Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:43])[S:10]([C:13]2[CH:14]=[C:15]([CH:40]=[CH:41][CH:42]=2)[C:16]([NH:18][CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])=[O:17])(=[O:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.CC(OC([N:51]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][CH:63]=2)[CH2:53][C@H:52]1[CH3:67])=O)(C)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH2:31]([N:28]1[C:23]2=[N:24][C:25]([CH2:26][CH3:27])=[C:20]([CH2:19][NH:18][C:16](=[O:17])[C:15]3[CH:40]=[CH:41][CH:42]=[C:13]([S:10]([N:9]([CH3:43])[CH2:8][C:4]4[CH:3]=[C:2]([C:62]5[CH:61]=[CH:60][CH:59]=[C:58]([CH2:57][N:54]6[CH2:55][CH2:56][NH:51][C@@H:52]([CH3:67])[CH2:53]6)[CH:63]=5)[CH:7]=[CH:6][CH:5]=4)(=[O:12])=[O:11])[CH:14]=3)[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]2[CH:30]=[N:29]1)[CH3:32]
Reactant: C[C@@H]1CN(Cc2cccc(B(O)O)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(S(=O)(=O)N(C)Cc2cccc(Br)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(S(=O)(=O)N(C)Cc2cccc(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)c1
Temperature: 130 °C
Yield: 30.8 %

Procedure:
To a solution of 3-{[[(3-bromophenyl)methyl](methyl)amino]sulfonyl}-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (120 mg, 0.179 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL) was added {3-[((3R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]phenyl}boronic acid (59.9 mg, 0.179 mmol), Pd(Ph3P)4 (10.35 mg, 8.96 μmol), and K2CO3 (74.3 mg, 0.538 mmol) and the reaction was heated in microwave at 130° C. for 15 min. The organic layer was separated, filtered, concentrated, and purified using a Gilson HPLC (with 0.1% TFA). Before the sample was concentrated with a GeneVac EZ-2, TFA (5 drops) was added to each tube (12 mL). The resultant mixture was concentrated, purified using a Gilson HPLC (with 0.1% TFA), concentrated, and basified with amino cartridge to afford 0.0429 g (30%) of the title compound. LC-MS m/z 779 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.35-1.45 (m, 6 H) 1.48 (t, J=7.28 Hz, 3 H) 1.82-1.96 (m, 2 H) 2.10 (d, J=12.55 Hz, 2 H) 2.66 (s, 3 H) 3.18 (q, J=7.61 Hz, 3 H) 3.33-3.39 (m, 1 H) 3.42-3.53 (m, 1 H) 3.60-3.79 (m, 6 H) 3.98-4.10 (m, J=8.41, 3.14 Hz, 2 H) 4.27 (s, 2 H) 4.31-4.40 (m, 1 H) 4.41-4.54 (m, 4 H) 4.75 (s, 2 H) 7.31-7.37 (m, 1 H) 7.40-7.65 (m, 5 H) 7.68-7.85 (m, 3 H) 8.05 (d, J=7.28 Hz, 1 H) 8.23 (d, J=7.78 Hz, 1 H) 8.28 (s, 1 H) 8.39 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[C:6]([S:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:15])=[O:14])=[CH:5]2.C(OC1C=CC=C2C=1OC(=O)C(S(NC1C=CC(OC)=CC=1)(=O)=O)=C2)C.ClC1C=C2C(=CC=1)OC(=O)C(S(NC1C=CC(OC)=C(O)C=1)(=O)=O)=C2.NC1C=C(NS(C2C(=O)OC3C(C=2)=CC=CC=3OCC)(=O)=O)C=CC=1F.NC1C=C(NS(C2C(=O)OC3C(C=2)=CC(OC)=CC=3)(=O)=O)C=CC=1F.[Br:127]C1C=CC(NS(C2C(=O)OC3C(C=2)=CC(OC)=CC=3)(=O)=O)=CC=1.BrC1C=CC(NS(C2C(=O)OC3C(C=2)=CC=CC=3Cl)(=O)=O)=CC=1.BrC1C=CC(NS(C2C(=O)OC3C(C=2)=CC=CC=3Br)(=O)=O)=CC=1>>[Br:127][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[C:6]([S:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:15])=[O:14])=[CH:5]2
Reactant: COc1ccc(NS(=O)(=O)c2cc3cc(Cl)ccc3oc2=O)cc1
Reactant: COc1ccc2oc(=O)c(S(=O)(=O)Nc3ccc(Br)cc3)cc2c1
Agent: CCOc1cccc2cc(S(=O)(=O)Nc3ccc(F)c(N)c3)c(=O)oc12
Agent: CCOc1cccc2cc(S(=O)(=O)Nc3ccc(OC)cc3)c(=O)oc12
Agent: COc1ccc(NS(=O)(=O)c2cc3cc(Cl)ccc3oc2=O)cc1O
Product: COc1ccc(NS(=O)(=O)c2cc3cc(Br)ccc3oc2=O)cc1

