Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH3:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:16][CH2:17][CH:18]=[C:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]=2[CH2:23][O:22][C:21]2[CH:30]=[CH:31][C:32]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:33][C:20]1=2.[I-].[K+]>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH3:14])[CH2:9][CH2:10][N:11]([CH2:16][CH2:17][CH:18]=[C:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[N:29][C:24]=3[CH2:23][O:22][C:21]3[CH:30]=[CH:31][C:32]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:33][C:20]2=3)[CH2:12][CH2:13]1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CC1(c2ccccc2Cl)CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(C)(c3ccccc3Cl)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 12 h
Yield: 24.6 %

Procedure:
A solution of 4-(2-Chloro-phenyl)-4-methyl-piperidine (0.29 g, 1.38 mmol) in isopropanol (5 mL) was treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.19 g, 0.50 mmol) and catalytic potassium iodide. The solution was stirred at 80° C. for 12 hr, and evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate→87:10:3 ethyl acetate/methanol/triethylamine) to yield 0.062 g (25%) of the title compound, 1H-NMR (CDCl3) ∂: 1.10 (3H, s), 1.58 (6H, s), 1.78 (2H, m), 1.90 (1H, m), 2.10 (2H, m), 2.40 (8H, m), 5.30 (2H, brs), 6.18 (1H, t), 6.79(1H, m), 6.92 (1H, m), 7.19–7.39 (6H, m), 7.42 (1H, m), 7.55 (1H, m), 8.55 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:6]=1[CH3:20])=[O:4].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:6]=1[CH2:20][Br:21])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)c(=O)n(CC2CCOCC2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(CC2CCOCC2)c1CBr
Yield: 45.9 %

Procedure:
A mixture of 5-bromo-2-methyl-6-oxo-1-(tetrahydro-pyran-4-ylmethyl)-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (0.906 g, 2.63 mmol), N-bromosuccinimide (0.516 g, 2.89 mmol), and benzoyl peroxide (64 mg, 0.26 mmol) in CCl4 (30 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-60% EtOAc/hexanes) to give 511 mg of the title compound. MS: (+) m/z 424.10 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH:10]1([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc(N)cc1
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(NC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A solution of p-anisidine (615 mg), cyclopentanone (420 mg) and acetic acid (2 ml) in methanol (30 ml) was cooled to 0° C., and sodium cyanoborohydride (315 mg) was added portionwise. The resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was then basified with 1N aqueous sodium hydroxide, and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (SiO2 30 g, diethyl ether:n-hexane=1:3) to give N-cyclopentyl-p-anisidine (530 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N+:3]=1[O-:20]
Reactant: Cc1ccc(C(F)(F)F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(F)(F)F)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 146 %

Procedure:
To a solution of crude 2-methyl-5-trifluoromethylpyridine from Step 1 (3.8 g) in CHCl3 (40 mL) was added m-chloroperbenzoic acid (3.0 g, 17.4 mmol) and the resulting mixture was stirred 5 hours at r.t. More peracid (1.5 g, 8.7 mmol) was added and the reaction stirred another 2 hours. Calcium hydroxide (3.0 g, 40.5 mmol) was added and the slurry was vigorously stirred 20 minutes before filtering through celite. Evaporation of the solvents gave 4.5 g of the title compound containing a little dioxane and CHCl3. This material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([N:30]2[CH2:31][CH2:32][N:27]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:28][CH2:29]2)=[O:13])=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc(CSc2ccccc2C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CSc2ccccc2C(=O)N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
N1-(S-(4-methoxybenzyl)thiosalicyloyl)-N4-benzylpiperazine (compound 5) was prepared using the same procedure described above using: 10 mM(2.743 g) of S-(4-methoxybenzyl) thiosalicylic acid, 3 mM(728 mg) of 1-Benzylpiperazine and 20 mM (3.525 g) triethylamine. The product was dissolved in 5 ml of methylene chloride and purified by column chromatography on a silica gel column (eluent: Ethyl acetate) to give 870 mg (20.1%) of a white crystal. The product was then further purified by crystallization from hexane. The purified product had having a melting point of 84-85° C. and had the following specifications:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([C@@H:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:9]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH:5]=[CH:6][CH:7]=1.IC.[CH3:34][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH:12]([CH3:34])[C:11](=[O:14])[N:10]([C@@H:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:9]2[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 11.2 g (24.2 mmol) of (S)-tert-butyl 2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate (Example 66, Step A) and iodomethane (1.813 mL, 29.1 mmol) in THF (120.0 mL) was added a lithium bis(trimethylsilyl)amide, (1M solution in THF; 26.6 mL, 26.6 mmol) at −78° C. The reaction was allowed to warm to R.T., then was quenched (sat. aqueous NH4Cl) and extracted (2×EtOAc). The combined organic layers were washed with water and sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was absorbed onto a plug of silica gel and purified by chromatography on silica gel, eluting with a gradient of 10% to 30% EtOAc in hexane, to provide the title compound as a mixture of stereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[OH-:13].[Na+].Cl>C(Cl)(Cl)Cl.CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:4]([CH3:9])([CH3:3])[C:5]([OH:8])=[O:13])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(Oc1ccc(Cl)cc1C(F)(F)F)C(=O)O
Reaction time: 0.67 h
Yield: 37 %

