Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>C(Cl)Cl>[Br:39][CH2:2][C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11]
Reactant: BrC(Br)(Br)Br
Reactant: CN1CCCCC(CO)(c2cccc(O)c2)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1CCCCC(CBr)(c2cccc(O)c2)C1=O
Reaction time: 16 h

Procedure:
3-Hydroxymethyl-3-(3-hydroxy-phenyl)-1-methyl-azepan-2-one (as described in Example 6, Step B) (0.60 g, 2.40 mmol), triphenylphosphine (0.94 g, 3.60 mmol), and carbon tetrabromide (1.19 g, 3.60 mmol) were dissolved in CH2Cl2 (15 mL), stirred under Ar for 16 h, then the solution was concentrated in vacuo and purified using SiO2 chromatography (0.5% MeOH/CH2Cl2) to give the title compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([CH3:19])=[C:14]([CH2:20][CH3:21])[N:13]=1>>[CH3:19][C:15]1[C:16]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[N:17][C:12]([Cl:11])=[N:13][C:14]=1[CH2:20][CH3:21]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCc1nc(Cl)nc(Cl)c1C
Product: CCc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Yield: 62.7 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 1,2,3,4-tetrahydroisoquinoline(3.5 ml, 28 mmol) and 2,4-dichloro-5-methyl-6-ethylpyrimidine(4.9 g, 27.7 mmol) prepared in Preparation 4 were used as starting materials, 5.0 g of the titled compound was prepared.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[F:37]>CC#N>[F:37][C:29]1[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=[CH:33][C:28]=1[O:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COc1cc2nccc(O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 51.3 %

Procedure:
A solution of 6,7-dimethoxyquinolin-4-ol (50 g, 0.244 mol) and Cs2CO3 (159 g, 0.488 mol) in CH3CN (300 mL)/DMF (300 mL) was stirred at room temperature for 30 min. 1,2-Difluoro-4-nitrobenzene (42.7 g, 0.268 mol) was then added dropwise. After stirring at rt for 3.5 h, the reaction solution was concentrated in vacuo. Ice (500 mL) was added to the residual suspension and the mixture was stirred overnight for precipitation. The solid was collected by filtration and further purified by a silica gel column chromatography (EtOAc) to give the title compound as a pale yellow powder (43.1 g, 51.2%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]([CH:27](O)[C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)=[C:25]([CH:40]([CH3:42])[CH3:41])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:45])[CH2:20][C:21]([CH3:44])([CH3:43])[O:22]3)=[CH:13][CH:12]=1.O>ClCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]([CH:27]([F:7])[C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:36])([F:38])[F:37])=[CH:32][CH:33]=3)=[C:25]([CH:40]([CH3:41])[CH3:42])[CH:24]=[C:23]3[C:18]=2[C:19](=[O:45])[CH2:20][C:21]([CH3:43])([CH3:44])[O:22]3)=[CH:13][CH:12]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 2.5 h

Procedure:
At −78° C., a solution of 45 μl (340 μmol) of diethylaminosulfur trifluoride in 1 ml of dichloromethane is slowly added dropwise to a solution of 157 mg (310 μmol) of rac-5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethoxy)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 24A) in 4 ml of dichloromethane, and the mixture is stirred at this temperature for 2.5 h. The mixture is then allowed to thaw slowly to −15° C. and stirred for a further 1.5 h. Water is then added, and the mixture is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. Column chromatography of the residue on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1→15:1) gives the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:11][CH2:12][CH2:13][CH3:14])[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
To a solution of 7-chlorothiene[3,2-b]pyridine 2 (9.82 g, 57.89 mmol) in THF (290 mL) BuLi (2.5 N, 25 mL) was added at −78° C. and the mixture stirred for 20 min at the same temperature. Tributyltin chloride (63.68 mmol, 17.3 mL) was added dropwise and the mixture stirred for 2 h at −78° C. The homogeneous mixture thus obtained was poured in water (200 mL) and extracted with EtOAc (2×200 mL). The organic phase was collected, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent EtOAc/Hex 1:4) to afford 7-chloro-2-(tributylstannyl)thieno[3,2-b]pyridine (6, 24.79 g, 93% yield) as a syrup. MS (m/z): cluster of signals centered around 460.1 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH2:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CS[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][NH:11][C:14]2[S:15][C:16]3[C:21]([N:22]=2)=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CN)CC1
Reactant: CSc1nc2cccnc2s1
Product: CC(=O)N1CCC(CNc2nc3cccnc3s2)CC1
Temperature: 140 °C
Yield: 93 %

