Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[C:29]([C:37](O)=[O:38])[CH:28]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:37]([C:29]4[CH:28]=[C:27]([CH3:26])[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[O:38])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Cc1cc(C(=O)O)nc2ccccc12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(C)c5ccccc5n4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-methylquinoline-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from methanol to yield the title compound.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:32][S:33]([C:36]2[S:37][C:38](Br)=[CH:39][CH:40]=2)(=[O:35])=[O:34])[CH:26]=1>>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:32][S:33]([C:36]2[S:37][C:38]([C:13]#[C:12][C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]5[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=5)=[N:6][C:7]=34)=[CH:39][CH:40]=2)(=[O:35])=[O:34])[CH:26]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCc1cccnc1)c1ccc(Br)s1
Product: O=S(=O)(NCc1cccnc1)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (pyridin-3-ylmethyl)-amide (example B.56) (167 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (139 mg, 47%). MS (ISN) 588.0 [(M−H)−]; mp 152° C.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[N+]([C:22]1C=CC(CCBr)=CC=1)([O-])=O.N1(C(OC(C)(C)C)=O)CCCNCC1>>[ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][N:13]2[CH2:22][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: CC(C)(C)OC(=O)N1CCCNCC1
Agent: Cl
Product: O=[N+]([O-])c1ccc(CCN2CCCNCC2)cc1

Procedure:
1-[2-(4-nitrophenyl)ethyl]-1,4-diazepane hydrochloride was prepared in an analogous fashion to that described above for 1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride starting with 4-nitrophenethyl bromide and tert-butyl 1,4-diazepane-1-carboxylate. LC-MS: M+1=250.2.
Reaction SMILES: Br[C:2]1[C:10]2[O:11][CH2:12][CH2:13][C:9]=2[C:8]2[C:7](=[O:14])[CH2:6][CH2:5][C:4]=2[C:3]=1Br.C([O-])(=O)C.[Na+].O>CO.[Pd]>[CH2:13]1[CH2:12][O:11][C:10]2[CH:2]=[CH:3][C:4]3[CH2:5][CH2:6][C:7](=[O:14])[C:8]=3[C:9]1=2
Reactant: O=C1CCc2c(Br)c(Br)c3c(c21)CCO3
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CCc2ccc3c(c21)CCO3
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
To a suspension of 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (18.4 g, 55.4 mmols) in methanol (400 mL) was added 10% Palladium on activated carbon (2.0 g, 50% hydrous) followed by sodium acetate (12.6 g, 154 mmols). The mixture was stirred at 40° C. for 1.5 hours under hydrogen atmosphere (4 kgf/cm2). The catalyst was filtered off and the filtrate was concentrated under reduced pressure. Crystals were collected by filtration, washed with water and recrystallized successively with methanol:water=5:1 to obtain 8.0 g (yield: 83%) of the title compound.
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1.CN([CH:17]=[O:18])C.[BH4-].[Na+].[NH4+].[Cl-]>CCOCC.CCO>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:17][OH:18])=[CH:9][N:8]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCO
Solvent: CCOCC
Product: OCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.2 %

Procedure:
Two simultaneous reactions were conducted whereby: BuLi (29.9 ml of a 1.6 M solution in hexanes, 47.7 mmol) was added to a stirred solution of 2,5-dibromopyridine (10.3 g, 43.4 mmol) in Et2O (250 ml) at −78° C. under nitrogen over 10 min. The resulting mixture was stirred for 15 min, then DMF (10.07 ml, 0.13 mol) was added. The reaction was allowed to warm to room temperature and then stirred for a further 30 min. The reaction was quenched by addition of H2O (30 ml). The reaction mixtures were combined and extracted with EtOAc (3×250 ml). The combined organic extracts were washed with brine (100 ml), dried and concentrated under reduced pressure. The crude residue was taken up in EtOH (100 ml) and cooled to 0° C. NaBH4 (3.26 g, 86.4 mmol) was added portionwise over 10 min, the reaction was warmed to room temperature and stirred for 90 min. NH4Cl (sat., 50 ml) was added cautiously, most of the EtOH was removed under reduced pressure and the reaction mixture was diluted with H2O (100 ml). After extraction with EtOAc (3×250 ml), the combined organic extracts were washed with brine (50 ml), dried and concentrated under reduced pressure. Column chromatography on silica using 75-80% Et2O/hexanes as eluent gave the title alcohol (5.65 g, 35%).
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]=1I)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O1CCCC1.[Cu]I>[CH3:20][O:19][C:18]1[C:13]2[N:12]=[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:11][C:14]=2[C:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][CH:17]=1
Reactant: COc1cnc(-c2ccccc2)c(I)c1NC(=S)NC(=O)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cnc(-c2ccccc2)c2sc(NC(=O)c3ccccc3)nc12
Temperature: 130 °C
Yield: 81.2 %

