Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:12]([O:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]C(C)(C)C)=[O:23])=[CH:16][CH:15]=3)=[C:11]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH:35]([CH3:37])[CH3:36])[S:10][C:9]=2[CH:38]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:12]([O:13][C:14]3[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=3)=[C:11]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH:35]([CH3:36])[CH3:37])[S:10][C:9]=2[CH:38]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)c(-c3ccccc3C(C)C)sc2c1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3C(C)C)sc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a solution of (E)-tert-butyl 3-(4-((6-acetoxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (65 mg, 0.123 mmol) in DCM (3.0 mL) at 0° C. was added TFA dropwise over 5 min. The reaction was stirred at 0° C. for 1 h after which time it was warmed to room temperature for an additional 55 min. The mixture was then diluted with DCM and concentrated in vacuo to remove both DCM and TFA. The crude material was then further azeotroped with DCM (3×) to make sure all of the TFA was removed and gave a pale yellow solid. The resulting crude material was dissolved in MeOH (3 mL) and purified by reverse phase HPLC (acidic conditions, 0.1% TFA in 45-70% CH3CN/H2O) to afford (E)-3-(4-((6-acetoxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (39.1 mg, 0.083 mmol, 67% yield). 1H NMR (400 MHz, CD3OD) δ ppm=7.69 (d, J=2.0 Hz, 11), 7.57 (d, J=15.9 Hz, 1H), 7.45 (dd, J=8.7, 6.4 Hz, 3H), 7.40-7.26 (m, 3H), 7.18-7.10 (m, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.32 (d, J=16.0 Hz, 1H), 3.20 (p, J=6.9 Hz, 1H), 2.32 (s, 3H), 1.17 (d, J=6.9 Hz, 6H). HRMS (m/z, MH+): 473.1399.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:14])[O:13][CH2:12]2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Cl-].[Mg+2].[Cl-].C1(SC)C=CC=CC=1>ClCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:14])[CH:12]=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C2(C)CO2)cc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CSc1ccccc1
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(C)C=O)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 98.3 %

Procedure:
To a solution of 38.0 g (0.2 mole) of 2-(4-isobutylphenyl)-1,2-epoxypropane in 130 ml of dichloromethane was added 3.43 g (0.036 mole) of anhydrous powdered (100 mesh, Tyler) magnesium chloride and 5.0 g (0.04 mole) of thioanisole and the mixture was stirred for 10 hours at room temperature. The reaction mixture was washed with dilute hydrochloric acid and then with aqueous sodium chloride several times until neutral, and subjected to distillation under atmospheric pressure to remove dichloromethane. The resulted residue was distilled under reduced pressure to afford 37.4 g of 2-(4-isobutylphenyl)propionaldehyde as colorless oil distilled at 127°-130° C. (8 mmHg). The yield is 98.5%
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([OH:28])=O)[CH:7]=1.[NH2:41][C@H:42]([C:45]([NH2:47])=[O:46])[CH2:43][OH:44]>>[NH2:47][C:45](=[O:46])[C@@H:42]([NH:41][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([N:17]2[C:18]3[C:14](=[C:13]([NH:12][CH2:11][C:10]([OH:36])([C:32]([F:33])([F:35])[F:34])[CH2:9][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:39][CH3:40])([CH3:38])[CH3:37])[CH:21]=[C:20]([CH3:22])[CH:19]=3)[CH:15]=[N:16]2)[CH:24]=1)[CH2:43][OH:44]
Reactant: NC(=O)[C@@H](N)CO
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N[C@@H](CO)C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and L-serinamide with System A used for purification by mass directed autopreparation.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].CCN(CC)CC.[Br:20][CH2:21][C:22]1[C:23]([CH2:28]Br)=[CH:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C>[Br:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: BrCc1ccccc1CBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCc1ccccc1CBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
To a stirred solution of N-hydroxyphthalimide (0.60 g, 3.68 mmol) and Et3N (0.60 mL, 4.30 mmol) in DMF (6 mL) was added α,α′-dibromo-o-xylene (3.30 g, 0.0125 mol) and the mixture stirred at room temperature for 4 h. The resultant brown precipitate was filtered and washed with CH2Cl2. The filtrate was diluted with EtOAc (40 mL) and water (30 mL) and the organic phase washed with brine (1×30 mL), dried (Na2SO4) and concentrated under reduced pressure. The resultant yellow oil was purified by column chromatography on silica gel (4:1 Hexanes/EtOAc) to give the title compound (581 mg, 46%) as a white solid. 1H NMR (CDCl3) δ4.99 (s, 2H), 5.37 (s, 2H), 7.27-7.40 (m, 2H), 7.41-7.45 (m, 2H), 7.73-7.76 (m, 2H), 7.81-7.84 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][C:7]3([C:10]42[N:14]=[C:13]([NH2:15])[C:12]([CH3:16])=[N:11]4)[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1)[C:23]#[N:24].C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[NH2:15][C:13]1[C:12]([CH3:16])=[N:11][C:10]2([C:17]3[C:5](=[CH:4][CH:3]=[C:2]([C:26]4[CH:25]=[C:22]([CH:21]=[C:20]([Cl:19])[CH:27]=4)[C:23]#[N:24])[CH:18]=3)[CH2:6][C:7]32[CH2:9][CH2:8]3)[N:14]=1
Reactant: CC1(C)OB(c2cc(Cl)cc(C#N)c2)OC1(C)C
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC1=NC2(N=C1N)c1cc(-c3cc(Cl)cc(C#N)c3)ccc1CC21CC1
Temperature: 130 °C
Yield: 8.5 %

