Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][C:25]=1[Cl:32].[Cl-].[NH4+]>C1COCC1>[Br:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][C:25]=1[Cl:32])[CH2:30][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: Clc1ccc(CBr)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(Br)c2)CC1
Temperature: -30 °C
Reaction time: 4 h

Procedure:
Under argon, 140.2 ml (1.0 mol) of diisopropylamine were dissolved in 1200 ml of dry THF and cooled to −30° C. 400 ml (1.0 mol) of n-butyllithium solution (2.5 M in hexane) were added dropwise. The resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 94.8 g (0.667 mol) of tert-butyl cyclopropanecarboxylate in 750 ml THF was added to the reaction solution, with the temperature being kept below −60° C. After 4 h of stirring at −60° C., a solution of 208.6 g (0.733 mol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 550 ml of THF was added, the temperature again being kept below −60° C. The reaction mixture was slowly warmed to RT overnight, and saturated aqueous ammonium chloride solution was then added carefully. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 4:1). This gave 95.5 g (41.4% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2
Reactant: CCCCCCC(Nc1ccc(C(=O)N(C)CCC(=O)OCC)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCC(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a mixture of ethyl 3-[({4-[(1-{5-chloro-1-[3-(trifluoromethyl)phenyl]-1H-indol-2-yl}heptyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (254 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (223 mg, 92%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][NH:14][CH3:15])=[CH:11][C:10]=1[Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>ClCCl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][N:14]([CH3:15])[C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:11][C:10]=1[Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1ccc(OCc2ccccc2)c(Br)c1
Reactant: CCCCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(Br)c1
Yield: 98.3 %

Procedure:
In a manner similar to that of Example 37(e), by reacting 9.9 g (32 mmol) of N-(4-benzyloxy-3-bromo benzyl)-N-methylamine with 5.3 g (32 mmol) of octanoyl chloride in 90 ml of dichloromethane, 13.6 g (97%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][S:12]([CH2:15][CH2:16][O:17][CH3:18])(=[O:14])=[O:13])=O)(C)(C)C.[ClH:19]>CO>[ClH:19].[NH2:8][CH2:9][CH2:10][NH:11][S:12]([CH2:15][CH2:16][O:17][CH3:18])(=[O:14])=[O:13]
Reactant: COCCS(=O)(=O)NCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COCCS(=O)(=O)NCCN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(2-tert-butoxycarbonyl)-ethylenediamine (0.63 ml, 4.00 mmol) and triethylamine (0.67 ml, 4.80 mmol) in dichloromethane (10 ml) was added 2-methoxyethanesulfonyl chloride (761 mg, 4.80 mmol) at 0° C., and the mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to obtain N-(2-tert-butoxycarbonylaminoethyl)-2-methoxyethanesulfonamide. The mixture of N-(2-tert-butoxycarbonylaminoethyl)-2-methoxyethanesulfonamide and 5N HCl (8 ml) in methanol (8 ml) was stirred at room temperature for 2 h, then at 50° C. for 1 h, and concentrated in vacuo to obtain N-(2-aminoethyl)-2-methoxyethanesulfonamide hydrochloride salt. The free base of the title compound was prepared following the method of Example 6 using methanesulfonic acid 3-[7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indol-3-yl]-([1,2,4]-thiadiazol-5-yl)methyl ester and N-(2-aminoethyl)-2-methoxyethanesulfonamide hydrochloride salt. The obtained crude free base of the title compound was purified by prep. LCMS to afford the trifluoroacetic acid salt of the title compound. EsIMS: m/z 528.0 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].Cl.[C:16]1([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:30]1([CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:23][CH:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:14])[CH2:26][CH2:25]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 4.8 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 6.1 parts of 4-(diphenylmethoxy)piperidine hydrochloride, 7.5 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled and water is added. The layers are separated and the 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 1-{3-[4-(diphenylmethoxy)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 149.2° C.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:12]([F:20])[C:13]2[O:17][N:16]=[C:15]([CH3:18])[C:14]=2[CH:19]=1)=[O:9])=C.Cl.[OH-].[Na+]>CCO.CCOC(C)=O>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:12]([F:20])[C:13]2[O:17][N:16]=[C:15]([CH3:18])[C:14]=2[CH:19]=1)=[O:9]
Reactant: C=COCCONC(=O)c1cc2c(C)noc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCCO)cc12
Yield: 96 %

