Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[CH:22]([O:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][N:42]([CH2:45][C:46](O)=[O:47])[C:41](=[O:49])[N:40]=1)=[O:37])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH:22]([O:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][N:42]([CH2:45][C:46]([N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][C:5]=3[N+:19]([O-:21])=[O:20])(=[O:11])=[O:10])[C:13](=[O:18])[CH2:14]2)=[O:47])[C:41](=[O:49])[N:40]=1)=[O:37])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3ccc(Cl)cc3[N+](=O)[O-])C(=O)C2)c(=O)n1)OC(c1ccccc1)c1ccccc1
Yield: 27.4 %

Procedure:
The title compound (0.56 g, 27%) was synthesized by reaction of 1-(4-chloro-2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (1.07 g, 3.0 mmol) with [4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid (1.14 g, 3.0 mmol), as per the procedure of example 77. 1H NMR(DMSO-d6) δ 10.98(s, 11H), 8.40(s, 1H), 8.32(m, 11H), 8.07(m, 11H), 7.89(d, 0.6H), 7.85(d, 0.4H), 7.46˜7.28(m, 1H), 6.96(m, 1H), 6.79(s, 1H), 4.81(s, 1.2H), 4.73(s, 0.8H), 4.45(s, 0.8H), 4.27(s, 1.2H), 4.07˜3.97(m, 2.4H), 3.90˜3.80(m, 1.6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Br[C:18]1[O:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[O:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)[N:3]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: O=[N+]([O-])c1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C#CC=C2CCN(c3ccc([N+](=O)[O-])o3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of the Compound of Example 3 (100 mg, 0.47 mmol), 2-bromo-5-nitrofuran (98 mg, 0.51 mmol) and potassium carbonate (72 mg, 0.52 mmol) in DMF (2 mL) was stirred at r.t. for 4 h. Afterwards, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography eluting with Petroleum Ether-EtOAc 6:4 affording the title product (94 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13]O)[CH2:10][C:9]2=[O:15])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>N1C=CC=CC=1>[Br:36][CH2:13][CH:11]1[CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9](=[O:15])[CH2:10]1
Reactant: O=C1CC(CO)CN1c1ccc(F)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: O=C1CC(CBr)CN1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a cooled solution of 1-(4-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-2-one (0.05 g, 0.25 mmol) in pyridine (3 ml) was added triphenylphosphine (0.130 g, 0.5 mmol). The solution was stirred and carbon tetrabromide (0.08 g, 0.25 mmol) was added in 3 separate portions. The reaction mixture was then allowed to warm to room temperature and stirred for three hours. The reaction was quenched with methanol and the solvent removed. The residue was dissolved in EtOAc (75 ml) and sequentially washed with ammonium chloride (sat, 2×25 ml) and water (25 ml). The organic layer was concentrated and purified using preparative tlc (1:1 EtOac:Hexanes) to yield 4-(bromomethyl)-1-(4-fluorophenyl)pyrrolidin-2-one (HNMR).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=O.CN(C)CCN>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:25][CH2:26][CH2:27][N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0151 mole), 1,1'-carbonyldiimidazole (2.45 g, 0.0151 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 3 hours. The nitrogen flow was stopped and a solution of N,N-dimethylethylenediamine (1.46 g, 0.0166 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction micture was concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake was recrystallized from ethanolisopropyl ether-tetrahydrofuran to give 4.45 g (73%) of white flakes, mp 195°-197° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)([O-:3])=[O:2].[O:11]=[C:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(OCC)(=O)C.O>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([N:13]2[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:17][C:12]2=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)C(=O)C1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 2-nitro-5-bromopyridine (1.00 g, 5.00 mmol), 2-oxo-4-(tert-butoxycarbonyl)piperazine (1.01 g, 5.00 mmol), cesium carbonate (3.58 g, 11.0 mmol) and 1,4-dioxane (40 mL). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (246 mg, 0.425 mmol) and tris(dibenzylidene-acetone)dipalladium(0) (230 mg, 0.250 mmol) were added, and the reaction mixture was heated at reflux for 6 h. Water (30 mL) and ethyl acetate (150 mL) were added after the reaction mixture was cooled to room temperature. The resulting mixture was filtered through a bed of Celite 521. The organic layer of the filtrate was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and purified by column chromatography to afford a 96% yield (1.55 g) of 121a as an amber oil: 1H NMR (300 MHz, CDCl3) δ 8.67 (d, 1H, J=2.4 Hz), 8.32 (d, 1H, J=8.7 Hz), 8.15 (dd, 1H, J=8.7, 2.4 Hz), 4.33 (s, 1H), 3.89 (m, 4H), 1.48 (s, 9H); MS (ESI+) m/z 323.1 (M+H).
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([C:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]>CO>[OH:3][N:2]=[C:5]([C:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: NO
Reactant: COC(=O)C(=O)c1csc2ccccc12
Agent: Cl
Solvent: CO
Product: COC(=O)C(=NO)c1csc2ccccc12
Reaction time: 8 h
Yield: 73.7 %