Procedure:
6′-Bromo-5″-methyl-3′H-dispiro[cyclopropane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 77, 0.10 g, 0.33 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (Intermediate 35, 0.121 g, 0.46 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.048 g, 0.07 mmol), 2 M aq. K2CO3 (0.493 mL, 0.99 mmol) and THF (1 mL) were added to microwave vial. The mixture was degassed by bubbling N2 (g) through it. The vial was sealed and heated in a microwave reactor at 130° C. for 30 min. [1,1′-Bis(diphenylphosphino)-ferrocene]palladium(II) chloride (0.048 g, 0.07 mmol) was added and the mixture was degassed by bubbling N2 (g) through it. The vial was sealed and heated in a microwave reactor at 130° C. for 30 min. The residue was dissolved in EtOAc and the mixture was extracted with 1.0 M HCl (2×10 mL). The organic layer was discarded while the aq phase was basified to pH 12 by addition of 1 M NaOH (aq). The basic water phase was extracted with DCM (2×20 mL). The organic phase was dried through a phase separator and concentrated in vacuo. The crude product was purified by flash chromatography (0-10% 0.1 M NH3 in McOH, in DCM, 25 g SiO2 column). The product was purified by a second flash chromatography (0-100% EtOAc in heptane, 25 g SiO2 column) followed by preparative chromatography. The fractions containing pure product were combined and concentrated. DCM was added and the organic phase was collected and dried through a phase separator and concentrated in vacuo, yielding the title compound (10 mg, 0.028 mmol, 8% yield): 1H NMR (500 MHz, CD3OD) δ ppm 0.14-0.23 (m, 1H), 0.50-0.58 (m, 1H), 0.62-0.70 (m, 1H), 0.80 (ddd, 1H), 2.30 (s, 3H), 2.96 (d, 1H), 3.49 (d, 1H), 7.02-7.08 (m, 1H), 7.47 (d, 1H), 7.59 (dd, 1H), 7.73 (s, 1H), 7.88 (s, 2H); MS (MM-ES+APCI)+ m/z 361 [M+H]+.
Reaction SMILES: [CH:1]1([CH:4](O)[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[Cl:18][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1CC(O)C1CC1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1CC(Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 4 g (18.5 mmol; purity 96%) of 1-cyclopropyl-2-(2-nitrophenyl)ethanol in 50 ml of toluene are added, at room temperature, 2.3 g (19.5 mmol) of thionyl chloride, and then the mixture is stirred at 80° C. for 0.5 h. Then another 460 mg of thionyl chloride are added and the mixture is stirred at room temperature for a further 45 minutes.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=O)[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:3].[OH-].[Na+]>C(O)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][C:11]3[NH:1][C:2](=[O:3])[C:4]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:10]=3)[CH2:16][CH2:17]2)=[O:29])=[CH:23][CH:24]=1
Reactant: NC(=O)c1ccccc1NC(=O)CCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccc(F)cc1)C1CCN(CCCc2nc3ccccc3c(=O)[nH]2)CC1
Yield: 10.5 %

