Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[C:45]2[N:44]=[CH:43][N:42]([CH3:46])[C:41]=2[CH:40]=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[C:45]3[N:44]=[CH:43][N:42]([CH3:46])[C:41]=3[CH:40]=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: Cn1cnc2c(CCl)cccc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2ncn3C)cc1

Procedure:
Analogously to Method D, 0.800 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.317 g of 4-chloromethyl-1-methyl-1H-benzimidazole are reacted. The title compound is obtained as a yellow resin. Rf=0.30 (15:1 dichloromethane-methanol); Rt=4.74.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:13][C:12]3([CH2:22][C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:28][O:29]C5CCCCO5)=[O:27])[CH:19]=4)[O:14]3)[CH2:11]2)=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][C:12]3([CH2:22][C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:28][OH:29])=[O:27])[CH:19]=4)[O:14]3)[CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccc(F)cc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccc(F)cc3)C1)O2)NO
Yield: 91.1 %

Procedure:
(E)-3-{1′-[2-(4-Fluoro-phenyl)-ethyl]-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (85 mg, 0.18 mmol) in DCM (8 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving (E)-3-{1′-[2-(4-fluoro-phenyl)-ethyl]-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl}-N-hydroxy-acrylamide (65 mg, hydrochloride salt) as as a light brown solid.
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH2:11]([C:15]1[S:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[CH:16]=1)[CH2:12][CH2:13][CH3:14]>>[CH2:11]([C:15]1[S:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16]=1[S:6]([Cl:10])(=[O:8])=[O:7])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1cc2ccccc2s1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCc1sc2ccccc2c1S(=O)(=O)Cl

Procedure:
2-n-Butylbenzo[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with DMF (6.6 mmoles, 0.51 ml), sulfuryl chloride (5.6 mmoles, 0.45 ml) and 2-n-butylbenzo[b]thiophene (3.3 mmoles, 0.63 g). Flash chromatography (2% ethyl acetate/hexanes) provided 0.68 g (71%) of an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:23])=[C:18]([CH:22]=1)[C:19](O)=O>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:23])=[C:18]([CH2:19][C:10]2[S:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:12][CH:11]=2)[CH:22]=1
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: Clc1cccc(-c2cccs2)c1
Product: Cc1ccc(Br)cc1Cc1ccc(-c2cccc(Cl)c2)s1

Procedure:
2-(3-Chlorophenyl)thiophene obtained in Reference Example 85-(1) and 5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) were treated in a manner similar to Reference Example 5 to give the target compound as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([N:18]=[N+:19]=[N-:20])[CH2:12]2)=[C:4](Cl)[N:3]=1.[NH3:22].CO>>[N:18]([C@H:13]1[CH2:12][C@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([NH2:1])=[N:3][C:4]=3[NH2:22])[O:15][C@@H:14]1[CH2:16][OH:17])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(Cl)nc(N)nc32)O[C@@H]1CO
Reactant: N
Solvent: CO
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(N)nc(N)nc32)O[C@@H]1CO
Temperature: 80 °C
Yield: 58 %

Procedure:
A mixture of compound 77 (190 mg, 0.61 mmol) and NH3/CH3OH (30 mL) was heated to 80° C. at seal bomb for 18 h, then cooled to room temperature. The reaction mixture was evaporated and purified by flash column chromatography with dichloromethane:ethyl acetate:methanol=7:7:1 to obtain the white solid 100 mg 58%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.Cl[C:19]1[N:24]=[C:23]([Cl:25])[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=1>ClCCCl.CC(O)(C)C.[Zn+2].[Br-].[Br-]>[Cl:25][C:23]1[C:22]([C:26]([F:28])([F:27])[F:29])=[CH:21][N:20]=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=2)[N:24]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(N)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Br-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
C2 (690 mg, 2.92 mmol) was dissolved in 10 mL DCE:t-BuOH (1:1 vol:vol), and the resultant solution was treated with ZnBr2 (1.97 g, 8.76 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (748 mg, 3.45 mmol). The resultant mixture was then treated drop-wise with TEA (406 ml, 2.92 mmol), and the mixture was allowed to stir at 25° C. for about 20 hours. The reaction mixture was concentrated, and the resultant residue was treated with EtOAc. The resultant solution was washed with water and brine, and dried over MgSO4. The mixture was then filtered, concentrated, and purified by column chromatography eluting with 22% EtOAc/Heptane. The product-containing eluents were combined and concentrated to provide C3 as a white solid. Yield: 680 mg, 56%. MS-415.2. 1H NMR (500 MHz, DMSO) δ: 10.59 (s, 1H), 8.74 (s, 1H), 7.53 (d, 2H), 7.31 (d, 1H), 7.23 (d, 2H), 4.54 (m, 1H), 1.33 (s, 9H), 1.25 (d, 3H).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C[O-].[Na+:31]>C(O)C>[Na+:31].[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([O-:13])=[O:12])=[CH:5][CH:6]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (R1=Boc, R2=H, R3=CO2H) is added to ethanol (10 ml). Sodium methoxide (141 mg) is then added and the mixture is stirred at room temperature for 30 minutes. The mixture is then concentrated in vacuo to afford (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid sodium salt (1-a, R1=Boc, R2=H, R3=CO2−Na+). 1H NMR (DMSO-d6): 0.91 (3H), 1.29 (1H), 1.34 (9H), 1.61 (1H), 2.12 (1H), 2.68-2.81 (2H), 3.60 (1H), 7.25-7.27 (2H), 7.32-7.36 (1H), 7.43-7.47 (2H), 7.55-7.57 (2H), 7.64-7.66 (2H), 7.76 (1H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][NH:4][N:3]=1.CN(C)[CH:10]=[CH:11][C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=O>C(O)(=O)C>[CH3:7][C:6]1[CH:5]=[N:4][N:3]2[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:11][CH:10]=[N:1][C:2]=12
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: Cc1cnn2c(-c3cccnc3)ccnc12

