Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][N:5]1[CH2:29][CH2:28][C:8]2([N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:11](=[O:20])[N:10]=[C:9]2[NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:7][CH2:6]1.[CH3:34][C:35]([CH3:37])=O>>[CH:22]1([NH:21][C:9]2[C:8]3([CH2:28][CH2:29][N:5]([CH2:4][C:3]4[CH:30]=[CH:31][CH:32]=[CH:33][C:2]=4[NH:1][CH:35]([CH3:37])[CH3:34])[CH2:6][CH2:7]3)[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:11](=[O:20])[N:10]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)=O
Reactant: Nc1ccccc1CN1CCC2(CC1)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1
Product: CC(C)Nc1ccccc1CN1CCC2(CC1)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1

Procedure:
Produced using Method Z substituting acetone for the aldehyde and 8-(2-aminobenzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (example 80) for the substrate. MS 492.4
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C([Li])CCC.[B:26](OC)([O:29]C)[O:27]C.Cl>O1CCCC1>[C:7]1([N:6]2[C:5]3[CH:13]=[CH:14][C:2]([B:26]([OH:29])[OH:27])=[CH:3][C:4]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reaction time: 2 h
Yield: 80 %

Procedure:
In a 500 mL three-neck flask were stirred 29 g (90 mmol) of 3-bromo-9-phenylcarbazole obtained by the above Step 3 described in Synthesis Example 1 and 200 mL of tetrahydrofuran (abbreviation: THF) at −78° C. to provide a solution. Then, 110 mL (69 mmol) of n-butyllithium (1.6 mol/L hexane solution) was dropped therein, and the mixture was stirred for 2 hours at the same temperature. Furthermore, 13 mL (140 mmol) of trimethyl borate was added therein, and the mixture was stirred for 24 hours at room temperature. After the reaction, 200 mL of 1.0 mol/L hydrochloric acid was added therein, and the mixture was stirred for 1 hour at room temperature. This mixture was washed with water, aqueous sodium hydroxide, and water in this order, and magnesium sulfate was added so that the moisture was removed. This suspending solution was filtered and the obtained filtrate was concentrated. Then, chloroform and hexane were added therein, ultrasonic waves were applied thereto, and then recrystallization thereof was performed. Accordingly, 21 g of a powdery white solid of 9-phenyl-9H-carbazol-3-boronic acid, which was the object of the synthesis, was obtained in a yield of 80% (synthesis scheme (b-1)).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[F:9].[H-].[Na+].[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:14]=1[C:15](Cl)=[O:16]>CN(C=O)C>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:14]=1[C:15]([NH:8][C:4]1[C:3]([F:9])=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=1)=[O:16]
Reactant: Nc1ncnc(Cl)c1F
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ncnc(Cl)c1F)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.2 %

Procedure:
To a solution of 6-chloro-5-fluoropyrimidin-4-amine (1.21 g, 8.2 mmol) in DMF (25 mL) at 0° C. was added NaH (60% in mineral oil, 0.46 g, 11.5 mmol). The reaction mixture was stirred at 0° C. for 20 minutes. 2,6-dichlorobenzoyl chloride (2.06 g, 9.8 mmol) was then added dropwise over 5 minutes. The reaction mixture was warmed to room temperature and stirred under nitrogen overnight. The reaction was quenched with saturated NH4Cl solution (100 mL), and extracted with EtOAc (3×100 mL). The combined organics layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-25% EtOAc in hexane gradient to give the desired compound as a white solid (1.32 g, 50% yield). 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.10 (s, 1H), 7.39-7.35 (m, 3H). LCMS (ESI) m/z: 320.0 [M+H+].
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH:7]=[CH2:8])[CH:2]([CH3:4])[CH3:3].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10]>N1C=CC=CC=1>[CH2:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:18]([C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:17][CH:16]=1)(=[O:19])=[O:20])[CH:7]=[CH2:8]
Reactant: C=CCNCC(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: C=CCN(CC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 5 h