Procedure:
A mixture of 11 parts of 1-acetyl-4-piperidinemethanamine and 9 parts of 2-(methylthio)thiazolo[5,4-b]pyridine was stirred and heated for 20 hours at 140° C. The whole was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 13.5 parts (93%) of 1-acetyl-N-(thiazolo[5,4-b]pyridin-2-yl)-4-piperidinemethanamine as a residue (intermediate 51).
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C@@H:10]([C@H:25]([CH3:28])[CH2:26][CH3:27])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:28][C@@H:25]([C@H:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:12][C:2](=[O:3])[NH:9]1)[CH2:26][CH3:27]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H](C)[C@H](N)C(O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](C)[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
Trichloromethyl chloroformate (5.4 g, 27.3 mmol) was added to a mixture of (S)-2-amino-1,1-diphenyl-3-methylpentan-1-ol 13 (4.97 g of 60%, 11.1 mmol) and triethylamine (5.3 g, 52.0 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred for 3 h at 0° C., then allowed to warm to room temperature for 18 h. The mixture was then washed with HCl (3×100 ml) and water (2×100 ml) and dried over MgSO4. Concentration gave a crude product, which was washed with diethyl ether to afford the title compound 14 (2.7 g, 83%) as a white amorphous solid. m.p. 221–223° C. [α]D25=−243.9° (c, 4.33 in CHCl3). δH 0.41 (3H, t, J=7.2 Hz, CH3), 0.80 (3H, d, J=6.9 Hz, CH3), 0.80–0.96 (1H, m, CH2), 1.18–1.32 (1H, m, CH—Me), 1.34–1.50 (1H, m, CH2), 4.27 (1H, d, J=3.6 Hz, CH—NH), 6.98 (1H, s, NH), 7.10–7.50 (10H, m, Ar—H). δC 11.3 (CH3—CH2), 17.2 (CH3—CH), 22.7 (CH2), 36.3 (CH—Me), 66.1 (CH—NH), 89.5 (C), 125.9, 126.5, 127.7, 128.0, 128.3, 128.6, 139.3, 144.0 (Ar), 159.1 (C═O). νmax (cm−1): 3281, 3162 (N—H), 3058 (Ar C—H), 2980, 2960, 2933, 2877 (methyl and methylene C—H), 1760, 1725 (C═O), 1493, 1448 (Ar C═C), 1243 (C—O). m/e 313 (MNH4+, 6%), 296 (MH+, 8%), 237 (100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[CH:21]=3)[CH:17]=1)[N:5]=2.[Cl:33][CH2:34][C:35](Cl)=[O:36]>CN(C)C=O.C(OCC)(=O)C>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:27][CH2:28]4)[CH:21]=3)[CH:17]=1)[N:5]=2)=[O:36]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CCl)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (200 mg, 0.453 mmol) produced in Example C29(iv) in N,N-dimethylformamide (4.0 mL) was added chloroacetyl chloride (54 μL, 0.68 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure to give N-[5-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-methylphenyl]-3-(1-cyanocyclopropyl)benzamide as a colorless solid.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]([NH:15][C:16]1[C:17](=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[C:18]([OH:20])=[O:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(=O)C>[C:8]([NH:15][C:16]1[C:17](=[CH:21][C:22]([O:25][CH2:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:16]=2)=[CH:23][CH:24]=1)[C:18]([O:20][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1C(=O)O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Reaction time: 6 h
Yield: 56.3 %