Procedure:
A stirred suspension of 600 mg (1.23 mmol) 1-benzoyl-3-(3-iodo-5-methoxy-2-phenyl-pyridin-4-yl)-thiourea, 23 mg (0.12 mmol)-copper(I) iodide, 44 mg (0.25 mmol) 1,10-phenanthroline and 799 mg (2.45 mmol) cesium carbonate in 4 ml toluene was heated at 130° C. for 2×5 min in a microwave oven. The resulting mixture was then cooled to room temperature and diluted with tetrahydrofuran, stirred and filtered. The filter cake was washed with tetrahydrofuran and the combined filtrate and washings were concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) afforded 361 mg (81%) N-(7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-yl)-benzamide as a white solid. ES-MS m/e (%): 362 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: C1COCCN1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: CCO
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCOCC1
Reaction time: 1 h
Yield: 92.3 %

Procedure:
2-Chloro-5-nitrobenzonitrile (16.7 g) and morpholine (16 g) were added to ethanol (300 ml) and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give 5-nitro-2-morpholinobenzonitrile (19.7 g), melting point: 138–140° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9](Cl)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15]CC)=O)[N:6]2[CH3:12].[CH3:18][NH2:19].CO>>[CH3:18][NH:19][C:13]([C:5]1[N:6]([CH3:12])[C:7]2[C:3]([CH:4]=1)=[CH:2][CH:10]=[CH:9][CH:8]=2)=[O:15]
Reactant: CN
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2n1C
Solvent: CO
Product: CNC(=O)c1cc2ccccc2n1C
Temperature: 50 °C
Reaction time: 17.5 h
Yield: 99 %

Procedure:
A suspension of ethyl 4,6-dichloro-1-methyl-1H-indole-2-carboxylate (1.06 g, 3.90 mmole) in 2.0 M CH3NH2/CH3OH (40 mL) in a sealed pressure bottle was heated in an oil bath preset at 50° C. A homogeneous solution formed within 2.5 hr. The reaction was kept at 50° C. for 17.5 hr, during which time a solid precipitated. The mixture was cooled to RT and poured into H2O (40 mL). The resulting mixture was concentrated on the rotavap to remove the methanol, and the solid was collected by suction filtration. This was washed with plenty of H2O and dried in high vacuum at 45-50° C. to afford the title compound (0.99 g, 99%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 7.16 (d, J=1.5 Hz, 1H), 6.86 (s, 1H), 6.21 (br s, 1H), 4.02 (s, 3H), 3.02 (d, J=4.9 Hz, 3H); MS (ES) m/e 257 and 259 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([OH:13])[CH2:10][C:11]#[CH:12]>C(NCC)C.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]#[C:11][CH2:10][CH2:9][OH:13])=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Solvent: CCNCC
Product: OCCC#Cc1ccc(F)cc1
Reaction time: 16 h
Yield: 34.2 %

Procedure:
Copper (I) iodide was added to a stirred solution of 1-fluoro-4-iodobenzene (11.09 g), 3-butyn-1-ol (3.5 g), and BTPC (100 g) in diethylamine (70 ml) and the mixture stirred under nitrogen for 16 h. The mixture was evaporated in vacuo and purified by FCC on eluting with H - EA (2:1) gave the title compound as a yellow solid (2.8 g). T.l.c. (H - EA 2:1) RF 0.20.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C@@H:3]([N:5]1[CH2:10][CH2:9][C@@:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)([CH2:11][CH2:12][OH:13])[O:7][C:6]1=[O:21])[CH3:4].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:13][CH2:12][CH2:11][C@@:8]1([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:7][C:6](=[O:21])[N:5]([C@H:3]([C:2]([CH3:22])([CH3:1])[CH3:23])[CH3:4])[CH2:10][CH2:9]1)(=[O:34])=[O:33]
Reactant: C[C@H](N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](N1CC[C@](CCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Temperature: 25 °C
Yield: 102.6 %

Procedure:
To a solution of (S)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (220 mg, 0.68 mmol) and triethylamine (206 mg, 2.04 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (233 mg, 2.04 mmol) at 0° C., and the reaction mixture was stirred at rt till the reaction was over. The reaction was quenched with H2O. The mixture was extracted with EtOAc, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude 2-((S)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methanesulfonate (280 mg, crude), which was used for the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][N:13]3C(OC(C)(C)C)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O.C(Cl)Cl>>[N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][C@@H:14]3[CH2:16][C@H:11]2[CH2:12][NH:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc([N+](=O)[O-])nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(N2C[C@@H]3C[C@H]2CN3)cn1

