, 127.6, 127.4, 108.5, 52.3, 38.8, 36.6, 35.8, 31.9, 30.6, 29.7, 29.6, 29.5, 29.4, 29.2, 28.0, 27.9, 27.7, 25.8, 24.1, 23.6, 23.4, 22.6, 13.4 ppm; HRMS (ESI) calcd for C26H47N7O (M+) 473.3842, found 473.3834.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][C:4]=1[CH3:11].[Cl:12]C(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Cl:12])=[CH:5][C:4]=1[CH3:11]
Reactant: COc1ccc(CO)cc1C
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of (4-methoxy-3-methylphenyl)methanol (2.31g, 15.18mmoles, 1eq) in anhydrous CH2Cl2(50ml, 0.3M) was added hexachloroethane (3.59g, 15.18mmoles, 1eq) and triphenylphosphine (3.98g, 15.18mmoles, 1eq). This mixture was stirred at room temperature overnight at which point the reaction was transferred to a separatory funnel and washed with H2O, brine, dried over Na2SO4, filtered, concentrated in vacuo and filtered through a plug of silica gel (30% EtOAc/Hexanes) to yield 2.59g (100%) of product.
Reaction SMILES: [C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:42])=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH:31]([N:35]([CH:37]([CH3:39])[CH3:38])[CH3:36])[C:32](O)=[O:33])=[CH:27][CH:26]=4)[C:21](=[O:40])[N:20]([CH3:41])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([CH:31]([N:35]([CH:37]([CH3:38])[CH3:39])[CH3:36])[C:32]([N:49]5[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]5)=[O:33])=[CH:29][CH:30]=4)[C:21](=[O:40])[N:20]([CH3:41])[CH:19]=3)[C:13]=2[CH3:42])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(C(=O)O)N(C)C(C)C)cc2)n1
Reactant: CN1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(C(=O)N3CCN(C)CC3)N(C)C(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a sealed tube equipped with a magnetic stirrer, were charged 29 (100 mg, 0.168 mmol), 1-methylpiperazine (14.6 mg, 0.168 mmol), DMF (3 mL), Hunig's base (65.1 mg, 0.503 mmol), and BOP (74.3 mg, 0.168 mmol). The reaction mixture was stirred at room temperature for 26 hrs. Most solvent was removed by rotary evaporation and the resulting residue was dissolved in ethyl acetate (100 mL). The solution was washed with water (15 mL×3), dried over MgSO4, filtered and solvent removed in vacuo. Silica gel column chromatography (MeOH:CH2Cl2=5:95) afforded 30 as a light yellow solid, 25 mg (22%). 1H NMR (300 MHz, CDCl3) δ8.45 (s, 1 H), 8.09 (s, 1 H), 7.95 (s, 1 H), 7.92 (s, 1 H), 7.85 (m, 2 H), 7.75 (m, 1 H), 7.54 (s, 1 H), 7.51 (s, 1 H), 7.40 (m, 2 H), 7.19-7.23 (m, 2 H), 6.79 (s, 1 H), 5.19 (s, 1 H), 3.62 (s, 3 H), 3.40 (broad s, 2 H), 3.21 (broad s, 2 H), 2.26-2.50 (m, 9 H), 2.18 (s, 3 H), 1.92 (broad s, 2 H), 1.34 (s, 9 H), 1.25-1.31 (m, 6 H) ppm; MS (ESI+) m/z 678.19 (M+H).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:10][C:11]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[F:10][C:11]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][N:9]=2)=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(O)ccc1F
Reactant: O=Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cccnc1Oc1ccc(F)c(C(=O)O)c1
Temperature: 80 °C