Procedure:
As for Example 2, 3-amino-4-methylpyrazole is heated at reflux temperature for 6 hours with 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in glacial acetic acid to give the product of the example.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](O)([C:15]3[C:23]([OH:24])=[CH:22][C:18]4[O:19][CH2:20][O:21][C:17]=4[CH:16]=3)[C:7]2=[O:26])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH:1]1([CH2:4][CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]([C:15]3[C:23]([OH:24])=[CH:22][C:18]4[O:19][CH2:20][O:21][C:17]=4[CH:16]=3)[C:7]2=[O:26])[CH2:3][CH2:2]1
Reactant: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2cc3c(cc2O)OCO3)c2ccccc2N1CCC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a solution of 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (2.22 g, 6.27 mmol) in dichloromethane (30.0 mL) was added trifluoroacetic acid (2.12 g, 18.8 mmol) and triethylsilane (2.14 g, 18.8 mmol). The brown solution was stirred at ambient temperature for 0.5 h and concentrated in vacuo to dryness. The residue was diluted with dichloromethane (100 mL), washed with water (3×50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexane (20/80) to give the title compound (1.69 g, 80%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 9.21-9.10 (br, 1H), 7.38-7.30 (m, 2H), 7.16 (t, 1H), 6.96 (d, 1H), 6.63 (s, 1H), 6.33 (s, 1H), 5.84 (dd, 2H), 5.01 (s, 1H), 3.87-3.72 (m, 2H), 1.66-1.46 (m, 2H), 0.69-0.59 (m, 1H), 0.43-0.30 (m, 2H), 0.09-0.06 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.8, 151.3, 147.6, 144.1, 141.5, 128.7, 126.2, 123.1, 115.2, 109.5, 109.4, 106.5, 101.5, 101.2, 47.4, 40.5, 32.2, 8.6, 4.3, 4.2; MS (ES+) m/z 338.3 (M+1).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>CN(C)C=O>[CH3:18][S:19]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([S:4][CH2:1][CH2:2][CH3:3])[N:10]=1)(=[O:21])=[O:20]
Reactant: CCCSc1cccc(O)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCSc1cccc(OS(C)(=O)=O)n1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
3.4 g of 6-n-propylthio-2-pyridinol and 2.2 g of anhydrous sodium carbonate were suspended in 25 ml of N,N-dimethylformamide, followed by stirring. 2.4 g of methanesulfonyl chloride was added dropwise to the suspension at 10° C. After the addition, the bath was removed and the resulting mixture was allowed to stand to raise the temperature of the mixture to room temperature. The mixture was heated to 50° C. and stirred for 2.5 hours. The reaction mixture was poured into 200 ml of chilled water and extracted with ether twice. The ether layer was washed with 5% aqueous caustic soda solution and water and dried over anhydrous sodium sulfate. The residue obtained by distilling away the solvent was purified by silica gel column chromatography (with toluene and n-hexane) to obtain 3.9 g of 6-n-propylthio-2-pyridyl methanesulfonate as a pale yellow oil (yield: 78.8%).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=O.Cl.[NH2:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:11]([NH:13][CH:14]1[CH2:16][CH2:15]1)=[O:12]>C1(C)C=CC=CC=1>[CH:14]1([NH:13][C:11](=[O:12])[C:10]2[CH:17]=[CH:18][C:19]([CH3:20])=[C:8]([NH:7][C:3](=[O:5])[CH2:2][SH:1])[CH:9]=2)[CH2:15][CH2:16]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: O=C(O)CS
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)CS
Temperature: 25 °C
Yield: 32 %