Procedure:
6-chloro-N-(4-methoxyphenyl)-2-oxo-2H-chromene-3-sulfonamide; 8-ethoxy-N-(4-methoxyphenyl)-2-oxo-2H-chromene-3-sulfonamide; 6-chloro-N-(3-hydroxy-4-methoxyphenyl)-2-oxo-2H-chromene-3-sulfonamide; N-(3-amino-4-fluorophenyl)-8-ethoxy-2-oxo-2H-chromene-3-sulfonamide; N-(3-amino-4-fluorophenyl)-6-methoxy-2-oxo-2H-chromene-3-sulfonamide; N-(4-bromophenyl)-6-methoxy-2-oxo-2H-chromene-3-sulfonamide; 8-ethoxy-N-(4-methoxyphenyl)-2-oxo-2H-chromene-3-sulfonamide; N-(4-bromophenyl)-8-chloro-2-oxo-2H-chromene-3-sulfonamide; N-(4-bromophenyl)-8-bromo-2-oxo-2H-chromene-3- sulfonamide; mixtures thereof; and salts thereof.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[NH4+].[Cl-].O>[Fe].CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cc(Cl)cc2cccnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)cc2cccnc12
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of 6.30 g (30.3 mmol) 6-chloro-8-nitroquinoline, 14.7 g (272 mmol) NH4Cl, 120 mL H2O and 250 mL EtOH is added 5.0 g (90.6 mmol) Fe powder, and the resulting mixture is refluxed for 2.5 h. The volatiles are evaporated, and the residue is stirred in mixture of 200 mL CH2Cl2 and 300 mL water for 30 min. The resulting bi-phasic solution is filtered through celite, the layers are separated, and the aqueous layer is extracted 2×100 mL CH2Cl2. The combined organics are washed with 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered, and the volatiles are evaporated. Flash chromatography on SiO2, eluting with hexanes/EtOAC (10/1 to 4/1), gives 2.80 g (15.7 mmol, a 52% yield) of the title compound as a tan solid. mp: 70-73° C.; MS (ES) m/z 179 (MH)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10](Br)[CH:9]=2)=[O:5].[CH3:25]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>COCCOC.O.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.C(OCC)(=O)C>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([CH3:25])[CH:9]=2)=[O:5]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCOC(=O)c1cc2cc(OC)c(Br)cc2n1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OC)c(C)cc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of 0.20 g (0.50 mmol) 6-bromo-5-methoxy-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 8 mL 1,2-dimethoxyethane were added 58 μg (0.050 mmol) tetrakis(triphenylphosphine)palladium(0). After stirring 30 min at room temperature, 76 μg (0.60 mmol) trimethylboroxine and 0.16 g (1.50 mmol) sodium carbonate dissolved in 4 mL water were added and the reaction mixture was heated 3 h at reflux. The solution was poured into 10% aqueous sodium bicarbonate solution and ethyl acetate, the layers were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified twice by flash chromatography on silica gel using a gradient of dichloromethane:methanol (100:0 to 50:50 v/v) as eluant, to afford 95 mg (57%) of the title compound as colourless oil.
Reaction SMILES: CN(C)C=O.[O:6]=[C:7]1[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:9][CH:8]1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[H][H]>ClCCl.C1C=CC=CC=1.C1C=CC=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[OH:6][C@@H:7]1[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:9][C@H:8]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Reactant: [H][H]
Agent: Cl[Ru]Cl
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 125.4 %