Procedure:
The product from Example 3A was treated with trifluoroacetic acid:methylene chloride (1:2) at ambient temperature for 2 hours. The volatiles were removed under reduced pressure, and the residue was purified on SiO2 (5% MeOH/CH2Cl2/1%NH4OH) to provide the title compound as a yellow gum. MS (DCI/NH3) m/z 221 (M+H)+, 238 (M+NH4)+.
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[C:24]([C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH:14]=1.[OH-].[K+]>O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[C:24]([C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:29])[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1
Reactant: COc1cccc(OC)c1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(=O)N4CCOCC4)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(OC)c1-c1c[nH]c2ncc(-c3cccc(C(=O)N4CCOCC4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Methanol (1 mL) was added to crude (3-(3-(2,6-dimethoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone from step 1 and potassium hydroxide (50% w/v, 0.038 mL, 0.34 mmol) was added to the resulting solution. The mixture was stirred for 30 minutes at room temperature before being diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography afforded (3-(3-(2,6-dimethoxyphenyl)-1H-pyrrolo [2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (7) (31% yield from (3-(3-iodo-1-tosyl-1H-pyrrolo [2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone) as light yellow solids. 1H NMR (500 MHz, CD3OD) δ 3.65 (m, br, 8H), 3.75 (s, 6H), 6.77 (d, J=8.5 Hz, 2H), 7.31 (t, J=8.5 Hz, 1H), 7.39 (m, 1H), 7.46 (s, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.67 (m, 1H), 7.74 (m, 1H), 7.91 (d, J=2.0 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H). MS: m/z 444.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[C:9]#[N:10])(=[O:3])[CH3:2].[Br:13]Br>C(Cl)Cl>[Br:13][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[C:9]#[N:10])=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(F)c(C#N)c1
Solvent: ClCCl
Product: N#Cc1cc(C(=O)CBr)ccc1F
Reaction time: 8 h

Procedure:
A solution of 5-acetyl-2-fluorobenzonitrile (20.0 g, 0.123 mol) in 500 mL of DCM was heated to reflux for 2 h, and then a solution of bromine in 300 mL DCM was added dropwise into the boiling mixture. The reaction mixture was heated to reflux and stirred under N2 protection overnight. The reaction mixture was washed with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified via silica gel column chromatography to give 5-(bromoacetyl)-2-fluorobenzonitrile.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[C:8]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:9]=1.[CH:24]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]1[S:30]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[C:8]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:9]=1)(=[O:32])=[O:31]
Reactant: CCOC(=O)CCc1cc(CCN)cc(Cc2cccnc2)c1
Reactant: O=S(=O)(Cl)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1cc(CCNS(=O)(=O)C2CCCCC2)cc(Cc2cccnc2)c1
Yield: 45.5 %

Procedure:
A solution of ethyl 3-[3-(2-aminoethyl)-5-(3-pyridylmethyl)phenyl]propanoate (Preparation 47; 0.60 g), cyclohexylsulphonyl chloride (0.526 g), triethylamine (0.194 g) and 4-dimethylaminopyridine (0.352 g) in dichloromethane (6 ml) was stirred at room temperature for 3 hours and then washed with water and dried (MgSO4). Evaporation under vacuum of the solvent gave a gum which was chromatographed on silica gel. Elution with dichloromethane, followed by a dichloromethane:methanol (97:3) mixture gave the title compound as a gum (401 mg); Rf 0.70 (SS 2); δ (CDCl3): 1.10-1.25(2H,m), 1.21(3H,t,J=7.1 Hz), 1.37-1.50(2H,m), 1.65-1.70(2H,m), 1.83-1.86(2H,m), 2.05-2.09(2H,m), 2.57(2H,t,J=7.7 Hz), 2.79(2H,t,J=6.9 Hz), 2.88 (2H,t,J=7.7 Hz), 3.30-3.37(2H,m), 3.91(2H,s), 3.99-4.02 (1H,m), 4.10(2H,q,J=7.1 Hz), 6.86(1H,s), 6.89(1H,s), 6.91(1H,s), 7.21-7.23(1H,m), 7.44(1H,d,J=7.9 Hz), 8.45-8.47(2H,m).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].[C:6]1(=[O:12])C[CH2:10][CH2:9][CH2:8][CH2:7]1.C(OCC)=O>CCOCC>[OH:5][CH:3]=[C:4]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:12]
Reactant: CCO
Reactant: O=C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC=O
Product: O=C1CCCCC1=CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 50% sodium hydride dispersion in oil (24 g., 0.5 mole) and absolute ethanol (2.5 ml., 43 mmole) in 1 liter ether were stirred under N2 at 0° C. To the cold solution, cyclohexanone (51.5 ml., 0.5 mole) in ethyl formate (60 ml., 0.75 mole) was added dropwise at 0°-5° C. The cooling bath was removed. The temperature rose to the boiling point of ether over 30 minutes. The reaction mixture was recooled, warmed gradually to room temperature over 6 hours and finally stirred for an additional 16 hours. Ether lost by evaporation was replaced by diluting to 1 liter with fresh ether. Ethanol (12.5 ml.) was added and stirring continued for 1 hour. The mixture was extracted with 125 ml. water in two portions. The combined aqueous extracts were washed 1×50 ml. ether, acidified with 82 ml. 6N HCl, and extracted 2×150 ml. with fresh ether. The acid ether extracts were combined, washed 1×25 ml. brine, dried over Na2SO4, evaporated to an oil and distilled to yield title product, 44 g., b.p. 92°-98°/15-20 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:8]2.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>>[Cl:24][CH2:25][C:26]([N:13]([CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:8]1)[CH2:14][CH2:15][CH3:16])=[O:27]
Reactant: CCCNC1CCc2c(cccc2OC)C1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Product: CCCN(C(=O)CCl)C1CCc2c(cccc2OC)C1
Yield: 92.9 %