Procedure:
A three-neck round bottom flask affixed with an overhead stirrer was charged with 4-chloro-2-(trifluoromethyl)phenol (prepared according methods described in U.S. Pat. No. 4,262,152), (5.0 g, 127 mmol, 1.0 eq) and dissolved in chloroform (3.3 mL) and acetone (8.4 mL). NaOH pellets (4.2 g, 104 mmol, 3.75 eq) were added in 2 portions and the mixture was stirred vigorously for 40 min. The resulting slurry was acidified to pH 2 with 3N HCl and extracted with EtOAc. The organic extracts were treated with satd. aq. sodium bicarbonate, and the basic layer was acidified to pH 4 with conc. HCl and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford 2.7 g (37%) of 2-(4-chloro-2-(trifluoromethyl)phenoxy)-2-methylpropanoic acid as a light brown crystalline solid. 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J=2.6 Hz, 1H), 7.40 (dd, J=8.9, 2.6 Hz, 1H), 6.91 (d, J=8.9 Hz, 1H), 1.67 (s, 6H). LCMS (0-99% MeCN/water, 5 min, negative ion), Tret=2.99 min, [M−H]−=281.3 observed.
Reaction SMILES: [OH-].[K+].C(O)C.[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[NH:20]C(=O)OC>O>[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[NH2:20]
Reactant: COC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A 4N potassium hydroxide aqueous solution (4.75 liters) was added to an ethanol solution (3 liters) of methyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (2.25 Kg, 7.85 mol), followed by refluxing under heating for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water (5 liters) was added thereto, and the mixture was extracted with toluene (5 liters×2 portions). The organic layer was washed with water and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and the filtrate was distilled off under reduced pressure to obtain 2-fluoro-4-chloro-5-cyclopentyloxyaniline as an oily substance (1.75 Kg, 7.62 mol, 98.3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([F:17])[N:3]=1.ClC1C=C([C:25]2[N:29]3[CH:30]=[C:31]([NH:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH:37]([OH:41])[CH2:36]4)[CH:32]=[CH:33][C:28]3=[N:27][CH:26]=2)C=CN=1.BrC1N2C=C(NC3CCCC(O)C3)C=CC2=NC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:25]2[N:29]3[CH:30]=[C:31]([NH:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH:37]([OH:41])[CH2:36]4)[CH:32]=[CH:33][C:28]3=[N:27][CH:26]=2)[CH:5]=[C:4]([F:17])[N:3]=1
Reactant: CC1(C)OB(c2cc(F)nc(Cl)c2)OC1(C)C
Reactant: OC1CCCC(Nc2ccc3ncc(-c4ccnc(Cl)c4)n3c2)C1
Agent: OC1CCCC(Nc2ccc3ncc(Br)n3c2)C1
Product: OC1CCCC(Nc2ccc3ncc(-c4cc(F)nc(Cl)c4)n3c2)C1