Procedure:
A solution of mercaptoacetic acid (1.65 mL, 24.2 mmol) and 5.0 g (22 mmol) of 3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride (prepared as described in WO 04/071440) in toluene (40 mL) was refluxed for 16 h. At this time, an additional 0.8 mL of mercaptoacetic acid was added and the mixture was continued at reflux for an additional 2 days. After cooling to rt, the solid was collected by vacuum filtration and was rinsed with EtOAc (2×50 mL). The resulting solid was then slurried in water (50 mL) and the solid was recollected by vacuum filtration and rinsed with add'n water. The resulting solid was air dried in the funnel then under vacuum overnight to afford 1.86 g (32%) of a white solid as compound a. HPLC Ret time=1.83 min. LCMS [M+H]+ 265.37.
Reaction SMILES: [Cl:1]/[C:2](=[C:6](\[Cl:10])/[C:7](O)=[O:8])/[C:3](O)=[O:4].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>O>[F:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]2[C:3](=[O:4])[C:2]([Cl:1])=[C:6]([Cl:10])[C:7]2=[O:8])=[CH:14][CH:13]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)/C(Cl)=C(/Cl)C(=O)O
Solvent: O
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccc(F)cc1
Yield: 97.6 %

Procedure:
18.5g (0.1 mol) of 2,3-dichloromaleic acid was dissolved in 120 ml of water. To the resulting solution 8.9g (0.08mol) of 4-fluoroaniline was added dropwise over a period of 5 min. at reflux temperatures under agitation. The mixture was then allowed to react for 2 hours at reflux temperatures. Upon cooling the reaction mixture, precipitated crystal was separated by filtration to obtain 20.3g of N-(4-fluorophenyl)-2,3-dichloromaleimide melting at 239°-240° C (not corrected) at a yield of 98.1%. An analysis by gas chromatography showed the product had a purity of 95.5%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Cl[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][CH:6]=1
Reactant: ClCOc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.0 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.262 g), stirred for 15 minutes and treated with chloromethoxybenzene (1.1 g). The mixture was heated at 60° C. for 1.5 hours and worked up as in Example 20. The material was crystallized from diethyl ether-hexane to provide 1 g of alpha-oxo-4-[[(phenoxy)methyl]oxy]benzeneacetic acid methyl ester, mp 52°-54° C.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:3][C:6]1[CH:18]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.17 g of 5% palladium-carbon was added to a mixed solution of 8 mL of methanol and 8 mL of ethyl acetate containing 0.82 g of tert-butyl 2-nitro-4-phenoxybenzoate and stirred under hydrogen atmosphere at room temperature for 4 hours and 30 minutes. Insoluble were removed by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane; ethyl acetate=10:1] to obtain 0.63 g of tert-butyl 2-amino-4-phenoxybenzoate as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:11][CH2:10][CH2:9][CH:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: OCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(c2ccc(F)cc2)c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 3,3-bis(4-fluorophenyl)propan-1-ol (4.99 g, 20.1 mmol) in pyridine (60 mL) at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (4.20 g, 22.0 mmol). The reaction mixture was stirred at 0° C. for 4 h, warmed to room temperature and stirred for 4 h. The reaction mixture was partially concentrated, diluted with EtOAc, washed with 1 M HCl (2×), saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated to give 3,3-bis(4-fluorophenyl)propyl 4-methylbenzenesulfonate which was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])[CH2:10][CH2:9]2)(=[O:4])=[O:3]>CO.O.[Pd]>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:9]2)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)CCN2CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2c(c1)CCN2CC(=O)O
Yield: 82.8 %