Procedure:
To N-iso-Butyl-allylamine (11) (5 mmol) in pyridine (50 mL) at 55°-65° C. is added slowly 4-nitrobenzenesulfonyl chloride (12) (5.1 mmol). The mixture is allowed to stir for 4-6 hours at 55°-65° C. and the pyridine is then removed in vacuo and the residue purified by flash chromatography to afford N-allyl-N-iso-butyl-4-nitrobenzenesulfonamide (13).
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[NH2:17][C:18]1[N:23]=[C:22]([CH:24]2[CH2:26][CH2:25]2)[N:21]=[C:20]([O:27][CH3:28])[N:19]=1>C(Cl)Cl>[CH:24]1([C:22]2[N:21]=[C:20]([O:27][CH3:28])[N:19]=[C:18]([NH:17][C:14]([NH:13][S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH:2]([F:1])[F:16])(=[O:12])=[O:11])=[O:15])[N:23]=2)[CH2:26][CH2:25]1
Reactant: COc1nc(N)nc(C2CC2)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(F)F
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)nc(C2CC2)n1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
3.75 g of 2-difluoromethoxybenzenesulfonylisocyanate are added to a solution of 2.5 g of 2-amino-4-cyclopropyl-6-methoxy-1,3,5-triazine in 15 ml of methylene chloride, and the mixture is stirred for 70 hours at room temperature. It is then concentrated by evaporation, and 25 ml of ether are added to the residue. A crystalline precipitate occurs, which is filtered off. The yield is 4.7 g of the above urea, which melts at 121°-124° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[N:14][C:15]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:16]([CH3:19])[C:17]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][C@H:28]([CH3:32])[C:29](O)=[O:30].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][NH:11][C:12]1[N:13]=[N:14][C:15]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:16]([CH3:19])[C:17]=1[CH3:18])[C:29](=[O:30])[C@H:28]([Cl:27])[CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NCCNCc2ccccc2)nnc(-c2ccc(F)cc2)c1C
Reactant: C[C@@H](Cl)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(NCCN(Cc2ccccc2)C(=O)[C@@H](C)Cl)nnc(-c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Sequentially treat a solution of N1-benzyl-N2-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-yl)ethane-1,2-diamine (4.90 g, 13.98 mmol) in CH2Cl2 (70 mL) with (R)-(+)-2-chloropropionic acid (1.84 mL, 20.97 mmol), triethylamine (2.92 mL, 20.97 mmol), HOBT (3.21 g, 20.97 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.02 g, 20.97 mmol). Stir the resulting mixture at ambient temperature overnight. Wash the reaction mixture with saturated aqueous NaHCO3. Extract the aqueous layer with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (20% EtOAc in hexanes) to afford the title compound as a yellow foam (4.59 g, 74%). ES/MS m/z 441.2 (M+1).
Reaction SMILES: [C:1]([CH2:14][C:15]([CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21])([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[CH3:24][N:25]([CH2:27][CH2:28][CH2:29][NH2:30])[CH3:26]>>[C:1]([CH2:14][C:15]([CH2:18][CH2:19][S:20]([NH:30][CH2:29][CH2:28][CH2:27][N:25]([CH3:26])[CH3:24])(=[O:22])=[O:21])([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CN(C)CCCN
Reactant: O=S(=O)(Cl)CCC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CN(C)CCCNS(=O)(=O)CCC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 75 °C
Yield: 96.8 %