Procedure:
The title compound is prepared from 2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and (1SR,3RS)-3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol [Intermediate R (step 1)] by a procedure analogous to [Intermediate J (step 2)]
Reaction SMILES: CN(C)CCCN=C=NCC.[Br:12][C:13]1[CH:14]=[C:15]([NH2:23])[C:16]([NH:19][CH:20]([CH3:22])[CH3:21])=[CH:17][CH:18]=1.[N:24]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)=[C:25]=S>O1CCCC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH:20]([CH3:21])[CH3:22])[C:25]([NH:24][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=3)=[N:23][C:15]=2[CH:14]=1
Reactant: CC(C)Nc1ccc(Br)cc1N
Reactant: COC(=O)c1ccc(N=C=S)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Nc2nc3cc(Br)ccc3n2C(C)C)cc1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 331 mg, 2.18 mmol) is added to a solution of 4-bromo-N-1-isopropylbenzene-1,2-diamine (180 mg, 0.786 mmol) and methyl 4-isothiocyanatobenzoate (140 mg, 0.725 mmol) in tetrahydrofuran was added. The reaction was heated to reflux for 2 hr and cooled to room temperature. The mixture was diluted with ethyl acetate and washed with 1 N HCl and saturated sodium bicarbonate solution. The organic layer was concentrated and purified by Biotage column chromatography to give methyl 4-(5-bromo-1-isopropyl-1H-benzo[d]imidazol-2-ylamino)benzoate (202 mg)
Reaction SMILES: [CH3:1][C:2]1[C:6]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][C:23]([N:26]6[CH2:30][CH2:29][CH2:28][CH2:27]6)=[N:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8]2=[O:32])=[CH:5][N:4]([CH2:33][C:34](O)=[O:35])[N:3]=1.CN(C=O)C.[Cl-].[CH2:43]([NH:45][CH2:46][CH3:47])[CH3:44]>ClCCl.C([O-])(O)=O.[Na+]>[CH2:43]([N:45]([CH2:46][CH3:47])[C:34](=[O:35])[CH2:33][N:4]1[CH:5]=[C:6]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][C:23]([N:26]6[CH2:30][CH2:29][CH2:28][CH2:27]6)=[N:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8]2=[O:32])[C:2]([CH3:1])=[N:3]1)[CH3:44]
Reactant: Cc1nn(CC(=O)O)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N5CCCC5)nc4)cc3c21
Reactant: CCNCC
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Cn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5cnc(N6CCCC6)nc5)cc4c32)c(C)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of {3-methyl-4-[3-methyl-2-oxo-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetic acid (Stage 247.1.1, 0.12 mmol) and DMF (0.007 ml) in dichloromethane (2 ml) was added oxallyl chloride (0.36 mmol) and the RM was stirred for 45 min at rt. The RM was quenched with diethylamine (Riedel-deHaën, Buchs, Switzerland, 2.4 mmol) and stirred for 5 min at it then diluted with saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with brine (2×), dried over Na2SO4, filtered and evaporated. The residue was taken in MeOH/DMF and purified by preparative HPLC. The fractions containing pure product were basified with NaHCO3, concentrated, cooled at 4° C. and the precipitate was filtered, washed with water and dried under vacuum to give the title compound as white solid. (HPLC: tR 2.63 min (Method A); M+H=540 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.57 (s, 2H), 8.07-8.04 (m, 2H), 7.87-7.84 (m, 1H), 7.67-7.65 (m, 1H), 5.21-5.04 (m, 2H), 3.57 (s, 3H), 3.52-3.46 (m, 4H), 3.42-3.34 (m, 2H), 3.32-3.34 (m, 2H), 1.96-1.90 (m, 4H), 1.94 (s, 3H), 1.18 (t, 3H), 0.99 (t, 3H))
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[F:30][C:31]1[CH:40]=[CH:39][C:34]2[N:35]=[C:36]([NH2:38])[S:37][C:33]=2[CH:32]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([NH:38][C:36]2[S:37][C:33]4[CH:32]=[C:31]([F:30])[CH:40]=[CH:39][C:34]=4[N:35]=2)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2nc3ccc(F)cc3s2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 6-fluoro-1,3-benzothiazol-2-amine (44 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol), DMAP (27 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 15 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 3.59 (s, 2H), 7.19 (t, J=74.7 Hz, 1H), 7.21-7.28 (m, 1H), 7.32-7.38 (m, 1H), 7.42-7.48 (m, 2H), 7.57-7.62 (m, 1H), 7.70-7.76 (m, 1H), 7.84-7.93 (m, 2H), 8.05-8.12 (m, 1H), 8.47-8.53 (m, 1H), 13.48 (br s, 1H); ESI-MS (m/z) 573.46 (MH)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:30]=[CH:29][C:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][C:20]=3[CH3:28])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1.[NH3:32]>>[O:1]=[S:2]1(=[O:31])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH2:32])=[O:24])=[CH:21][C:20]=3[CH3:28])[CH2:17][CH2:18]2)=[O:12])=[CH:29][CH:30]=1
Reactant: N
Reactant: Cc1cc(C(=O)O)ccc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2)CC1
Product: Cc1cc(C(N)=O)ccc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2)CC1