Procedure:
A solution of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic acid (2-vinyloxyethoxy) amide (11a) (55.4 mg, 0.114 mmol) and aqueous HCl (1 M, 0.23 mL) in EtOH (3 mL) was stirred for 2 hours at room temperature. The pH of the reaction mixture was adjusted to 6–7 with aqueous NaOH (2 N). The reaction was diluted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give 50.2 mg (96% yield) of the desired product (12a). MS APCI (−) m/z 456, 458 (M+, Br, Cl pattern) detected: 1H NMR (400 MHz, CD3OD) δ 7.87 (s, 1H), 7.57 (d, 1H), 7.31 (dd, 1H), 6.74 (dd, 1H), 4.01 (t, 2H), 3.74 (t, 2H), 2.60 (s, 3H): 19F NMR (376 MHz, CD3OD) −140.85 (s, 1F).
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:14].[H-].[Na+].[CH3:17]I>CN(C=O)C>[Br:1][C:2]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:13])[N:7]([CH3:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:14]
Reactant: CI
Reactant: Cc1ccc2c(c1Br)CCCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1Br)CCCC(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
6-Bromo-7-methyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (100.0 mg, 1.998 mmol) was treated with NaH (18.9 mg, 0.472 mmol, 1.2 equiv) in DMF (3 mL) at 0° C. to room temperature for 30 min. To the mixture was added MeI (111.7 mg, 0.787 mmol, 2 equiv). The mixture was stirred at to room temperature for 1 h The mixture was quenched with water and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure and the crude product was purified by a silica-gel column chromatography (hexane/EtOAc 87:13 to 50:50) to give 6-bromo-1,7-dimethyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (88.5 mg, 83.9%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][CH:6]=[CH:5]2.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.CCN(C(C)C)C(C)C.[CH2:64]([SH:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CCCCCCC.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].O1CCOCC1>[CH2:64]([S:71][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[N:7][CH:6]=[CH:5]2)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: SCc1ccccc1
Reactant: Clc1nccc2cc(Br)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCCC
Product: Clc1nccc2cc(SCc3ccccc3)ccc12
Temperature: 80 °C

Procedure:
A round-bottom flask was charged with 6-bromo-1-chloro-isoquinoline (1.574 ml, 10.86 mmol), Xantphos (0.314 g, 0.543 mmol), and Pd2(dba)3 (0.249 g, 0.271 mmol). The flask was flushed with Ar (g), then 1,4-dioxane (21.72 ml), n,n-diisopropylethylamine (3.79 ml, 21.72 mmol), and benzyl mercaptan (1.349 ml, 11.40 mmol) were added in sequence. The flask was fitted with a reflux condenser and heated to 80° C. for 1 h. The mixture was cooled and concentrated under a vacuum. The crude product was purified by chromatography on silica gel (80-g Redi-Sep Gold column, 25-g silica gel loading column, 0-40% EtOAc/Heptane) to give a yellow solid. The solid was suspended in heptane, sonicated, and filtered. The collected solid was washed with heptane, dried under a stream of N2 (g), then dried under vacuum for to give 6-(benzylthio)-1-chloroisoquinoline as an off-white powder: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.26-8.10 (m, 2H), 7.63-7.51 (m, 2H), 7.46-7.39 (m, 3H), 7.37-7.28 (m, 3H), 4.31 (s, 2H); m/z (ESI) 286.2 (M+H)+.
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:32][CH3:33])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][NH:25][C@H:24]([C:28]([NH:30][CH3:31])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O.C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:32][CH3:33])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][N:25]([CH3:35])[C@H:24]([C:28]([NH:30][CH3:31])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CNC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C
Yield: 64.7 %