Procedure:
C4F9CH2CF2CH2CH2SO2Cl (100 g, 0.23 mol, 70.3% in toluene) was added dropwise to a mixture of dimethylaminopropylamine (DMAPA) at 45° C. After the addition, the reaction was heated at 75° C. overnight. The reaction mass was filtered and the wet cake was washed with 60° C. toluene. After stripping off the toluene, the concentrated organic product was washed with 200 mL of 95° C. deionized water. The product Intermediate 2, C4F9CH2CF2CH2CH2SO2N(H)—CH2CH2CH2N(CH3)2 (106 g, 96.8%) was obtained as a brown colored solids after removing water under reduced pressure.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[Cl:22][C:23]1[CH:24]=[C:25]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35](O)=[O:36])[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:36])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6].[N+:12]([C:15]1[CH:16]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[CH:18]=[CH:19][C:20]=1[Cl:21])([O-:14])=[O:13]>O.C(#N)C>[CH2:3]([N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[S:22]([C:17]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)(=[O:23])=[O:24])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNCCCC
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCCCN(CCCC)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
150 g of sodium hydroxide was dissolved in 200 ml of water, and the solution was cooled. To this solution was added 600 ml of dibutylamine, and the solution was cooled to 0° C. A solution of 954 g of 3-nitro-4-chlorobenzenesulfonyl chloride in 950 ml of acetonitrile was dropwise added thereto under vigorous stirring while keeping the solution temperature at not higher than 10° C. After completion of the dropwise addition, the reaction mixture was stirred for 1 hour at 10° C., and the crystals which precipitated were collected by filtration, washed wellwith a dilute hydrochloric acid aqueous solution (1N), and dried.
Reaction SMILES: [F-].[K+].C[Si](C)(C)[C:5]([F:8])([F:7])[F:6].[Cl:11][C:12]1[CH:13]=[CH:14][C:15](I)=[N:16][CH:17]=1>CN1C(=O)CCC1.[Cu]I>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:5]([F:8])([F:7])[F:6])=[N:16][CH:17]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Clc1ccc(I)nc1
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc(Cl)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a solution of KF (53 mg, 0.91 mmol, 1.10 equiv) in NMP (3 mL), CuI (175 mg, 0.92 mmol, 1.10 equiv), trimethyl(trifluoromethyl)silane (119 mg, 0.84 mmol, 1.00 equiv) and 5-chloro-2-iodopyridine (as prepared in the previous step, 200 mg, 0.84 mmol, 1.00 equiv). The reaction mixture was stirred overnight at 60° C. The reaction was then quenched by the addition of 20 mL of ammonia (12%). The resulting solution was extracted with 2×20 mL of ethyl acetate. The combined organic layers were washed with 50 ml of brine, dried (Na2SO4), and concentrated to yield 5-chloro-2-(trifluoromethyl)pyridine as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[CH:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CCCCCCC.CCOC(C)=O>[C:18]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C#CCCCCC
Reactant: Cc1ccc(S(=O)(=O)Oc2cccnc2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC#Cc1cccnc1

Procedure:
This product was prepared from toluene-4-sulfonic acid pyridin-3-yl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (60 mg, 70%); 1H NMR δ (CDCl3): 8.62-8.63 (m, 1H), 8.48-8.46 (m, 1H), 7.68-7.64 (m, 1H), 7.21-7.17 (m, 1H), 2.46 (t, J=7.21 Hz, 2H), 1.63 (p, J=7.15 Hz, 2H), 1.49-1.3 (m, 4H), 0.93 (t, J=7.22 Hz, 3H); LCMS m/z: 173.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[O:13][CH:14]([CH2:17][NH2:18])[CH2:15][O:16][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[CH:31][C:32](=[O:36])[O:33]2)=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[C:2]1([CH2:1][O:8][C:9]2[CH:20]=[CH:19][C:12]3[O:13][CH:14]([CH2:17][NH:18][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:27]=[CH:28][C:29]5[CH:30]=[CH:31][C:32](=[O:36])[O:33][C:34]=5[CH:35]=4)[CH2:15][O:16][C:11]=3[CH:10]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1COc2cc(OCc3ccccc3)ccc2O1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc2ccc(OCCCNCC3COc4cc(OCc5ccccc5)ccc4O3)cc2o1
Temperature: 108 °C

