Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1CCN([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)CC1)(=O)C.BrC1C=CC([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)=CC=1>>[CH3:23][C:20]1([CH3:22])[C:19]([CH3:24])([CH3:25])[O:18][B:17]([C:14]2[CH:13]=[CH:12][C:11]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)=[CH:16][CH:15]=2)[O:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)CC1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Yield: 80 %

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (200 mg, 0.59 mmol). Crude product was purified by flash chromatography using EtOAc/hexanes as eluent (2:98 to 15:85) to give the title compound as a colourless oil (239 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J=7.9 Hz, 2H), 7.21 (d, J=7.9 Hz, 2H), 4.25-4.22 (m, 2H), 2.78 (t, J=12.5 Hz, 2H), 2.67-2.61 (m, 1H), 1.82-1.78 (m, 2H), 1.67-1.57 (m, 2H), 1.48 (s, 9H), 1.32 (s, 12H); MS ESI 410.1 [M+Na]+, calcd for [C11H34BNO4+Na]+410.25.
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7]([CH3:12])([CH2:10][CH3:11])[CH2:8][OH:9])([CH3:5])[CH3:4].CS(O)(=O)=O>>[CH3:12][C:7]1([CH2:10][CH3:11])[CH2:8][O:9][CH2:2][C:3]([CH3:5])([CH3:4])[NH:6]1
Reactant: CCC(C)(CO)NC(C)(C)CO
Agent: *CC(*)C
Agent: CS(=O)(=O)O
Product: CCC1(C)COCC(C)(C)N1
Yield: 50 %

Procedure:
In a manner analogous to that described in example 5A hereinabove, starting with (1-hydroxy-2-methyl-2-propyl)(1-hydroxy-2-methyl-2-butyl)amine and reacting with methanesulfonic acid, then working up the reaction mixture, a colorless oil having a bp 71°-3° C./20 mm, is obtained in about 50% yield. Less than 5% by weight of the oil is found to provide excellent u-v light stability in polypropylene.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[S:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:22])[CH2:13]1>ClCCl>[O:9]=[S:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:22])[CH2:13]1
Reactant: O=C1CSc2ccccc2N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1CS(=O)c2ccccc2N1
Temperature: 0 °C

Procedure:
A solution of 3-chloroperbenzoic acid (1.35 g, 6.6 mmol) in dry dichloromethane (40 ml) was added dropwise to an ice cooled solution of 2H-1,4-benzothiazin-3(4H)-one (1.10 g, 6.6 mmol) in dry dichloromethane (100 ml) with stirring. The reaction mixture was allowed to reach room temperature, then stirred overnight. The product was collected by filtration and washed with dichloromethane. Yield 0.54 g (45%) mp 184–6° C.
Reaction SMILES: [C:1]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[C:7]([OH:33])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:36](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[C:7]([O:33][CH3:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2cccc3cc[nH]c23)c(O)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1cc(C(C)(C)C)ccc1CN(CCc1ccc(F)cc1)C(=O)c1cccc2cc[nH]c12
Temperature: 60 °C
Yield: 39.3 %

Procedure:
133 mg (0.3 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-2-hydroxy-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amide, 64 mg (0.45 mmol) of methyl iodide and 83 mg (0.6 mmol) of potassium carbonate were heated in 3 ml acetonitrile for 2 h to 60° C. Additional 32 mg (0.22 mmol) of methyl iodide were added and the reaction mixture was heated to 60° C. over night. The reaction mixture was filtered and the solvent was evaporated. The residue was purified by column chromatography (20 g silica gel; DCM/diethyl ether 10:1) to yield 54 mg (39%) product as a colorless gum. MS (ISP) 459.6 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:9]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:17][C:16]3[N:15](S(C4C=CC(C)=CC=4)(=O)=O)[N:14]=[C:13]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[C:12]=3[CH:11]=[CH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCCC1>[C:34]1([C:9]2([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:17][C:16]3[NH:15][N:14]=[C:13]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[C:12]=3[CH:11]=[CH:10]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(-c3cccnc3)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C1=CC(c2ccccc2)(c2ccccc2)Cc2[nH]nc(-c3cccnc3)c21
Temperature: 40 °C
Reaction time: 20 h
Yield: 63.1 %