Procedure:
Sodium hydride (95%, 36.2 g, 1.51 mol) was placed into a dry 5 liter 3-necked round bottom flask under an atmosphere of argon. Anhydrous dimethylformamide (DMF) (2.0 liters) was added via canula followed by the careful addition of N-Boc-5-hydroxyanthranilic acid (150 g, 0.59 mol). The reaction mixture was cooled with an ice/water bath and benzyl bromide (148 mL, 1.24 mol) was added via syringe keeping the reaction temperature below 50° C. After addition was complete, the reaction mixture was stirred at 45° C.-50° C. for 6 hours. At this time additional benzyl bromide (35 mL, 0.29 mol) was added and the reaction continued at 45° C.-50° C. for an additional 2 hours. Acetic acid (20 mL) was carefully added and the reaction mixture was transferred to a round bottom flask and concentrated to a volume of approximately 400 mL. Ethyl acetate (1.0 liters) was added and the resulting solution was decanted from any solids present. The flask was rinsed with additional ethyl acetate (2×500 mL), decanting after each rinse. The combined organics were washed with water (1.0 liter) and saturated NaCl (500 mL). The organics were filtered and concentrated in vacuo to yield crude N-Boc-5-benzyloxyanthranilic acid, benzyl ester as a reddish brown syrup. The crude product was transferred to boiling hexanes (3 liters) and refluxed an additional 10 minutes. The solution was filtered while still hot and allowed to cool for 48 hours to yield 72 g of product (28% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([C:11]#[N:12])[C:5]=1[OH:13])([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([C:11]#[N:12])[C:5]=1[OH:13]
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1c(Cl)ccc(N)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
A mixture of 2-nitro-5-chloro-6-cyanophenol (750 mg, 3.78 mmol) and tin (II) chloride (2.6 g, 11.4 mmol) in ethanol(50ml) is heated at 80° C. under argon. After 2 hours, the starting material has disappeared and the solution is allowed to cool down and then poured into ice. The pH is made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(410 mg, 65%). 1H NMR (CD30D): δ8 6.89 (d, 1H), 6.88 (d,1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH3:17]>O1CCOCC1>[Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:17])=[O:5]
Reactant: O=C(O)c1ccc(F)c(F)c1Cl
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: NC(=O)c1ccc(F)c(F)c1Cl
Temperature: 80 °C

Procedure:
2-Chloro-3,4-difluorobenzoic acid (2 g, 10.4 mmol) was treated with thionyl chloride (3.04 ml) and the mixture was heated to 80° C. for 90 minutes. The mixture was then cooled and reduced in vacuo. The residue was dissolved in anhydrous 1,4-dioxane (10 ml) and the mixture was then cooled in an ice-water bath. 0.88 Ammonia (aqueous, 25 ml) was added dropwise to the mixture which was subsequently allowed to warm to 22° C. over a period of 2 hrs. This process was repeated using 10.8 g of 2-chloro-3,4-difluorobenzoic acid, 8.2 ml of thionyl chloride, and 45 ml of 0.88 ammonia and then both mixtures were combined and partitioned between ethyl acetate (150 ml) and water (100 ml). The aqueous layer was separated and extracted with 2×150 ml aliquots of ethyl acetate. The combined organic extracts were then washed with saturated aqueous sodium hydrogen carbonate (100 ml), dried using a hydrophobic frit, and reduced in vacuo to give 2-chloro-3,4-difluorobenzamide (11.86 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:14][CH2:15][N:16]1[C@H:21]2[CH2:22][CH2:23][C@@H:17]1[CH2:18][CH:19]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])[CH2:20]2)[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].[H-].[Na+].I[CH3:43].O>C1COCC1>[CH3:43][N:4]([CH2:3][C:2]([CH3:1])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:14][CH2:15][N:16]1[C@H:21]2[CH2:22][CH2:23][C@@H:17]1[CH2:18][CH:19]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])[CH2:20]2)[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CNS(=O)(=O)c1ccccc1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CN(C)S(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a solution of the title compound from example 19 (65 mg, 0.12 mmol) in dry THF (2 mL) was added sodium hydride (6 mg, 0.14 mmol) as a 60% suspension in mineral oil and the solution stirred under a nitrogen atmosphere at room temperature for 30 min. Iodomethane (0.03 mL, 0.48 mmol) was added and the reaction stirred at room temperature for 1 h. An additional portion of iodomethane (0.02 mL, 0.32 mmol) was added and the solution stirred for 1 h more at room temperature. Water was added and the reaction partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-4% methanol/CH2Cl2 to afford the title compound (50 mg, 75%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:36])(=[O:35])[N:20]=1.[OH-].[Na+:38]>O>[CH2:33]([S:30]([NH:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:19]([C:3]3[C:4](=[O:18])[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[O-:1])=[N:20][S:21](=[O:36])(=[O:35])[C:22]=2[CH:28]=1)(=[O:31])=[O:32])[CH3:34].[Na+:38]
Reactant: CCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C([O-])c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Yield: 87.6 %