Procedure:
2,3-Dihydro-6-benzyloxy-1,4-benzodioxin-2-methanamine (2.4 g, 8.85 mmole), 7-(3-chloropropoxy)coumarin (2.15 g, 9.0 mmole), diisopropylethylamine (7.0 ml, 40.2 mmole) and sodium iodide (1.35 g, 9.0 mmole) were combined in 200 ml of DMF and heated at 108° C. for 2 days under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of water dried over magnesium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on silica gel using 1% methanol/dichloromethane as eluant. The product-containing fractions (Rf=0.27 on silica gel tlc with 2.5% methanol/dichloromethane) were combined and concentrated in vacuum and the residue redissolved in dichloromethane and boiled on a hot plate, the solvent gradually being replaced with isopropanol. Upon addition of 6 ml of 4N HCl/isopropanol and cooling, 1.22 g of the title compound, m.p. 184°-187° C., precipitated as a beige solid, monohydrochloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10](O)=[O:11])[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([Cl:23])=[O:11])[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCc1cc(C(=O)Cl)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 28 (2 g; 7.80 mmol) in DCM (40 mL) was added oxalyl chloride (1.98 mL; 23.41 mmol) followed by DMF (60 μL) under vigorous stirring at RT. After 2 h, solvents were removed under vacuum to give 2-(methoxymethyl)-2′-methylbiphenyl-4-carbonyl chloride as a yellow oil that was dried under vacuum. To a solution of Intermediate 62 (150 mg; 0.49 mmol) in CH3CN (1.50 mL) and DI EA (0.33 mL) was added a solution of 2-(methoxymethyl)-2′-methylbiphenyl-4-carbonyl chloride (134.07 mg; 0.49 mmol) in CH3CN (1.50 mL). Reaction mixture was stirred at RT for 1 h 30 after which it was heated to 150° C., 30 min under microwave irradiations. Reaction mixture was concentrated under vacuum, dissolved in DCM and purified by column chromatography (EtOAc:cHex from 10:90 to 80:20) to give the title compound as a colorless oil. LC/MS (Method B): 528.5 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][CH2:13][CH:15]2[CH2:16][O:17]2)=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CO)cc1
Reactant: ClCC1CO1
Product: CC(C)(C)c1ccc(COCC2CO2)cc1

Procedure:
The title compound was prepared from 4-(tert-butyl)-benzyl alcohol and epichlorohydrin according to the procedures employed for the preparation of the compound in Step 1 of Example 2.
Reaction SMILES: Cl.[O:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][CH2:11][C:12](Cl)=[O:13].CCO>CS(C)=O>[Cl:10][CH2:11][C:12]([NH:9][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:13]
Reactant: O=C(Cl)CCl
Reactant: NOc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CS(C)=O
Product: O=C(CCl)NOc1ccccc1
Yield: 67 %

Procedure:
This compound was prepared from phenoxyamine hydrochloride and chloroacetyl chloride by the method described in Preparation 1, m.p. 126°-128° (decomp.), λmax (EtOH) 266.5 nm (ε15,400), νmax (Nujol) 3340, 3260, 3140 (--NH--), 1720, 1710, 1690 cm-1 (--CONH--), τ(DMSO d6) 5.79 (ClCH2CO--), -2.2 (--NH--), 2.3-3.2 (phenyl). Yield 67%
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[C:14]([Br:16])[N:13]=[C:12](Br)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][NH:19][CH3:20]>C(O)C.O1CCOCC1>[C:1]1([S:7]([C:10]2[CH:15]=[C:14]([Br:16])[N:13]=[C:12]([N:19]([CH3:20])[CH3:18])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1cc(Br)nc(Br)c1
Reactant: CNC
Solvent: CCO
Solvent: C1COCCO1
Product: CN(C)c1cc(S(=O)(=O)c2ccccc2)cc(Br)n1
Yield: 88 %