Procedure:
Aqueous 1N sodium hydroxide solution is added to a solution of 0.08 g of 6,6-diphenyl-3-pyrid-3-yl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazole in 2 cm3 of tetrahydrofuran. After stirring in the region of 40° C. for about 20 hours, the mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up in 20 cm3 of ethyl acetate. The solution obtained is washed with twice 10 cm3 of water and with 10 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure (13 kPa). The residue is taken up in 2 cm3 of diisopropyl ether and drained by suction. 0.035 g of 6,6-diphenyl-3-pyrid-3-yl-6,7-dihydro-1H-indazole is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: O1CCOCC1.C1COCC1.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.ClCCl.[C:23]1([CH3:31])[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=1>Cl[Ti](OC(C)C)(OC(C)C)OC(C)C>[CH3:31][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([OH:30])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Br[Mg]c1ccccc1
Agent: CC(C)O[Ti](Cl)(OC(C)C)OC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc([C@H](O)c2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
1.0 mL (12 mmol) of anhydrous 1,4-dioxane was added to 0.375 mL (0.375 mmol) of an anhydrous THF solution (1.00 mol/L) of commercial phenylmagnesium bromide, and the contents were stirred for 10 minutes, and then 0.402 mL (0.325 mmol) of an anhydrous dichloromethane solution (0.80 mol/L) of chloro-tri-iso-propoxy titanium prepared in Preparation Example 1 was added thereto, and further stirred for 10 minutes. 0.25 mL (0.0125 mmol) of an anhydrous dichloromethane solution (0.050 mol/L) of (R)—H8-BINOL was added thereto and stirred at room temperature for 30 minutes. The thus-obtained solution containing a white precipitate was added dropwise to 30 mg (0.25 mmol) of a dichloromethane solution (0.5 mL) of p-tolualdehyde using a syringe over a period of 10 minutes, and stirred at room temperature for 1 hour for the reaction. Thereafter, an operation was carried out in the same manner as in Example 1 to obtain (R)-4-methylbenzhydrol. The conversion rate of the raw material was 80%, while the enantiomeric excess of the product was 94% ee. The amount of dioxane used during the reaction was 32 equivalents (64 equivalents in terms of the ether oxygen equivalent) relative to magnesium.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[F:7][C:8]1[CH:9]=[C:10]([C:17]([OH:19])=[O:18])[C:11](=[CH:15][CH:16]=1)[C:12]([OH:14])=O.[K]>>[F:7][C:8]1[CH:9]=[C:10]2[C:17](=[O:18])[O:19][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(F)cc1C(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [K]
Product: O=C1OC(=O)c2cc(F)ccc21

Procedure:
Diazotization (i) and conversion (ii) to the tetrafluoroborate followed by pyrolysis in benezene of that derivative (Balz-Schieman reaction) gives 3,4-dimethylfluorobenzene. This is oxidized by aqueous potassium permanganate to 4-fluorophthalic acid, monopotassium salt. Vacuum distillation of the latter in the presence of sulfuric acid yields 4-fluorophthalic anhydride. Treatment of the anhydride with urea in boiling chlorobenzene yields the imide which is converted with concentrated ammonium hydroxide to the diamide. Finally, dehydration of the diamide with thionyl chloride in dimethylformamide gives 4-fluorophthalonitrile.
Reaction SMILES: [C:1](=[O:17])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1([CH3:6])[CH2:5][CH2:4]1.[F:18][C:19]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:30]=[C:31]2[CH:37]=[C:36]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[O:35][C:32]2=[CH:33][N:34]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:6][C:3]1([O:2][C:1]([N:41]2[CH2:42][CH2:43][CH:38]([C:36]3[O:35][C:32]4=[CH:33][N:34]=[C:29]([C:20]5[CH:21]=[CH:22][C:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:24][C:19]=5[F:18])[CH:30]=[C:31]4[CH:37]=3)[CH2:39][CH2:40]2)=[O:17])[CH2:4][CH2:5]1
Reactant: CC1(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cc3cc(C4CCNCC4)oc3cn2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(OC(=O)N2CCC(c3cc4cc(-c5ccc(S(C)(=O)=O)cc5F)ncc4o3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Methyl-cyclopropyl 4-nitrophenyl carbonate (48 mg) is added to a solution of 5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine (75 mg) and N,N-diisopropyl-ethylamine (32 μL) in tetrahydrofuran (1 mL) at room temperature. The mixture is stirred at room temperature overnight. The solution is concentrated and the residue is taken up in ethyl acetate. The resulting mixture is washed with 1 M aqueous NaOH solution (3×), water, and brine. The organic phase is dried (Na2SO4) and concentrated. The residue is purified by HPLC on reversed phase (methanol/water) to give the title compound. Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)#[N:12]>N1C=CC=CC=1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[S:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[N:12]=1
Reactant: O=C(O)c1cccnc1S
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2ncccc12
Temperature: 135 °C
Yield: 1.3 %