Procedure:
Molecular sieves (5 g) followed by aqueous formaldehyde (10 ml) were added to a stirred solution of (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-methylpiperidine-2-carboxamide (3.0 g, 6.52 mmol) in DCM-AcOH (100:10 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (2.77 g, 13.1 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (100 ml) and the reaction was carefully neutralised with saturated aqueous NaHCO3(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam. The residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 2%) to give the title product as a white solid (2 g, 65%): 1H NMR Spectrum: (DMSO d6) 1.85-1.96 (m, 3H), 2.07 (m, 1H), 2.15 (s, 3H), 2.45-2.50 (m, 1H), 2.59 (d, 3H), 2.71 (m, 1H), 2.84 (m, 1H), 3.96 (s, 3H), 4.81 (m, 1H), 7.23 (s, 1H), 7.28 (t, 1H), 7.47-7.53 (m, 2H), 7.81 (s, 2H), 8.37 (s, 1H), 9.59 (s, 1H); Mass Spectrum: (M+H)+ 474.1.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.C([O:36][CH2:37][C:38](Cl)=[O:39])(=[O:35])C.C([O:44][CH2:45][C:46](N)=[O:47])(=[O:43])C>O1CCCC1>[OH2:17].[F:2][C:3]1[CH:4]=[C:5]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([C:37](=[O:36])[CH2:38][OH:39])[CH2:11][CH2:10]1.[OH2:35].[OH2:43].[F:2][C:3]1[CH:4]=[C:5]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([C:45](=[O:44])[CH2:46][OH:47])[CH2:11][CH2:10]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(=O)OCC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Product: O
Reaction time: 0.67 h

Procedure:
To a stirred mixture of (S)-N-[[3-[3-fluoro-4(-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide hydrochloride (EXAMPLE 7, 16.2 kg, 43.5 moles), tetrahydrofuran (205 kg) and triethylamine (10.1 kg, 100 moles) is added acetoxyacetyl chloride (6.5 kg, 47.8 moles) in tetrahydrofuran (11.1 kg) over 35 minutes keeping the temperature at 22°-23°. After 40 minutes, at which time TLC and HPLC analysis indicated complete formation of the acetoxyacetamide intermediate, the mixture is concentrated under reduced pressure to 30 l, diluted with methanol (100 l) and concentrated to 30 l. To the residue is added methanol (25 l) and an aqueous solution of potassium carbonate (5.6 kg in 56 l). The resulting mixture is stirred 20 hr at 22°-25° at which time TLC and HPLC analysis indicates the reaction is complete. The pH is adjusted to 7-7.5 with hydrochloric acid (4N, 14.3 l). The mixture is stirred 18 hr at 15°-22° then 3 hrs at 2°-5°. The solids are collected on a filter, washed with water (68 l) and dried at 20°-25° with recycled nitrogen to give the desired product. The crude product is dissolved in water (225 l) at 60°-70°, clarified through a 0.6 micron filter, diluted with water rinse (55 l) and stirred 17 hrs. at 15°. The solids are collected on a filter, washed with water at 15° and dried at 45° with recycled nitrogen to a water content of 0.33%. These solids are dissolved in a solution of ethyl acetate (143 l), methanol (65 l) and water (1.95 l) at 60°-65°. The solution is cooled to 15°-25° and stirred 16 hrs for crystallization. The solids are collected on a filter, washed with ethyl acetate (75 l) and dried with 45° nitrogen to give the desired product. The product is recrystallized two more times from water (147 1 then 133 l) at 60°-70°, clarified each time through a 0.6 micron filter and rinsed with water (40 1 and 30 l). The solids are dried on the filter at 30° with recycled nitrogen to give, after deagglomeration through a mill, the title compound as the sesquihydrate (6.45% water), TLC (silica gel; methanol/methylene chloride, 5/95) Rf =0.45; [α]D =-20° (c=1.0, ethanol).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][CH2:24][CH2:25][N:26]1[CH:30]=[CH:29][C:28]([NH2:31])=[N:27]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:9]([NH:31][C:28]2[CH:29]=[CH:30][N:26]([CH2:25][CH2:24][O:23][CH3:22])[N:27]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCCC2)N2Cc3ccccc3C2=O)n1
Temperature: 25 °C
Yield: 36 %