Procedure:
To 2-chloronicotinaldehyde (381 mg, 2.69 mmol), 2-fluoro-5-hydroxybenzoic acid (300 mg, 1.92 mmol) and cesium carbonate (1.25 g, 3.84 mmol) was added DMSO (2.5 mL). The mixture was heated to 80° C. in a sealed tube for 3 hours. The cooled reaction was diluted with water and extracted with EtOAc. The aqueous layer was acidified with TFA (pH˜3) and extracted with EtOAc. This layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was washed with Et2O dried to yield 2-fluoro-5-(3-formylpyridin-2-yloxy)benzoic acid as an off-white solid. MS m/z=262 [M+1]+. Calc'd for C13H8FNO4: 261.21.
Reaction SMILES: [CH:1]([C:3]1([C:6]2([CH3:11])[O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)=[CH2:2].[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[CH2:1]([C:3]1([C:6]2([CH3:11])[O:7][CH2:8][CH2:9][O:10]2)[CH2:4][CH2:5]1)[CH3:2]
Reactant: [H][H]
Reactant: C=CC1(C2(C)OCCO2)CC1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCC1(C2(C)OCCO2)CC1
Yield: 78.6 %

Procedure:
500 mg of olefin 8 is dissolved in 15 ml of ethyl acetate, 150 mg of platinum(IV) oxide is added and hydrogenated in a hydrogenating apparatus until no more hydrogen is taken up. After filtration, it is concentrated by evaporation, whereby 398 mg of title compound 195 is obtained as a colorless oil, which is immediately further reacted.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([OH:14])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].[C:16](O)(=[O:18])[CH3:17]>[C].[Pd]>[CH3:1][C:2]1[CH:10]=[C:9]([NH:11][C:16](=[O:18])[CH3:17])[C:8]([OH:14])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15]
Reactant: Cc1cc([N+](=O)[O-])c(O)c2c1CCC2=O
Reactant: CC(=O)O
Agent: [Pd]
Product: CC(=O)Nc1cc(C)c2c(c1O)C(=O)CC2

Procedure:
Into a solution of 11.5 g of 4-methyl-6-nitro-7-hydroxy-1-indanone in 500 ml of acetic acid was added 1.5 g of 5% palladium carbon, then the mixture was subjected to a catalytic hydrogenation under an atmospheric pressure at a room temperature. The catalyst was removed by filtration and the solvent was removed by evaporation. The residue obtained was washed with ether and was recrystallized from methanol to obtain 6.34 g of 4-methyl-6-acetamido-7-hydroxy-1-indanone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C(Cl)(Cl)Cl.[C:14](Cl)(=[O:16])[CH3:15]>C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:14](=[O:16])[CH3:15]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
At 0° C., to a mixture of 2,5-dimethylphenol 20 g and chloroform 150 ml was added acetyl chloride 15 g and triethylamine 49 g. The resulting mixture was raised to room temperature and was stirred for four hours. Then, the reaction mixture was extracted with chloroform. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give acetic acid 2,5-dimethylphenyl ester 24 g.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[I:23]I>C1C=CC=CC=1>[I:23][C:3]1[O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[C:2]=1[CH3:1]
Reactant: CCOC(=O)Cc1ccc(-c2ccc3occ(C)c3c2)cc1
Reactant: II
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccc3oc(I)c(C)c3c2)cc1
Temperature: 62.5 °C

Procedure:
To a solution of 2.8 g. of the product of step B in 50 ml. of benzene is added 2.7 g. of iodine and 2.4 g. of mercuric oxide followed by stirring and heating at 60-65° C. for about three days. The mixture is cooled and evaporated, and the residue is chromatographed on silica gel, eluting with a carbon tetrachloride-dichloromethane mixture, to provide ethyl 4-(2-iodo-3-methylbenzofuran-5-yl)phenylacetate. To this intermediate is added dichloromethane, then dinitrogen tetraoxide. After one hour the mixture is washed with water, then with sodium bisulfite solution and dried. Evaporation provides a residue which is recrystallized from a dichloromethane-hexane mixture to yield ethyl 4-(3-methyl-2-nitrobenzofuran-5-yl)phenylacetate.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][CH2:9]CO[C:6]=2[C:5]([CH3:12])=[CH:4][CH:3]=1.CC1C=CC(C)=[C:16]([OH:17])C=1O.C(=O)([O-])[O-].[K+].[K+].BrC(Br)C>C(O)CO.CCOCC>[CH3:12][C:5]1[C:6]2[CH2:16][O:17][CH2:9][O:10][C:11]=2[C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C)c(O)c1O
Reactant: Cc1ccc(C)c2c1OCCO2
Agent: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: OCCO
Product: Cc1ccc(C)c2c1COCO2
Temperature: 120 °C