Procedure:
A solution of benzyl 2-(5-(methylsulfonamido)indolin-1-yl)acetate (0.565 g, 1.568 mmol) in methanol was added to a suspension of 10% w/w Pd/C (a catalytic amount) in water and the mixture was hydrogenated in a Parr apparatus at 30 psi overnight. The catalyst was filtered off and the filtrate was evaporated to dryness affording 2-(5-(methylsulfonamido)indolin-1-yl)acetic acid (0.351 g, 1.299 mmol, 83% yield). MS/ESI+ 271.0 [MH]+.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[C:10]([C:12]#[N:13])[CH:11]=1)(=[O:5])[CH3:4]>CCOCC>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])[CH:9]=[C:10]([C:12]#[N:13])[CH:11]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1cc(C#N)cc(NS(C)(=O)=O)c1
Solvent: CCOCC
Product: CS(=O)(=O)Nc1cc(C#N)cc(C(=O)CBr)c1
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Al(CH3)3 (20 mmol) was added dropwise to the ice-water cooled solution of DMEDA (4.4 mmol) in dry toluene (60 mL) under nitrogen. After addition, it was continued to stir for 2 hours at room temperature. Then, methyl-3-cyano-5-(methylsulfonamido)benzoate (4 mmol) was added, and the reaction mixture was heated to reflux overnight. After cooling, it was poured into diluted hydrochloric acid, the mixture was extracted with EtOAc, the combined organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated to afford N-(3-acetyl-5-cyanophenyl)methanesulfonamide with a yield of 35%. Br2 (1.2 mmol) was added dropwise to the solution of N-(3-acetyl-5-cyanophenyl)methanesulfonamide (1 mmol) in Et2O (50 mL). After addition, it was continued to stir for 1.5 hours. Then the reaction mixture was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated to afford N-(3-(2-bromoacetyl)-5-cyanophenyl)methanesulfonamide with a yield of 85%.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([Li])CCC.[I:25]I>O1CCCC1>[I:25][C:11]1[N:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cccnc32)cc1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3cccnc32)cc1
Temperature: -78 °C
Yield: 50.2 %

Procedure:
A solution of 1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine 154.4 g, Reference Example 9(a)] in dry tetrahydrofuran (1200 mL) cooled to −78° C., was treated with a solution of butyllithium in hexanes (2.5M, 92 mL) over a 20 minute period. The solution was maintained at −78° C. for 30 minutes, then a solution of iodine (101 g) in tetrahydrofuran (600 mL) was added until the iodine colour persisted (ca.300 mL). The mixture was allowed to warm slowly to ambient temperature and the solvent removed under vacuo. The residue was partitioned between ethyl acetate (1000 mL) and water (500 mL) and the water re-extracted with ethyl acetate (2×500 mL). The organic extracts were combined, dried over sodium sulfate and removed under reduced pressure to give a yellow solid which was triturated with diethyl ether to give the title compound (79.6 g) as a pale yellow solid. m.p. 105-107° C. MS: 399(MH+).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(C(F)(F)F)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (74 mg, 82%), MS (ISP) m/z=363.4 [(M+H)+], mp 269.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2([O:21][CH3:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>C(Cl)Cl>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([C:15]2([O:21][CH3:22])[CH2:20][CH2:19][N:18]([S:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[Cl:23])(=[O:32])=[O:31])[CH2:17][CH2:16]2)=[O:14])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COC1(C(=O)Nc2ccc(C(C)(C)C)cc2)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1(C(=O)Nc2ccc(C(C)(C)C)cc2)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 25.5 mg (0.078 mmol) 4-Methoxy-piperidine-4-carboxylic acid (4-tert-butyl-phenyl)-amide, hydrochloride, 21.4 mg (0.1 mmol) 2-chlorobenzenesulfonyl chloride and 39.4 mg (0.39 mmol) NEt3 in 1.5 mL DCM was stirred for 16 h at room temperature. The mixture was concentrated and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid to yield after evaporation of the product containing fractions 20.2 mg (56%) of the title compound as light yellow oil. MS (m/e): 465.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][OH:14].N1C=CC=CC=1.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl>[CH3:24][S:21]([O:14][CH2:13][CH2:12][C:3]1[CH:4]=[C:5]([O:10][CH3:11])[C:6]([C:8]#[N:9])=[CH:7][C:2]=1[Cl:1])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CCO)c(Cl)cc1C#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(CCOS(C)(=O)=O)c(Cl)cc1C#N
Reaction time: 2 h

Procedure:
A solution of 2-(2-chloro-4-cyano-5-methoxyphenyl)ethanol (205 mg, 0.969 mmol) DIPEA (0.846 mL, 4.84 mmol) and pyridine (0.0780 mL, 0.969 mmol) in DCM (3 mL) was treated dropwise with mesyl chloride (0.110 mL, 1.42 mmol). The reaction was stirred for 2 hours and was then diluted with DCM and washed twice with aq. citric acid, then washed with brine, and dried over sodium sulfate. Purification of the residue by flash chromatography (20-50% ethyl acetate/hexanes) afforded the title intermediate. 1H-NMR (500 MHz, CDCl3) δ ppm 2.99 (s, 3H), 3.24 (t, J=6.6 Hz, 2H), 3.95 (s, 3H), 4.49 (t, J=6.6 Hz, 2H), 6.962 (s, 1H), 7.563 (s, 1H).