Procedure:
Hydroxylarnine hydrochloride (503 mg) was added to a stirred solution of methyl 2-oxo-2-(3-benzothienyl)acetate (790 mg) in methanol (30 ml). When all the solid had dissolved the mixture was allowed to stand overnight. The solvent was evaporated and the residue partitioned between ethyl acetace and water. The organic phase was washed with water and brine, dried over magnesium sulphate and evaporated. The title oxime (622 mg) was isolated as a mixture of isomers by column chromatography of the residue (Kieselgel: 3:1 going to 1:1 hexane:ethyl acetate. νmax (CHCl3)/cm-1 3568, 3296, 1737. δH (250 MHz, CDCl3), 3.90 and 4.00 (3H, two s's), 7.37-7.59 (2H, m), 7.61 and 7.77 (1H, two s's), 8.30 and 9.15 (1H, two broad s's), 8.43-8.47 (1H, m); m/z (EI) 235 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.[ClH:26].O1CCOCC1.C(OCC)C>O1CCOCC1>[ClH:26].[CH3:1][C:2]1[C:10]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(Oc2ccc(C#N)cc2)ccc2c1cnn2C1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1c(Oc2ccc(C#N)cc2)ccc2[nH]ncc12
Yield: 83 %

Procedure:
Under nitrogen, 4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]benzonitrile (338 mg, 1.01 mmol) was dissolved in 1,4-dioxane (6 ml), followed by adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (6 ml), and the resulting mixture was stirred at room temperature for 23 hours. After diethyl ether (30 ml) was added thereto and stirred, the precipitate was collected by filtration, washed with diethyl ether and then dried under reduced pressure to obtain 4-[(4-methyl-1H-indazol-5-yl)oxy]benzonitrile monohydrochloride (239 mg, yield 83%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[C:9]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=3)[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[N+:30]([O-:32])=[O:31].Cl.Cl[CH2:35][CH2:36][CH:37]1[CH2:41][CH2:40][CH2:39][N:38]1[CH3:42]>CN(C)C=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([N:23]([CH2:35][CH2:36][CH:37]3[CH2:41][CH2:40][CH2:39][N:38]3[CH3:42])[C:24](=[O:29])[C:25]([F:28])([F:26])[F:27])=[C:9]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=3)[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[N+:30]([O-:32])=[O:31]
Reactant: Cc1cc(C)cc(-c2c(NC(=O)C(F)(F)F)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Reactant: CN1CCCC1CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(-c2c(N(CCC3CCCN3C)C(=O)C(F)(F)F)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a suspension of 10 mg sodium hydride in 1.0 mL N,N-dimethylformamide was added 90 mg N-[7-chloro-3-(3,5-dimethylphenyl)-6-nitro-2-oxo-1,2-dihydroquinolin-4-yl]-2,2,2-trifluoroacetamide and the mixture stirred at room temperature for 1 hour. At this time, 75 mg of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride and the mixture heated to 80° C. on an oil bath. After 6 hours, the mixture was cooled to room temperature, diluted with ethyl acetate and extracted with water. The organic portion was washed with brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 95:5+1% ammonium hydroxide) gave the title compound (50 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][CH2:12][OH:13])[CH3:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][CH:12]=[O:13])[CH3:10]
Reactant: CC(C)(C)[S@@](=O)N[C@@](C)(CCO)c1cccc(F)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N[C@@](C)(CC=O)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of (R)-N-((S)-2-(2,3-difluorophenyl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (14.56 g, 47.7 mmol) in DCM (250 ml) at room temperature was added Dess-Martin periodinane (22.24 g, 52.4 mmol) in one portion. The reaction was stirred at room temperature overnight. The reaction was quenched with water (150 ml) and saturated NaHCO3 solution (150 ml). The resulted solution was diluted with DCM and the layers were separated. The organic layer was washed with saturated NaHCO3 (3×), water and brine. The solution was then dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (20-65% EtOAc/hexane) to afford (R)-N-((S)-2-(2,3-difluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (13.5 g, 44.5 mmol, 93% yield) as light yellow oil. MS m/z=304.1 [M+H]+. Calculated for C14H19F2NO2S: 303.4
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[CH3:13][CH:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][CH:14]([OH:15])[CH3:16])=[CH:6][CH:5]=1
Reactant: CC1CO1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)Cn1ccc2ccc(F)cc21
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A suspension of 0.26 g of sodium hydride dispersion in 35 ml of tetrahydrofuran was treated with 0.97 g of 6-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 1 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with 7 ml of water. The mixture was diluted with 180 ml of ether, washed twice with 90 ml of water and with 50 ml of saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 28 g of silica gel with toluene-ethyl acetate (19:1). There were obtained 1.1 g (79.3%) of (RS)-1-(6-fluoro-indol-1-yl)-propan-2-ol as a colourless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.F[C:20]1C=CC=C[C:21]=1[N+]([O-])=O.NC1C=CC=CC=1>>[N:14]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][CH2:6][C:2]2[NH:1][CH2:5][CH2:4][N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:21]=[CH:20]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: c1ccc(N2CCCC2)c(NCC2=NCCN2)c1
Solvent: Nc1ccccc1
Product: C1=CC=CN(c2ccccc2NCC2=NCCN2)C=C1