Procedure:
A mixture of 2-mercaptonicotinic acid (5.00 g, 32.2 mmol), 2-cyanopyridine (3.39 g, 32.5 mmol) and pyridine (30.0 ml) was refluxed at 135° C. for 72 hrs as described in Example 9. The mixture was concentrated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The resultant product was recrystallized from ethanol to give the titled compound (0.10 g, 1%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].C(OC([NH:26][C@H:27]1[C@@H:31]([CH3:32])[CH2:30][NH:29][CH2:28]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:26][C@H:27]1[C@@H:31]([CH3:32])[CH2:30][N:29]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:28]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@@H](N)[C@@H](C)C3)cc21
Yield: 0.6 %

Procedure:
A mixture of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.0 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.89 g), DBU (0.62 g) and anhydrous acetonitrile (30 ml) was refluxed for 27 hours. Then, the reacting mixture was treated as described in example 33 and recrystallized from chloroform-methanol-concentrated aqueous ammonia (20:20:1) to give the title compound (0.008 g) as white powder, mp 300~° C. (decompd.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H]4CCCNC4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=C(N[C@H:43]4[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]4)C(F)=CN=3)=CNC2=NC=1.C(N(C(C)C)CC)(C)C.[CH:59]1([C:63](Cl)=[O:64])[CH2:62][CH2:61][CH2:60]1>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][CH:44]4[CH2:43][CH2:48][CH2:47][CH2:46][N:45]4[CH:61]4[CH2:62][CH:59]([CH:63]=[O:64])[CH2:60]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=CC1CC(N2CCCCC2Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.04 g, 0.11 mmol) in CH2Cl2 (1.40 mL) and DMF (300 g was added N,N-diisopropyl-N-ethylamine (0.30 mL, 1.70 mmol) followed by cyclobutanecarbonyl chloride (0.01 g. 0.12 mmol). The reaction mixture was allowed to stir at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 395.
Reaction SMILES: C([O:8][C@H:9]([CH3:53])[CH2:10][NH:11][C:12]([CH3:52])([CH3:51])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:31][CH:30]=2)[C:18]1=[O:50])=[O:15])C1C=CC=CC=1.Cl>CO.[Pd]>[OH:8][C@H:9]([CH3:53])[CH2:10][NH:11][C:12]([CH3:52])([CH3:51])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH2:41][NH:42][C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])=[CH:33][CH:34]=2)[C:18]1=[O:50])=[O:15]
Reactant: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@@H](O)CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O
Reaction time: 24 h
Yield: 95 %

Procedure:
To a solution of 525 mg (0.695 mmol) of the intermediate prepared in Step A in 6 mL of methanol was added 0.350 mL (0.700 mmol) of 2N hydrochloric acid and 100 mg (20% w/w) of 30% palladium on carbon. The resulting mixture was shaken under a hydrogen atmosphere at 40 psi for 24 hours. The catalyst was removed by filtration through Celite and the solvent removed under vacuum. The residue was purified by column flash chromatography on silica gel, eluting with chloroform/10% ammonium hydroxide in methanol (95/5), to give 415 mg (95%) of the product as a white solid. 1H NMR (400 MHz, CD3OD): δ1.12-1.21 (m, 9H), 1.42 (s, 9H), 2.04-2.13 (m, 1H), 2.22-2.41 (m, 3H), 2.49-2.62 (m, 4H), 3.80-3.88 (m, 1H), 4.09 (s, 2H), 4.42 (dd; 12, 4 Hz; 1H), 4.97 (d, 15 Hz, 1H), 5.30 (d, 15 Hz, 1H), 7.11-7.42 (m, 12 H). FAB-MS: calculated for C37H48N4O5 628; found 629 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34](CCl)=[CH:33][CH:32]=1>>[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:1][N:2]2[C:10]3[C:5](=[CH:6][C:7]([S:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@H:15]4[CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:12])=[O:13])=[CH:8][CH:9]=3)[C:4](=[O:27])[C:3]2=[O:28])=[CH:33][CH:32]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Product: COc1ccc(CN2C(=O)C(=O)c3cc(S(=O)(=O)N4CCC[C@H]4COc4ccccc4)ccc32)cc1
Yield: 69 %