Procedure:
A mixture of Example 102A (70.4 mg, 0.132 mmol) and 0.998 M sodium hydroxide (0.133 mL, 0.132 mmol) in 3 mL water was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo to give the title compound (64 mg, 87% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.46 m, 1 H) 0.68 (d, J=6.62 Hz, 3 H) 0.70 (d, J=6.62 Hz, 3 H) 0.79 m, 1 H) 1.19 (t, J=7.35 Hz, 3 H) 1.29 m, 1 H) 1.38 (s, 3 H) 1.72 m, 1 H) 2.15 (m, 1 H) 3.02 m, 2 H) 7.23 (d, J=7.72 Hz, 1 H) 7.31 m, 2 H) 7.44 m, 3 H) 8.04 (d, J=7.35 Hz, 1 H) 9.96 (s, 1 H) 15.43 (s, 1 H). MS (ESI+) m/z 532.0 (M+H—Na)+, 549.0 (M−Na+NH4)+, (ESI−) m/z 530.0 (M−H—Na)−.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[OH:19].[N:20]#[C:21]Br>O1CCCC1.C(OCC)(=O)C>[NH2:20][C:21]1[O:19][C:3]2[CH:4]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=3)[C:10]([O:12][CH3:13])=[O:11])[CH:17]=[CH:18][C:2]=2[N:1]=1
Reactant: COC(=O)c1cccc(Oc2ccc(N)c(O)c2)c1
Reactant: N#CBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Oc2ccc3nc(N)oc3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a solution of methyl 3-(4-amino-3-hydroxyphenoxy)benzoate (13.1 g, 50.5 mmol) in tetrahydrofuran (200 mL) was added cyanogen bromide (9.76 g, 92.1 mmol), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added cyanogen bromide (1.78 g, 16.8 g), and the mixture was further stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate (300 mL), washed with saturated aqueous sodium hydrogencarbonate solution (150 mL×2) and saturated brine (150 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (13.6 g, yield (total of 4 steps) 95%) as brown crystals.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: NCC1CCN(CCCC(F)(F)F)CC1
Product: O[C@@H](CNCC1CCN(CCCC(F)(F)F)CC1)COc1cccc2[nH]c3ccccc3c12
Yield: 45.6 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.125 g, 0.52 mmol) and 4-aminomethyl-1-(4,4,4-trifluorobutyl)-piperidine (0.224 g, 1.0 mmol) according to the procedure used for Example 2 to give 0.110 g of the title compound as a tan solid.
Reaction SMILES: [N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[O:33])[NH:14][CH2:15][C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)=[O:33])[NH:14][CH2:15][C:16]([NH:18][C@H:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)=[O:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCNC1
Reaction time: 4 h

Procedure:
To a solution of the compound (7.82 g), which had been obtained in (1), in anhydrous dichloromethane (10 ml), trifluoroacetic acid (5 ml) was added dropwise under ice cooling, followed by stirring for 4 hours. The reaction mixture was concentrated by evaporation under reduced pressure. The residue was washed with hexane-ether and the solvent was distilled off, whereby 1.00 g of the title compound was obtained. The product was provided for use in the subsequent reaction without purification.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](=[O:21])=[N:16][S:17]([Cl:20])(=[O:19])=[O:18]>CCOCC>[C:2]1([CH:1]([NH:14][C:15]([NH:16][S:17]([Cl:20])(=[O:19])=[O:18])=[O:21])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOCC
Product: O=C(NC(c1ccccc1)c1ccccc1)NS(=O)(=O)Cl
Yield: 93.8 %

Procedure:
A solution of benzhydrylamine (4.0 g, 21.8 mmoles) in 50 mL Et2O was added dropwise to a solution of N-chlorosulfonyl isocyanate (1.90 mL, 21.8 mmoles) in 100 mL Et2O at 15° C. under an atmosphere of N2. Upon addition, the mixture turned cloudy but cleared up after one-half hour of stirring. The reaction mixture was concentrated in vacuo to give a pale yellow solid. Trituration with hexanes gave 6.64 g (94%) of the title compound, mp 80°-88° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[CH3:13]>>[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cncc(Br)c1
Product: CCc1ccc(-c2cncc(C(=O)OC)c2)cc1

Procedure:
32 g (148 mmol) of methyl 5-bromonicotinate and 27 g (178 mmol, 1.2 eq.) of 4-ethylphenylboronic acid were reacted according to General Method 1A. Yield: 24 g (64% of theory)