Procedure:
Under conditions similar to those used for the preparation of N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(1-pyrrolidinyl)aniline (Example 64), hexamethyleneimine was reacted with 2-fluoronitrobenzene, the nitro group was reduced and the aniline was coupled with CMI to give 2-(1-azepinyl)-N-(4,5-dihydro-1H-imidazol-2-ylmethyl)aniline .
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([C:26]([N:28]2[C:36]3[C:31](=[CH:32][C:33]([F:37])=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH:19]=1>CN1C(=O)CCC1>[F:37][C:33]1[CH:32]=[C:31]2[C:36](=[CH:35][CH:34]=1)[N:28]([C:26]([C:20]1[N:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:18]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:19]=1)=[O:27])[CH2:29][CH2:30]2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: COc1cc(Cl)cc(C(=O)N2CCc3cc(F)ccc32)n1
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)cc(C(=O)N2CCc3cc(F)ccc32)n1

Procedure:
436 mg (2.00 mmol) 1-Piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one and 200 mg (0.652 mmol) of (4-chloro-6-methoxy-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone in 2 mL NMP were stirred overnight at 120° C. The reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and evaporated down using the rotary evaporator.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2ccccc2C1=O
Product: CC(=O)N1C(=O)C(=O)c2ccccc21

Procedure:
To 60 g of isatin was added 140 ml of acetic anhydride and the mixture was refluxed for 4 hours. The reaction mixture was cooled, and the crystals precipitated were collected by filtration, and washed with ether to obtain 58 g of N-acetylisatin.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:23][C:24]([Cl:31])([Cl:30])[CH2:25][O:26][C:27](Cl)=[O:28]>C(#N)C>[Cl:23][C:24]([Cl:31])([Cl:30])[CH2:25][O:26][C:27]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][S:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:28]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: c1ccc(CN2CCC(CCSc3ccccc3)CC2)cc1
Solvent: CC#N
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC(CCSc2ccccc2)CC1
Yield: 93.7 %

Procedure:
A solution of 1.24 g (3.98 mmol) of 1-benzyl-4-(2-(phenylmercapto)-1-ethyl)piperidine and 0.61 mL (4.4 mmol) of 2,2,2-trichloroethylchloroformate in 10 mL of acetonitrile was stirred at rt for 2.5 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, hexanes:ehtyl acetate, 4:1) to give 1.48 g of the title compound.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:23]#[C:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.C(O)C.O>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:23]#[C:24][CH2:25][N:26]([CH3:27])[CH3:28])[C:13]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(C#CCN(C)C)cccc2c1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2c(C#CCN(C)C)cccc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Temperature: 50 °C
Yield: 19.9 %