Procedure:
(S)-1-(4-Methoxybenzyl)-5-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (11b) was prepared according to the same procedure for compound 11a, except using 4-methoxybenzyl chloride, and purified with hexanesether (1:3) to afford 175 mg (69%) of 11b as a yellow solid, mp 126.7-128.8° C. 1H NMR (300 MHz, CDCl3) δ 8.00 (s, 1H), 7.95 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.28-7.21 (m, 4H), 6.96-6.80 (m, 6H), 4.86 (s, 2H), 4.18-4.11 (m, 1H), 3.97-3.88 (m, 2H), 3.80 (s, 3H), 3.50 (m, 1H), 3.23 (m, 1H), 2.02 (m, 2H), 1.78 (m, 2H). Anal. Calcd for C27H2(N2O6S: C, 64.02, H, 5.17; N, 5.53. Found: C, 64.76, H, 5.24; N, 5.06.
Reaction SMILES: F[C:2]1[N:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=[O:5].Cl.Cl.[NH:29]1[C:33]2=[N:34][CH:35]=[CH:36][C:37]([CH2:38][NH2:39])=[C:32]2[CH:31]=[CH:30]1>>[NH:29]1[C:33]2=[N:34][CH:35]=[CH:36][C:37]([CH2:38][NH:39][C:2]3[N:26]=[CH:25][CH:24]=[CH:23][C:3]=3[C:4]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]([OH:22])([C:14]([F:17])([F:15])[F:16])[C:18]([F:19])([F:20])[F:21])=[CH:9][CH:8]=3)=[O:5])=[C:32]2[CH:31]=[CH:30]1
Reactant: NCc1ccnc2[nH]ccc12
Reactant: O=C(Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)c1cccnc1F
Agent: Cl
Product: O=C(Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)c1cccnc1NCc1ccnc2[nH]ccc12

Procedure:
The titled compound was prepared from 2-fluoro-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-nicotinamide and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 510 (M+H). Calc'd. for C23H17F6N5O2—509.41.
Reaction SMILES: Cl(O)(=O)(=O)=O.[OH:6][CH:7]([C:12]1[N:13]=[C:14]([CH3:17])[S:15][CH:16]=1)[C:8]([O:10][CH3:11])=[O:9].C(O[C:22]([CH3:25])([CH3:24])[CH3:23])(=O)C>>[C:22]([O:6][CH:7]([C:12]1[N:13]=[C:14]([CH3:17])[S:15][CH:16]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)C(O)c1csc(C)n1
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1csc(C)n1
Reaction time: 1 h
Yield: 21 %

Procedure:
Under a nitrogen atmosphere, perchloric acid (70%, 3.75 mL) was added at −10° C. to a solution of methyl 2-hydroxy-2-(2-methyl-1,3-thiazol-4-yl)acetate (15b) (590 mg, 3.15 mmol) in tertbutyl acetate (25 mL). After 1 hour, the reaction was quenched with a saturated aqueous solution of sodium carbonate and extracted with dichloromethane (2×20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 75/25) to afford the desired product (15c) as a white solid (160 mg, 0.66 mmol, 21%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([OH:14])([C:10]([F:13])([F:12])[F:11])[CH2:6][C:7]([CH3:9])=[CH2:8])[CH3:2].[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17]1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]([OH:14])([C:10]([F:13])([F:12])[F:11])[CH2:6][C:7]([C:21]1[C:20]2[O:16][CH2:17][CH2:18][C:19]=2[CH:24]=[CH:23][CH:22]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: c1ccc2c(c1)CCO2
Reactant: C=C(C)CC(O)(C(=O)OCC)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(O)(CC(C)(C)c1cccc2c1OCC2)C(F)(F)F
Temperature: 25 °C
Yield: 25.8 %