Procedure:
This compound was prepared from 32b (4.63 g, 21.1 mmol), triethyl amine (5.1 ml, 42.2 mmol), and chloroacetyl chloride (1.80 ml, 25.4 mmol) by following Procedure B to give 33b (5.8 g, 93%). 1H NMR (400 MHz, CDCl3) 0.90-0.98 (m, 3H), 1.64-1.72 (m, 2H), 3.19-3.27 (m, 2H), 4.00 (s, 3H), 6.61-6.68 (m, 2H), 6.96-7.04 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27](O)=[O:28])[CH:22]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:59][N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([N:63]3[CH2:64][CH2:65][N:60]([CH3:59])[CH2:61][CH2:62]3)=[O:28])[CH:22]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20]
Reactant: O=C(O)c1cccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)c1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2cccc(-c3ccc(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Charge a vial with 3′-chloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-3-carboxylic acid (Example 7) (70 mg, 0.17 mmol), EDCl (2.0 eq.) and HOBt (1.0 eq.). Dissolve in DMF (0.1 M) and add triethylamine (4.0 eq.) and N-methyl piperazine (34 mg, 0.34 mmol) (2.0 eq). Stir at room temperature overnight. Pour into water and extract with ether. Dry over sodium sulfate, filter and concentrate. Purify over silica gel. Dissolve the residue in methylene chloride and acidify with 4N HCl in dioxane. Concentrate in vacuo. Mass spec (apci) m/z=494.3 (M+H-HCl).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[C:39]([CH3:41])[C:38]([O:42][CH2:43][CH2:44][O:45][CH2:46][CH3:47])=[C:37]([CH3:48])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:46]([O:45][CH2:44][CH2:43][O:42][C:38]1[C:39]([CH3:41])=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][C:37]=1[CH3:48])[CH3:47]
Reactant: CCOCCOc1c(C)cc(OB([O-])[O-])cc1C
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: Cc1ccccc1
Solvent: CCO
Product: CCOCCOc1c(C)cc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.3 g), 4-(2-ethoxyethoxy)-3,5-dimethylphenyl borate (0.16 g), 1M potassium carbonate solution (1.3 ml), ethanol (1.3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.03 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to precipitate crude crystals, which were collected by filtration, washed with ethyl acetate/hexane, recrystallized from ethanol to give 7-[4-(2-ethoxyethoxy)-3,5-dimethylphenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 124) (0.32 g) as colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:57][O:58][CH:59]1[CH2:63][CH2:62][N:61]([CH2:64][C:65]2[CH:70]=[CH:69][C:68]([CH2:71][NH:72][CH3:73])=[CH:67][CH:66]=2)[CH2:60]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:72]([CH2:71][C:68]3[CH:67]=[CH:66][C:65]([CH2:64][N:61]4[CH2:62][CH2:63][CH:59]([O:58][CH3:57])[CH2:60]4)=[CH:70][CH:69]=3)[CH3:73])=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1ccc(CN2CCC(OC)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(OC)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (40 mg, 0.11 mmol), EDCI (30 mg, 0.15 mmol), HOBt (23 mg, 0.17 mmol), DIPEA (0.04 mL, 0.23 mmol) and 1-{4-[(3-methoxypyrrolidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (37 mg, 0.13 mmol) in DCM (10 mL).