Procedure:
43 mL of anhydrous N,N-dimethylformamide was added to 1.15 g of benzene ruthenium (II) chloride dimer (2.30 mmol) and 3.00 g of (R)-(−)-BINAP (4.82 mmol) in a stream of argon gas. The mixture was stirred in an oil bath at an external temperature of 95 to 105° C. for 10 minutes. The mixture was then allowed to cool to room temperature. Volatile materials were evaporated under reduced pressure (using a vacuum pump) in an oil bath at an external temperature of 50 to 70° C. to give a catalyst. 33.5 g of 1-benzyl 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (115 mmol) and 68 mL of dehydrated dichloromethane were placed in an autoclave and the air in the autoclave was replaced by argon. The catalyst dissolved in 100 mL of dehydrated dichloromethane was then added and the atmosphere in the autoclave was replaced by hydrogen gas three times. The mixture was stirred under a pressurized hydrogen atmosphere (8.83 MPa) at an external temperature of 50 to 60° C. for 4 hours. Heating/stirring was stopped, and the mixture was left overnight. Subsequently, hydrogen gas was released and the mixture was transferred to a different vessel and washed with 30 mL of dehydrated dichloromethane. The mixture was then concentrated under reduced pressure and dried in vacuo at room temperature for 30 minutes to give 42.3 g of a crude product of the title compound as a dark brown oil. This product was used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:18])[NH:13]2)[CH:2]=[CH2:3].Cl.[C:21]12([C:31](Cl)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.N>CN(C)P(=O)(N(C)C)N(C)C.O>[C:21]12([C:31]([O:19][CH:6]([CH2:5][NH:4][CH2:1][CH:2]=[CH2:3])[CH2:7][O:8][C:9]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:10]=3[CH2:11][C:12](=[O:18])[NH:13]4)=[O:32])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: C=CCNCC(O)COc1cccc2c1CC(=O)N2
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCNCC(COc1cccc2c1CC(=O)N2)OC(=O)C12CC3CC(CC(C3)C1)C2

Procedure:
1.35 g of 4-(3-allylamino-2-hydroxypropoxy)oxindole are converted into the hydrochloride, are then dissolved in 15 cc of hexamethyl-phosphoric acid triamide and allowed to stand at room temperature for 70 hours with 1.45 g of adamantane-1-carboxylic acid chloride. The mixture is poured into water, is rendered alkaline with a 10% ammonia solution and is extracted with methylene chloride. The evaporation residue of the methylene chloride phase is chromatographed on silica gel with methylene chloride and 1% of methanol, and the resulting title compound is converted into its hydrogen oxalate. M.P. 170°-172° from ethanol.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]([Br:12])[S:9][C:10]=1[CH3:11])(=O)C.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[Br:12][C:8]1[S:9][C:10]([CH3:11])=[C:6]([CH2:5][OH:4])[N:7]=1
Reactant: CC(=O)OCc1nc(Br)sc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1sc(Br)nc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
To a mixed solution of the compound (1.2 g, 4.8 mmol) obtained in Example 80c in ethanol/tetrahydrofuran (v/v=1/1, 4 mL) was added 2N aqueous sodium hydroxide solution (4.8 mL, 9.6 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=50/50) to give the title compound (590 mg, 59%) as a colorless solid.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:22][O:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][O:6][CH2:5]2)[CH2:3][O:2]1.[OH2:23]>>[OH:2][CH2:3][C:4]1([CH2:1][OH:23])[CH2:22][O:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][O:6][CH2:5]1
Reactant: O
Reactant: C1COCCOCCNCCOCC2(COCCN1)COC2
Product: OCC1(CO)COCCNCCOCCOCCNCCOC1

Procedure:
The oxetane ring in these macrocycles can be opened, by addition of water as well as of alcohols. For example, acid-catalysed hydrolysis of 2,6,12,15,21-pentaoxa-9,18-diazaspiro[3.18]docosane yields 12,12-bis(hydroxymethyl)-1,4,10,14-tetraoxa-7,17-diazacyclononadecane. ##EQU16##
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([OH:16])[CH2:10][CH2:9][N:8](C(OCC)=O)[CH2:7][CH2:6]1)[CH3:3].[ClH:17]>>[ClH:17].[ClH:17].[CH3:3][N:2]([CH2:4][C:5]1([OH:16])[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: CCOC(=O)N1CCC(O)(CN(C)C)CC1
Agent: Cl
Product: CN(C)CC1(O)CCNCC1