Procedure:
A mixture of 10 parts of N-[2-(aminocarbonyl)phenyl]-4-(4-fluorobenzoyl)-1-piperidinebutanamide, 60 parts of sodium hydroxide solution 2N and 80 parts of ethanol is stirred and refluxed for 1.50 hours. The reaction mixture is evaporated and water is added to the residue. The oily product is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized twice from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 1 part (10.5%) of 2-[3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl]-4(3H)-quinazolinone; mp. 184° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[CH:9][CH:8]=[C:7]([Br:27])[CH:6]=2.[C:28](OCC)(OCC)(OCC)[CH2:29][CH3:30]>>[Br:27][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]4)[C:28]([CH2:29][CH3:30])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2c(N)cnc3cc(Br)ccc23)CC1
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nc2cnc3cc(Br)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 77.1 %

Procedure:
The method described in Part A of Examples 142–144 was used to treat tert-butyl 4-[(3-amino-7-bromoquinolin-4-ylamino)methyl]piperidine-1-carboxylate (15.0 g, 34.5 mmol) with triethyl orthopropionate (6.68 g, 37.9 mmol). After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 95:5 chloroform:CMA) followed by recrystallization from ethyl acetate to provide 12.6 g of tert-butyl 4-[(7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as a white powder, mp 208–209° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=O)[CH3:12].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[CH3:12][C:11]1[O:18][C:16](=[O:17])/[C:15](=[CH:7]/[C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)/[N:14]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CSc1ccc(/C=C2\N=C(C)OC2=O)cc1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
4-(Methylsulfanyl)benzaldehyde (31.8 g), (acetylamino)acetic acid (24.5 g) and acetic anhydride (35 ml) were combined, and then sodium acetate (8.57 g) was added to the suspension at room temperature under nitrogen atmosphere. The reaction mixture was refluxed for 3.5 hours. After cooled to room temperature, the mixture was poured into ice-water and ethyl acetate with stirring, and filtered in vacuo. The filtrate was separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue and the previously obtained solid were combined, and the mixture was purified by flash column chromatography over silica gel with chloroform/ethyl acetate (30:1) as an eluent, and triturated with isopropyl ether to give (4Z)-2-methyl-4-(4-(methylsulfanyl)benzylidene)-1,3-oxazol-5(4H)-one (17.8 g) as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[C:11](OCC)=[O:12])=[O:5])[CH3:2].[BH4-].[Na+].O.Cl>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH2:11][OH:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncsc1C(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ncsc1CO
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.3 %