Procedure:
5,8-Dimethyl-1,4-benzodioxane. To a stirred solution of 3 g of 3,6-dimethylcatechol and 6.15 g of potassium carbonate in 35 mL of ethylene glycol is added 3.74 mL of dibromoethane. A reflux condenser is attached and the mixture heated in an oil bath to 120° C. for 4 hours. The mixture is allowed to cool to room temperature and then is distributed between 100 mL of saturated potassium carbonate solution and 200 mL of ether. The ether layer is dried over magnesium sulfate and concentrated under reduced pressure to yield a red liquid, which is purified by chromatography on silica gel to afford 2.90 g of 5,8-dimethyl-1,3-benzodioxane as a light yellow liquid.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:12](=O)[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].CC(C)([O-])C.[K+].Cl>C(O)(C)(C)C>[OH:15][C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[CH2:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[OH:11]
Reactant: O=Cc1ccccc1O
Reactant: O=C1CCCc2ccccc21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Oc1ccccc1Cc1ccc2ccccc2c1O
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A solution of 1-tetralone (5.85 g, 0.040 mole) and salicylaldehyde (4.88 g, 0.040 mole) in t-butanol (400 mL) was treated with potassium t-butoxide (17.6 g, 0.160 mole) was heated at reflux for 16 hours. After cooling to room temperature, the solution was poured into stirred 1.0N hydrochloric acid. After isolation by extraction with ethyl acetate, the crude product was chromatographed with 4:1 petroleum ether/ether, to provide a tan solid. This was recrystallized (cyclohexane/chloroform) to give the titel compound as white needles (5.24 g, 52%), mp 124°-125°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)N=1.BrC1C=CC2[O:21][CH2:22][O:23]C=2C=1C(O)=O.ClC1N=C(C)C=CC=1C(O)=O>>[N:12]1[N:11]([C:4]2[CH:1]=[CH:2][C:10]3[O:21][CH2:22][O:23][C:9]=3[C:5]=2[C:6]([OH:8])=[O:7])[N:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1c(Br)ccc2c1OCO2
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Agent: Cc1ccc(C(=O)O)c(Cl)n1
Product: O=C(O)c1c(-n2nccn2)ccc2c1OCO2

Procedure:
The title compound was prepared in a manner analogous to Intermediate 70 substituting 5-bromobenzo[1,3]dioxole-4-carboxylic acid for 2-chloro-6-methylnicotinic acid. MS (ESI): mass calculated for C10H7N3O4, 233.18; m/z found 234.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.85 (s, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.16 (s, 2H).
Reaction SMILES: [N:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[C:18](Cl)(=[O:21])[CH2:19][CH3:20]>ClCCl>[N:10]1[CH:11]=[CH:12][C:7]([N:6]([N:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[C:18](=[O:21])[CH2:19][CH3:20])=[CH:8][CH:9]=1
Reactant: CCC(=O)Cl
Reactant: c1ccn(Nc2ccncc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)N(c1ccncc1)n1cccc1

Procedure:
To a solution containing 2.9 g of N-(1H-pyrrol-1-yl)-4-pyridinamine and 5 g of sodium bicarbonate in 100 ml of dichloromethane was added a solution containing 1.9 g of propionyl chloride in 20 ml of dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([S:16]C#N)=[CH:8][C:7]=1[CH3:19].SC[C@H]([C@@H](CS)O)O>CCO>[CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:9]([SH:16])=[CH:8][C:7]=1[CH3:19]
Reactant: COC(=O)COc1cc(C(C)(C)C)c(SC#N)cc1C
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CCO
Product: COC(=O)COc1cc(C(C)(C)C)c(S)cc1C