Procedure:
A solution of 2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acid ethyl ester (100 g, 442 mmol) and 2,3-dihydrobenzofuran (57.7 g, 480 mmol) in 500 mL of dichloroethane was treated with AlCl3 (87.8 g, 660 mmol) while maintaining the internal temperature below 10° C. The reaction was allowed to warm to room temperature overnight and quenched with 1 L of cold 1 N HCl. The mixture was then extracted with three 1 L portions of ethyl acetate. The combined organic layers were washed with 1 L of saturated aqueous sodium bicarbonate solution, 1 L of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified on SiO2 (10% diethyl ether in hexanes). The resulting solid was recrystallized in hot hexanes to afford 39.5 g of 4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester as a white solid (26% yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[N:20]1[C:25](=[O:26])[CH2:24][O:23][C:22]2[CH:27]=[C:28]([S:31]([N:34](CC3C=CC(OC)=CC=3)[C:35]3[S:36][CH:37]=[CH:38][N:39]=3)(=[O:33])=[O:32])[CH:29]=[CH:30][C:21]1=2>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:11]=1[N:20]1[C:25](=[O:26])[CH2:24][O:23][C:22]2[CH:27]=[C:28]([S:31]([NH:34][C:35]3[S:36][CH:37]=[CH:38][N:39]=3)(=[O:32])=[O:33])[CH:29]=[CH:30][C:21]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCC(=O)N3c2ccc(C(F)(F)F)cc2OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(F)(F)F)ccc1N1C(=O)COc2cc(S(=O)(=O)Nc3nccs3)ccc21
Yield: 83 %

Procedure:
In a 25-mL round bottom flask was dissolved 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide in 4 mL of DCM then treated with TFA (2.384 mL, 30.9 mmol). After 30 min the reaction mixture was concentrated under reduced pressure and purified by MPLC (ISCO) with DCM:MeOH 100:0 to 90:10 to afforded 4-(2-methoxy-4-(trifluoromethyl)phenyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H benzo[b][1,4]oxazine-7-sulfonamide (250 mg, 0.515 mmol, 83.0% yield from INTERMEDIate AB2) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.81 (s, 3 H) 4.91 (s, 2 H) 6.41 (d, J=8.41 Hz, 1 H) 6.83 (d, J=4.60 Hz, 1 H) 7.26 (d, J=4.60 Hz, 1 H) 7.34 (dd, J=8.36, 2.01 Hz, 1 H) 7.38 (d, J=1.96 Hz, 1 H) 7.51 (d, J=8.12 Hz, 1 H) 7.55-7.65 (m, 2 H) 12.75 (br. s., 1 H). m/z (ESI) 486.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=2[N+:13]([O-:15])=[O:14])[CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CCl
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 75 °C

Procedure:
To 1-chloromethyl-2-nitro-4-trifluoromethyl-benzene (1.5 g, 6.2 mmol), N-methylpiperazine (0.83 mL, 7.5 mmol), and THF (31 mL) was added NaHCO3 (1.43 g, 17.1 mmol). The mixture was heated overnight at 75° C. in a sealed tube. The cooled reaction was filtered, concentrated, diluted with CH2Cl2, and extracted with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to yield 1-methyl-4-(2-nitro-4-trifluoromethyl-benzyl)-piperazine.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=O)[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1>[C:1]1([CH2:7][O:8][CH2:9][CH2:10][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:14][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCc1ccccc1)N1CCN(C(=O)COCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc(CCCN2CCN(CCOCc3ccccc3)CC2)cc1
Yield: 99.8 %

Procedure:
To a stirred solution of 1-[(phenylmethoxy)acetyl]-4-(3-phenylpropionyl)piperazine (193 g) in tetrahydrofuran (967 ml) under a nitrogen atmosphere, was added a molar solution of borane-tetrahydrofuran complex solution in tetrahydrofuran (2.4 l) and the mixture was refluxed for 1 h. The residual borane reagent was destroyed by dropwise addition of 5N hydrochloric acid solution (430 ml) and the tetrahydrofuran was removed by distillation. The cooled reaction mixture was basified with sodium hydroxide solution, the product was extracted with ethyl acetate, and the solvents were evaporated in vacuo, after which 1-[2-(phenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (178 g) was obtained.