Procedure:
Using 4-{4-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoyl]piperazin-1-yl}-3-methylbenzoic acid (200 mg) described in Example 218 and 28% aqueous ammonia (5 mL) and by the reaction and treatment in the same manner as in Example 220, the title compound (68 mg) was obtained.
Reaction SMILES: [K].[SH:2][C:3]1[N:4]([CH3:13])[C:5](=[O:12])[C:6]2[CH:11]=[N:10][NH:9][C:7]=2[N:8]=1.[F:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>CN(C=O)C.O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][S:2][C:3]3[N:4]([CH3:13])[C:5](=[O:12])[C:6]4[CH:11]=[N:10][NH:9][C:7]=4[N:8]=3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(S)nc2[nH]ncc2c1=O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(F)cc3)cc2)nc2[nH]ncc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of 6-mercapto-5-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4(5H)-one potassium (1.0 g) in DMF (20 ml) was added 4-(4-fluorobenzoyl)benzyl bromide (1.745 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol to provide the title compound as colorless solid (1.467 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:23]([CH2:24][CH3:25])[CH2:22][CH2:21][C@H:17]1[C:18](O)=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:28](CC)CC)C.ClC(OCC)=O.N>C1COCC1.O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:23]([CH2:24][CH3:25])[CH2:22][CH2:21][C@H:17]1[C:18]([NH2:28])=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC[C@H]1CC[C@@H](C(=O)O)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC[C@H]1CC[C@@H](C(N)=O)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
N-(tert-butoxycarbonyl)-L-leucyl-(5S)-5-ethyl-L-proline was mixed with triethylamine (0.426 mL, 3.25 mmol) in THF (4 mL) and cooled to 0° C. followed by the addition of ethyl chloroformate (0.287 mL, 3.0 mmol). After 20 minutes, 0.5 M ammonia in dioxane (6 mL) was added. After 4 hours, the mixture was concentrated, and the residue was partitioned between 1 N HCl and ethyl acetate. The organic extracts were washed with saturated NaHCO3, dried (Na2SO4), filtered, concentrated under reduced pressure and purified by flash chromatography (80% to 100% ethyl acetate/hexane) to provide the titled compound. MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C:4]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:3]1=2.O1C2C(=CC=C(O)C=2)CCC1.[O:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[C:31]1=[O:40].C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[OH:39][C:32]1([C:10]2[C:9]([OH:12])=[CH:8][C:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]=3[CH:11]=2)[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]([CH2:29][C@H:25]2[CH2:26][CH2:27][CH2:28][O:24]2)[C:31]1=[O:40]
Reactant: O=C1C(=O)N(C[C@H]2CCCO2)c2ccccc21
Reactant: CN1CCOc2cc(O)ccc21
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: Oc1ccc2c(c1)OCCC2
Product: CN1CCOc2cc(O)c(C3(O)C(=O)N(C[C@H]4CCCO4)c4ccccc43)cc21