Procedure:
To a solution of ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-5-(3-(dimethylamino)prop-1-ynyl)-3-methylnaphthalen-2-yl)acetate (6.5 mg, 0.013 mmol) in tetrahydrofuran:ethanol:water (2:2:1, 4 mL) was added lithium hydroxide (2 mg, 0.066 mmol) and the reaction was heated to 50° C. overnight. The reaction was purified by reverse phase HPLC (Gemini, 40-60% ACN/H2O+0.1% TFA). The product was lyophilized to give a white powder (1.2 mg). 1H-NMR: 400 MHz, (CD3OD) δ: 8.14 (s, 1H), 7.74 (d, J=6.4 Hz, 1H), 7.58 (s, 2H), 7.56 (as, 1H), 7.33 (m, 3H), 5.18 (s, 1H), 4.42 (s, 2H), 3.04 (s, 6H), 2.67 (s, 3H), 0.99 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H31ClNO3: 464.19; found: 464.51.
Reaction SMILES: S([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[C:12]1[C:20]([O:22][CH2:23]C)=[O:21])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CO.C1COCC1>[NH:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[C:12]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CCOC(=O)c1cc2cnccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2cnccc2[nH]1
Temperature: 15 °C
Reaction time: 12 h

Procedure:
A mixture of compound 6-c (6 g, 17.4 mmol) and Cs2CO3 (CAS 534-17-8) (17 g, 52.2 mmol) in methanol (70 mL) and THF (140 mL) was stirred at 15° C. for 12 h. The solvent was removed under vacuum. H2O (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated under vacuum to yield product 6-d as a white powder (1.39 g, 46%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH:9]([CH3:22])[CH2:10][C:11]1[CH:21]=[CH:20][C:14]2[O:15][CH:16]([CH2:18][NH2:19])[O:17][C:13]=2[CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:23])[N:7]([CH:9]([CH3:22])[CH2:10][C:11]1[CH:21]=[CH:20][C:14]2[O:15][CH:16]([CH2:18][NH:19][C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[O:17][C:13]=2[CH:12]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Cc1ccc2c(c1)OC(CN)O2)N(C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2)N(C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 0.31 g (0.96 mmol) of 1F in 5 mL of dichloromethane was added 0.2 mL (1.14 mmol) of N,N-diisopropylethylamine and 10 mg (0.08 mmol) of 4-dimethylaminopyridine (4-DMAP) followed by 0.15 mL of benzyl chloroformate (1.04 mmol) at room temperature. The mixture was allowed to stir for 1 hours and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash column chromatography using 40% ethyl acetate in hexane to give 0.41 g (0.89 mmol, 94%) of 1G as a thick colorless gum (M+Na, 479).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[CH2:22][NH2:23])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>[OH-].[Na+].ClCCl>[F:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[CH2:22][NH:23][S:29]([CH3:28])(=[O:31])=[O:30])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
[2-({4-[(E)-2-(4-Fluorophenyl)vinyl]phenyl}sulfonyl)benzyl]amine hydrochloride (Example 178, 120 mg, 0.3 mmol) was added to a rapidly stirred mixture of methanesulfonyl chloride (50 μL, 0.6 mmol) in 1M sodium hydroxide (3 mL) and dichloromethane (3 mL). After 30 minutes, further methanesulfonyl chloride (100 μL, 1.2 mmol) and 4M sodium hydroxide (1 mL) were added and the reaction stirred for 30 minutes. The layers were separated and the organic layer washed with 1N HCl, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 60% ethyl acetate/isohexane to give the title compound as a white solid (30 mg, 22%). δH (500 MHz, d6 DMSO): 8.10 (1H, d, J=7.9 Hz), 7.90 (2H, d, J=8.4 Hz), 7.80 (2H, d, J=8.4 Hz), 7.75-7.67 (4H, m), 7.59 (1H, t, J=7.3 Hz), 7.55 (1H, s), 7.44 (1H, d, J=16.4 Hz), 7.29 (1H, d, J=16.5 Hz), 7.22 (2H, t, J=8.8 Hz), 4.44 (2H, s), 2.89 (3H, s).
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[N:12]=1>C(O)(=O)C>[N:10]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[N:12]=2)[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1cccc(N)n1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(-n2cccc2)n1

Procedure:
6.3 ml of 2,5-dimethoxy-tetrahydrofuran were added with stirring at room temperature to a solution of 7 g of the product of Step C in 17.5 ml of acetic acid and was refluxed for one hour. Acetic acid was evaporated under reduced pressure and the oil residue was chromatographed over silica gel. Elution with methylene chloride yielded 3.7 g of 2-(pyrrol-1-yl)-6-methoxy carbonyl-pyridine melting at 61° C.