Procedure:
4.5 g (19.4 mmol) of ethyl 4-dimethylaminomethyl-4-hydroxypiperidine-1-carboxylate are heated overnight under reflux with 35 ml of concentrated hydrochloric acid. The product is concentrated, and the crystals are triturated with acetone, filtered off with suction and dried in a vacuum desiccator over P4O10.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:11])[CH:3]=1.[N:12]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:11][C:4]1[CH:3]=[C:2]2[C:9]([CH:10]=[N:12][NH:1]2)=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1cc(C#N)c(C)cc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2[nH]ncc2cc1C#N
Reaction time: 48 h
Yield: 20.9 %

Procedure:
A solution of 4-amino-2,5-dimethylbenzonitrile (preparation 31) (111 mg, 0.76 mmol) in acetic acid (5 ml) was treated with a solution of sodium nitrite (53 mg, 0.76 mmol) in water (1 ml). The resultant mixture was stirred at room temperature for 10 mins then left to stand for 48 hrs. The solvent was removed by evaporation and the residue purified by chromatography (SiO2, eluting with 50:50 hexane:ethyl acetate) to give the desired product (25 mg, 21%). 1H NMR (CD3OD) δ 2.60 (s, 3H), 7.50 (s, 1H), 8.15 (s, 1H), 8.20 (s, 1H). LRMS m/z=158.1 (M+1)+.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([OH:67])=[CH:63][CH:62]=1)[C:6]([NH:8][CH:9]([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=1)[C:10]([N:12]1[CH2:17][C:16](=[O:18])[N:15]([CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH2:14][CH:13]1[CH2:31][CH2:32][CH2:33][NH:34][C:35]([NH:44]C(OC(C)(C)C)=O)=[N:36]C(OC(C)(C)C)=O)=[O:11])=[O:7])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:4][CH:5]([CH2:60][C:61]1[CH:62]=[CH:63][C:64]([OH:67])=[CH:65][CH:66]=1)[C:6]([NH:8][CH:9]([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=1)[C:10]([N:12]1[CH2:17][C:16](=[O:18])[N:15]([CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH2:14][CH:13]1[CH2:31][CH2:32][CH2:33][NH:34][C:35]([NH2:44])=[NH:36])=[O:11])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(Cc1ccc(O)cc1)C(=O)NC(Cc1ccc(F)cc1)C(=O)N1CC(=O)N(CCc2ccc3ccccc3c2)CC1CCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC(Cc1ccc(O)cc1)C(=O)NC(Cc1ccc(F)cc1)C(=O)N1CC(=O)N(CCc2ccc3ccccc3c2)CC1CCCNC(=N)N
Yield: 86 %

Procedure:
A solution of 2-acetylamino-N-[2-[2-[3-(N′,N″-di-Boc-guanidino)propyl]-4-(2-naphthalen-2-ylethyl)-5-oxo-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-3-(4-hydroxyphenyl)-propionamide, 36, (35 mg, 38 mmol), trifluoroacetic acid (1 mL) and dichloromethane (2 mL) is stirred at room temperature for 5 hours. The solution is concentrated in vacuo and the crude product purified over silica gel (acetonitrile:TFA:water) to afford 24 mg (86% yield) of the final product which corresponds to analog 227, Table IV.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24]C2CCCCC2)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:31][N:32]([CH3:45])[S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:38]4[CH:37]=[C:36]([S:33]([N:32]([CH3:45])[CH3:31])(=[O:34])=[O:35])[CH:41]=[CH:40][CH:39]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN(C)S(=O)(=O)c1cccc(B(O)O)c1
Reactant: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(S(=O)(=O)N(C)C)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 6.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(N,N-dimethylsulfamoyl)phenylboronic acid (24 mg, 0.104 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC followed by preparative HPLC to give pure 3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N,N-dimethylbenzenesulfonamide (1.7 mg, 7%). 1H-NMR (MeOD): 2.47 (m, 1H), 2.62 (m, 1H), 2.71 (s, 6H), 3.29 (s, 3H), 5.28 (d, 0.3H), 5.89 (d, 0.7H), 7.19 (m, 1H), 7.47 (m, 6H), 7.69 (m, 2H), 7.75 (m, 1H), 7.93 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:27]=[CH:26][C:19]2[N:20]([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:18]=2[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1F)[C:33]#[N:34].C([O-])([O-])=O.[Cs+].[Cs+].C(O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:27]=[CH:26][C:19]2[N:20]([CH3:25])[C:21](=[O:24])[N:22]([CH3:23])[C:18]=2[CH:17]=1)([OH:15])[C:11]([F:12])([F:13])[F:14])[O:8][C:37]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[F:29]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC(c1ccc(Oc2ccc(C#N)cc2F)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F