Procedure:
0.113 g (0.0003 mol) of 4-benzenesulphonyl-2,6-dibromopyridine and 0.54 ml of 5.6 M dimethylamine in ethanol were stirred at room temperature in a mixture of 3 ml of ethanol and 3 ml of dioxan for 5 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:10. There was obtained 0.09 g (88%) of (4-benzenesulphonyl-6-bromopyridin-2-yl) -dimethylamine as white crystals; m.p. 128-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:29][C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])=[C:6]2[C:10]=1[CH2:9][N:8]([CH:11]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:12][C:13](=[O:16])[NH:14][OH:15])[C:7]2=[O:28].[C:35](OC(=O)C)(=[O:37])[CH3:36]>CC#N>[C:35]([O:15][NH:14][C:13]([CH2:12][C@@H:11]([N:8]1[C:7](=[O:28])[C:6]2[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH:29][C:30]([CH:32]2[CH2:33][CH2:34]2)=[O:31])[CH2:9]1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)=[O:16])(=[O:37])[CH3:36]
Reactant: CCOc1cc(C(CC(=O)NO)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(C)=O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 8 h
Yield: 0.8 %

Procedure:
To the solution of cyclopropanecarboxylic acid {7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (0.45 g, 92 mmol) in CH3CN (50 ml) was added acetic anhydride (0.1 ml, 92 mmol) at room temperature. The mixture was stirred overnight. The solvent was removed in vacuo and the resulted solid was stirred with ether (10 ml) for 2 hrs. The suspension was filtered and the solid was dried in oven to give (1R)-cyclopropanecarboxylic acid {2-[2-acetoxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (0.4 g, 80%): mp 139-141° C.; 1HNMR (CDCl3): δ 0.85-0.92 (m, 2H, c-CH2), 1.05-1.11 (m, 2H, c-CH2), 1.43 (t, J=7.5 Hz, 3H, OCH2CH3), 1.62-1.68 (m, 1H, c-CH), 2.12 (s, 3H, CH3), 3.02 (dd, J=5, 16 Hz, 1H, CHH), 3.50 (dd, J=5, 16 Hz, 1H, CHH), 3.85 (s, 3H, OCH3), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 4.12 (d, J=17 Hz, 1H, CHH), 4.38 (d, J=17 Hz, 1H, CHH), 5.61-5.65 (m, 1H, CHN), 6.81-6.94 (m, 3H, Ar), 7.31 (d, J=10 Hz, 1H, Ar), 8.38 (d, J=10 Hz, 1H, Ar), 10.41 (s, 1H); 13C NMR (CDCl3): δ 9.0, 9.1, 15.3, 16.7, 18.7, 36.8, 48.2, 54.4, 56.5, 65.2, 112.2, 112.8, 119.7, 119.8, 120.2, 122.4, 131.1, 133.5, 137.2, 139.8, 149.3, 150.1, 167.0, 169.0, 170.0, 173.5; Anal. Calcd. for C26H28ClN3O7: C, 58.92; H, 5.33; N, 7.93; Found: C, 58.58; H, 5.00; N, 7.76.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][O:39][C:40](=[O:57])[C:41]1[CH:46]=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][C:42]=1[F:56].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=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>[CH3:38][O:39][C:40](=[O:57])[C:41]1[CH:46]=[CH:45][C:44]([C:20]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:43][C:42]=1[F:56]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(C)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Yield: 82.8 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 128, 1.28 g, 2.4 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.01 mg, 2.4 mmol) and dichlorobis(triphenylphosphine)palladium (II) (170 mg, 0.24 mmol) in dioxane (10 mL) was added an aqueous sodium carbonate solution (2 M, 3.6 mL, 7.2 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-2-fluoro-benzoic acid methyl ester (1.03 g, 83%) as a light yellow solid: LC/MS m/e calcd for C29H27FN2O4S [M+H]+ 519.61, observed 518.8.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)\[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccncc2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol (1 g, 2.81 mmol, 1 equiv.) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. in ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) followed by HPLC to provide pure product. 1H NMR (DMSO, Oxalate Salt) δ (ppm): 8.60 (d,2H), 7.62 (m,3H), 7.40 (s,1H), 7.30 (d,1H), 7.20 (d,1H), 4.40 (m,2H), 3.10 (m,4H), 2.99 (s,3H), 1.90 (s,3H).