Procedure:
1.00 g (3.4 mmol) of (5-tert-butyl-2-methyl-4-thiocyanato-phenoxy)acetic acid methyl ester prepared in Example KKK was combined with 3.16 g (20 mmol) dithiothreitol (DTT) in a solution of 10 mL 0.02M K2PO4 buffer and 40 mL of EtOH. The reaction was refluxed overnight, then cooled and partially concentrated. After dilution with water, the mixture was extracted with EtOAc, and the organic layer washed with saturated aqueous brine, dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel eluting with 3:1 hexanes:EtOAc, to give the title compound. 1H NMR (CDCl3) δ 1.44 (s, 9 H), 2.19 (s, 3 H), 3.46 (s, 1 H), 3.80 (s, 3 H), 4.62 (s, 2 H), 6.76 (s, 1 H), 7.06 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH2:5]2.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[C:7](=[O:11])[O:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2cc(Br)ccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2cc(Br)ccc21

Procedure:
To a suspension of 5-bromoisobenzofuran-1(3H)-one (5 g, 23.5 mmol) in anhydrous carbon tetrachloride (50 mL) was added N-bromosuccinimide (4.18 g, 23.5 mmol) and a catalytic amount of benzoyl peroxide. The reaction mixture was heated under reflux for 2.5 hours. After cooling, the precipitated solid was filtered off, and the filtrate was concentrated on a rotary evaporator. The residual solid was partitioned between methylene chloride and water. The organic phase was washed with brine, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexanes to yield the title compound. MS (ESI) m/z 290 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([S:20][C:21]([F:24])([F:23])[F:22])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[C:38]([N:11]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:9]=[C:10]1[S:20][C:21]([F:23])([F:22])[F:24])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Fc1ccc(-c2cc(SC(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)n1c(SC(F)(F)F)cc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 2.1 g. (6 mmoles) of 4,5-bis-(4-fluorophenyl)-2-(trifluoromethylthio)pyrrole and 1.3 g. (12 mmoles) of potassium tert-butoxide in 60 ml. of toluene was heated to reflux with stirring and then cooled to room temperature under nitrogen. A solution of 1.7 g. of benzoyl chloride in 15 ml. of toluene was then added and the reaction mixture stirred overnight at room temperature. The mixture was diluted with methylene chloride, which was washed with 10% aqueous sodium bicarbonate solution, dried and evaporated. The residue was purified by chromatography on Fisher 100-200 mesh silica gel (eluted by hexane and then by mixtures of hexane/toluene), followed by recrystallization from ethanol/water to afford 1.8 g. of colorless crystals, m.p. 105.5°-106° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][CH:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[CH3:26])[C:13]21[C:34]1[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=1)[NH:28][C:27]2=[O:36].[CH:37]1([C:41](O)=[O:42])[CH2:40][CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:35][C:31]1[CH:30]=[C:29]2[NH:28][C:27](=[O:36])[C:13]3([CH:12]([C:6]4[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:1][C:41]([CH:37]4[CH2:40][CH2:39][CH2:38]4)=[O:42])[CH2:17][C:16](=[O:18])[NH:15][CH:14]3[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[CH3:26])[C:34]2=[CH:33][CH:32]=1
Reactant: O=C(O)C1CCC1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCN)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCNC(=O)C2CCC2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 8 h
Yield: 16.5 %

Procedure:
At room temperature, a mixture of racemic (2′S,3S,4′R)-4′-[2-(2-amino-ethoxy)5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.189 mmol) prepared in Example 32e, cyclobutanecarboxylic acid (98 mg, 0.948 mmol), EDC.HCl (181 mg, 0.948 mmol), HOBt (128 mg, 0.948 mmol) and DIPEA (245 mg, 1.897 mmol) in anhydrous DMF (4 mL) was stirred overnight. Then the mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC to give the title compound as a white solid (19 mg).