Procedure:
To a solution of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (60 mg, 0.21 mmol) and 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 72, 0.031 g, 0.22 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.11 g, 0.25 mmol) in methylene chloride (3 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.63 mmol) dropwise and the resulting solution stirred at room temperature over night. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (15 mL), a saturated sodium chloride solution (20 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-40 g column, 70-100% ethyl acetate/hexanes) to give (S)-3-cyclohexyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (31 mg, 36%) as an off white solid: [α]28D=−69.7°, (c=0.31, chloroform); HR-ES(+) m/e calcd for C23H30N4O3 [M+H]+ 411.2391, observed 411.2389; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.84-1.24 (m, 7H) 1.47-1.99 (m, 2H) 3.18 (s, 4H) 3.49-5.29 (m, 8H) 6.36 (s, 1H) 7.31-7.89 (m, 7H) 10.83 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH3:8][C:9](Br)([CH3:11])[CH3:10]>C(Cl)Cl>[CH3:8][C:9]([C:5]1[S:1][CH:2]=[C:3]([CH:6]=[O:7])[CH:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)Br
Reactant: O=Cc1ccsc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=O)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.63 g (32.4 mmol) of 3-thiophenecarboxaldehyde (Aldrich Chemical Co.) in 60 mL of methylene chloride cooled to 0° C. was added 9.17 g (80.9 mmol) of AICl3 and 2-methyl-2-bromopropane. The solution was stirred under N2 at room temperature for 16 hours and at reflux for 4 hours. The solution was then cooled to room temperature, and the reaction was quenched by pouring the solution into water. The mixture was made basic with aqueous NaHCO3 and extracted with ether. The ether extract was washed with water, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel, eluting with 15:1 hexane:ethyl acetate, to afford 2.23 g of the title product as an oil, after removal of the solvent. NMR (CD3OD) δ:1.41 (s, 9H), 7.26 (d, 1 H, J=1 Hz), 8.2 (d, 1H, J=l Hz), 9.78 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC(OC(C)C)=O.Cl.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]3=[N:37][CH:38]=[N:39][C:40]([O:41][CH:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)=[C:35]3[CH:34]=[N:33]2)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([N:45]2[CH2:46][CH2:47][CH:42]([O:41][C:40]3[N:39]=[CH:38][N:37]=[C:36]4[N:32]([C:29]5[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:24])=[O:25])=[CH:31][CH:30]=5)[N:33]=[CH:34][C:35]=34)[CH2:43][CH2:44]2)=[O:13])=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Reactant: CCCCc1ccc(C(=O)O)nc1
Agent: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1ccc(C(=O)N2CCC(Oc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 14.3 %

Procedure:
5-Butyl-pyridine-2-carboxylic acid (92 mg, 0.51 mmol) and isopropyl chloroformate (70 μL, 0.51 mmol) were dissolved in DMF and stirred at room temperature for 40 min. 1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (70 mg, 0.17 mmol) and triethylamine (72 μL, 0.51 mmol) were added next and continued to stir for 24 hours. Progress of the reaction was monitored by TLC and LCMS. Removal of organic solvents in vacuo and purification by HPLC afforded Compound A125 as a white solid (13 mg, 13%). Exact mass calculated for C22H30N6O4S 534.63, found 535.20 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[F:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1.[H][H]>C(O)C>[F:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([S:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1.[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:25]2[CH2:24][CH2:23][N:22]([C:20](=[O:21])[C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:29][CH:28]=3)[CH2:27][CH2:26]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(F)cc1)N1CCNCC1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccc(F)cc3)CC2)cc1
Product: O=C(c1ccc(F)cc1)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
1-(4-fluorobenzoyl)-4-(4-nitrobenzenesulphonyl)piperazine is prepared in a similar manner to Examples 1 and 2 by reacting equimolar quantities of 4-nitrobenzenesulphonyl chloride with 1-(4-fluorobenzoyl)piperazine hydrochloride. The reaction product is hydrogenated in ethanol at room temperature at atmospheric pressure with a 5% paladium on charcoal catalyst until hydrogen uptake ceases to yield 1-(4-aminobenzenesulphonyl)-4-(4-fluorobenzoyl)piperazine. Equimolar quantities of this compound and 4-chloro-7-trifluoroquinoline are reacted in 50% aqueous ethanol under reflux to yield the title compound.