Procedure:
4,5-Diethoxycarbonylthiazole (7.13 g) was dissolved in 100 ml of ethanol, 2.20 g of sodium borohydride was added to the solution in an argon atmosphere under ice cooling, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction solution, the mixture was adjusted to pH 4.5 by the addition of 1 N aqueous hydrochloric acid, and the organic solvent was removed by distillation under the reduced pressure. The remaining aqueous solution was extracted five times with chloroform, was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. Ethyl acetate and hexane were added to the concentrate, and the resultant solid was collected by filtration to give 2.29 g of 4-ethoxycarbonyl-5-hydroxymethylthiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:19]=[O:20])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[N:7]2.O1CCC[CH2:22]1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:19]([OH:20])[CH3:22])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[N:7]2
Reactant: C1CCOC1
Reactant: O=Cc1cc2c(Cl)cccc2nc1-c1cccc(F)c1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc2c(Cl)cccc2nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring heterogeneous mixture of 5-chloro-2-(3-fluorophenyl)quinoline-3-carbaldehyde (1.0120 g, 3.542 mmol) in tetrahydrofuran (35.42 mL, 3.542 mmol) was added methylmagnesium bromide 3 M in diethyl ether (3.542 mL, 10.63 mmol) dropwise at 0° C. (started at 11:10 am), and the mixture was then stirred at room temperature. After 3 h, the reaction was quenched with saturated aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(5-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethanol as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (1 H, s), 8.00-8.05 (1 H, m), 7.73-7.85 (2 H, m), 7.54-7.63 (1 H, m), 7.41-7.47 (2 H, m), 7.33-7.40 (1 H, m), 5.56 (1 H, d, J=4.3 Hz), 4.98-5.06 (1 H, m), 1.27 (3 H, d, J=6.7 Hz); LC-MS (ESI) m/z 302.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18](Cl)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].Cl.[F:27][C:28]1([F:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.CCOCC>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18]([N:31]4[CH2:32][CH2:33][C:28]([F:34])([F:27])[CH2:29][CH2:30]4)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: FC1(F)CCNCC1
Reactant: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CC(C)O
Product: COC(=O)C1(c2ccc(Nc3nc(N4CCC(F)(F)CC4)nc4c3CCC4)cc2)CCC1
Yield: 76.8 %

Procedure:
A mixture of 1-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclobutanecarboxylic acid methyl ester (0.36 g, 1 mmol), 4,4-difluoropiperidine hydrochloride (0.23 g, 1.5 mmol), diisopropylethylamine (0.5 mL, 3 mmol) in anhydrous isopropanol (10 mL) was heated to reflux for 48 hours. Thereafter, the mixture was cooled to a temperature in the range of 40° C. to 60° C. and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed sequentially with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a semi solid residue. Ether was added to the residue and the precipitates were filtered to afford the title compound as a white solid (0.34 g, 77% yield).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl.[Cl-].[Na+]>CO.O>[C:1]([C:5]1[O:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CC1c1ccc(C(C)(C)C)o1
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(C2CC2C(=O)O)o1
Temperature: 25 °C
Yield: 100.6 %

Procedure:
Ethyl 2-(5-t-butylfuran-2-yl)-cyclopropanecarboxylate (5.0 g, 0.021 mol) was dissolved in methanol (50 ml) and a solution of potassium hydroxide (2.4 g, 0.043 mol) in water (50 ml) was added dropwise at room temperature. The solution was refluxed for 3 hours, cooled to room temperature and carefully neutralised with 2M HCl. Saturated sodium chloride was added, the aqueous solution extracted with ethyl acetate (4×50 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave 2-(5-t-butylfuran-2-yl)-cyclopropanecarboxylic acid (4.4 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:17]O>>[N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:17])=[O:10])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Yield: 86 %