Procedure:
Following the procedure as described in PREPARATION 13A, and making non-critical variations using 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol to replace chroman-7-ol, and 1-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-indole-2,3-dione to replace 1-(diphenylmethyl)indoline-2,3-dione, 3-hydroxy-3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one was obtained (91%) as a pale grey solid: 1H NMR (300 MHz, CDCl3) (diastereomers) 8.94 (s, 0.4H), 8.80 (s, 0.6H), 7.52-7.48 (m, 1H), 7.41-7.34 (m, 1H), 7.20-7.08 (m, 2H), 6.52 (s, 1H), 6.16 (s, 1H), 4.51 (s, 0.4H), 4.44 (s, 0.6H), 4.29-4.17 (m, 3H), 3.90-3.64 (m, 4H), 3.17-2.99 (m, 2H), 2.58 (s, 3H), 2.04-1.78 (m, 3H), 1.74-1.60 (m, 1H); 13C NMR (diastereomers) (75 MHz, CDCl3) δ179.4, 179.2, 149.4, 149.3, 146.2, 143.2, 143.0, 130.2, 130.1, 129.8, 129.6, 125.9, 125.7, 123.6, 123.5, 117.6, 112.7, 112.4, 110.4, 110.3, 107.4, 79.3, 79.2, 76.9, 76.7, 68.3, 68.2, 65.3, 49.5, 44.7, 44.6, 39.5, 29.3, 29.1, 25.7, 25.6; MS (ES+) m/z 419.1 (M+23).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: N[C@@H](Cc1ccc(Oc2ncccc2Cl)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ncccc2Cl)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(3-chloro-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH3:14])=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].[Br:20][C:21]1[CH:22]=[C:23]([C:28](Cl)=[O:29])[C:24]([Cl:27])=[N:25][CH:26]=1.BrC1C=C(C(O)=O)C(O)=NC=1.O=S(Cl)Cl>CC#N>[Cl:27][C:24]1[C:23]([C:28]([NH:1][C:2]2[C:3]([NH:12][CH2:13][CH3:14])=[N:4][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:7]=2)=[O:29])=[CH:22][C:21]([Br:20])=[CH:26][N:25]=1
Reactant: CCNc1nc(C(F)(F)F)ccc1N
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Agent: O=C(O)c1cc(Br)cnc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCNc1nc(C(F)(F)F)ccc1NC(=O)c1cc(Br)cnc1Cl
Reaction time: 0.08 h

Procedure:
To a cooled solution of 3-amino-2-(ethylamino)-6-trifluoromethyl pyridine (1 g, 4.9 mmol) in MeCN (24 mL) was added solid NaHCO3 (906 mg, 11 mmol). After 5 min, crude 5-bromo-2-chloro-3-pyridinecarbonyl chloride (prepared from 5-bromo-2-hydroxy-3-pyridinecarboxylic acid and SOCl2 [as described by T. W. Gero et al. in Synth. Commun. 1989,19,553-559 (incorporated herein by reference) but with omission of the aqueous work-up] was added (1 equiv., 4.9 mmol). After 2 h, the reaction mixture was poured over ice/H2O (1.5 L) and the resulting solid was filtered, rinsed with H2O and then hexane. After drying under reduced pressure overnight, the title compound was obtained as a light brown solid (1.6 g, 77% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:29][CH2:28][CH2:27][C:26]3=[O:30])=[CH:3][C:4]=2[CH3:24])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1CCCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C)CC2)c(C)c1

Procedure:
Using (4-bromo-2-methylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (775 mg) described in Preparation Example 130 and pyrrolidin-2-one (0.16 mL) and by the reaction and treatment in the same manner as in Example 1, the title compound (182 mg) was obtained.