Procedure:
A mixture of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (Example 85, 25 mg), 3,4-difluorobenzonitrile (CAS Reg. No. 64248-62-0, 10 mg), and Cs2CO3 (59 mg) in DMF (1 ml) was heated in a microwave oven at 120° C. for 30 min. The mixture was acidified with HCOOH and then purified by prep. HPLC (C18-column, solvent gradient 30-98%) to give the title compound (19 mg) as a colorless oil. MS (m/e)=534.1 [M+H+].
Reaction SMILES: [CH2:1]([C:13]1([CH2:29][C:30]2[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=2[OH:37])[CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][C:20]([CH3:28])([CH3:27])[CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:13]1([CH2:29][C:30]2[C:31](=[O:37])[CH:32]=[CH:33][C:34](=[O:36])[CH:35]=2)[CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([CH3:27])([CH3:28])[CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCC1(Cc2cc(O)ccc2O)COCCOCC(C)(C)COCCOC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCCCCCCCCCC1(CC2=CC(=O)C=CC2=O)COCCOCC(C)(C)COCCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 67.6 g (129.3 mmol) of Compound 6 in 600 mL of dichloromethane was mixed with 50.6 g (581.9 mmol) of activated manganese dioxide. The heterogeneous mixture was stirred at room temperature for 1 hour. The insolubles were removed by filtration through Celite diatomaceous earth and the solvent removed. The oily residue was triturated with 500 mL of petroleum ether and cooled. The volume of solvent was reduced to 1/2 and the yellow solid suction filtered and washed with cold pentane.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[Br-].[Na+].C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C1COCC1.[O-]Cl.[Na+].CC1(C)N([O])C(C)(C)CCC1.O>[Br:1][C:2]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: OCc1cccc(OCc2ccccc2)c1Br
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccc(OCc2ccccc2)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
(2-bromo-3-benzyloxybenzyl alcohol (251 g, 0.86 mol) was dissolved in THF (300 ml) and sodium bromide (13.2 g, 0.128 mol) added. The reaction mixture was cooled to 0° C. and TEMPO (0.67 g, 4.28 mmol) was added followed by a freshly prepared (0° C.) solution of sodium bicarbonate (10.8 g, 0.128 mol) in 1 liter of commercial Chlorox® bleach. This was stirred rapidly at 0° C. for 3 h and sodium sulfite added. Any precipitated solids were dissolved upon addition of deionized water. The organics were separated and the aqueous layer extracted with ethyl acetate. The combined organics were washed with brine, dried (MgSO4) and concentrated. The residue was cooled in an ice bath and the precipitated solids collected by filtration to give 2-bromo-3-benzyloxybenzaldehyde (224 g, 90%): mp 125°-6° C. The above prepared aldehyde (215 g) was combined in toluene (200 ml) with 1,3-propane diol (107 ml, 1.48 mol) and pTSA.H2O (1.6 g) and heated at the reflux temperature with azeotropic removal of water via a Dean-Stark trap. After 1.5 h the reaction mixture was cooled and washed with saturated sodium bicarbonate and brine. The organics were separated, dried (MgSO4) and evaporated. The residue was crystallized from methanol to afford the title compound as a white solid (248 g, 96%): mp 73°-4° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(-c2ccc(Cl)cc2)c1
Yield: 120.4 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromopyridine (280 mg, 0.79 mmol) and 4-chlorophenylboronic acid (246 mg, 1.57 mmol, Lancaster Chemical Co.) in toluene (10 mL) was added Pd(0) (30 mg) and Na2CO3 (2.5 mL of a 2 M solution), and the mixture was heated at reflux for 6 h. The solvent was removed under vacuum, and the residue was chromatographed (silica gel; EtOAc/hexane, 1:5 to 1:2) to afford the title compound (370 mg, >100% yield): 1H NMR (CDCl3, 300 MHz) δ 1.47 (s, 9H), 1.80-2.10 (m, 3H), 3.30-3.49 (m, 2H), 3.90-4.30 (m, 3H), 7.40-7.60 (m, 5H), 8.31 (s, 1H), 8.42 (s, 1H); MS (CI/NH3) m/z 389 (M+H)+.