Procedure:
5-Nitro-3-pyrazole-carboxylic acid (8 g, 50.90 mmol) and sulfuric acid (5 mL, 1.48 mmol) in methanol (200 mL) were heated to reflux for 4 hrs. The solvent was evaporated and the residue was resuspended in CH2Cl2 and washed with water and brine and dried Na2SO4. Methyl 5-nitro-1H-pyrazole-3-carboxylate (7.5 g, 86%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:24][CH:25]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[N:3][CH:4]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(Cl)cc1)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared according to the two steps procedure described in step 2 and 3 of Example 45. Firstly, tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) was reacted with 4-chlorophenol. Next, the crude product was converted to the corresponding carboxylic acid: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.8 Hz), 8.14 (1H, d, J=2.8 Hz), 8.11–8.02 (3H, m), 7.50–7.39 (4H, m), 7.11 (2H, d, J=9.0 Hz), 5.44–5.31 (1H, m), 1.60 (3H, d, J=7.0 Hz); MS (ESI) m/z 431 (M+H)+, 429 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)(O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(O)C1CCCCC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cc(Cl)ccc2C1C1CCCCC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A suspension of rac-6-chloro-3-cyclohexyl-3-hydroxy-1,3-dihydro-indol-2-one (0.14 g, 0.52 mmol) (from Example 19a supra) in a mixture of triethylsilane (0.25 mL, 1.58 mmol) (Aldrich) and trifluoroacetic acid (0.77 g, 7.6 mmol) (Aldrich) was heated in a 90° C. bath for 48 hours. After cooling to room temperature, mixture was diluted with ethyl acetate. Solid potassium carbonate was added and mixture stirred at room temperature for 1 hour. Mixture was filtered and concentrated. Residue was redissolved in ethyl acetate and washed with water and brine, dried (Na2SO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-cyclohexyl-1,3-dihydro-indol-2-one as a grey solid. (Yield 0.11 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:54])[C@H:15]([NH:24][C:25]([C@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][CH2:40][CH:41]2[C:53]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:47]3[C:42]2=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.[CH3:55][S:56](Cl)(=[O:58])=[O:57].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C@@H:15]([NH:24][C:25]([C@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][CH2:40][CH:41]2[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:47]=3[C:48]3[C:53]2=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:38])=[O:26])[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][S:56]([CH3:55])(=[O:58])=[O:57])[CH2:13][CH2:12]2)=[O:54])=[CH:18][CH:19]=1
Reactant: Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@H]2Cc3ccccc3CN2C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Product: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@H]2Cc3ccccc3CN2C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Yield: 86.3 %

Procedure:
Fluoren-9-ylmethyl (3R)-3-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino] phenylpiperazinyl)-2-oxoethyl]carbamoyl}-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from fluoren-9-ylmethyl (3R)-3-(N-{(1R)-2-[4-(2-aminophenyl)piperazinyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (250 mg, 0.34 mmol) according to the procedure for Preparation III using methanesulfonyl chloride (30 μl, 0.39 mmol) and 2,6-di-tert-butyl-pyridine (80 μl, 0.36 mmol) (Aldrich). The crude product was concentrated in vacuo and purified by flash chromatography (SiO2, 15% EtOAc in CH2Cl2), to afford the desired compound (240 mg). MS (ESI, pos. ion) m/z: 818 (M+H), (ESI, neg. ion) m/z: 816 (M−H). Calc'd for C45H44ClN5O6S: 817.27.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]([O:15]CC)=O)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[NH3:18]>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]([NH2:18])=[O:15])(=[O:9])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)CNS(=O)(=O)c1cncc(Br)c1
Solvent: CO
Product: NC(=O)CNS(=O)(=O)c1cncc(Br)c1
Yield: 66 %

Procedure:
A solution of ethyl 2-(5-bromopyridine-3-sulfonamido)acetate (0.50 g, 1.7 mmol) and ammonia in methanol (2M, 10 mL) was heated to 60° C. in a sealed tube for 4 h. The cooled reaction mixture was concentrated under reduced pressure to yield 2-(5-bromopyridine-3-sulfonamido)acetamide (300 mg, 66%), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.96 (d, 1H, J=2.4 Hz); 8.90 (d, 1H, J=2 Hz); 8.39 (t, 1H, J=2 Hz), 8.21 (br s, 1H), 7.35 (br s, 1H), 7.07 (br s, 1H), 3.5 (s, 2H). LCMS Method D: retention time 0.945 min; [M+1]=294, 296.0.