Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([F:10])[CH:3]=1.C(O)C.[C-:14]#[N:15].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:14]#[N:15])=[C:4]([F:10])[CH:3]=1
Reactant: Fc1cc(Cl)ccc1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Cl)cc1F
Temperature: 25 °C
Yield: 86.2 %

Procedure:
Then, 18.5 g of 4-chloro-2-fluorobenzyl chloride was dissolved in a mixed solvent consisting of 130 ml of ethanol and 30 ml of water, to which 5.3 g of sodium cyanide was added, and the mixture was heated under reflux for 2 hours. After completion of the reaction, the reaction mixture was allowed to stand for cooling to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 15.1 g of 4-chloro-2-fluorophenylacetonitrile.
Reaction SMILES: [CH3:1][I:2].[C:3]12([CH2:13][CH2:14][N:15]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:16]([NH:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[O:17])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2>CC(C)=O>[I-:2].[C:3]12([CH2:13][CH2:14][N:15]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:16](=[O:17])[NH:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][N+:25]([CH3:1])=[CH:26][CH:27]=3)[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:9]([CH2:11]3)[CH2:10]1)[CH2:12]2
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Reactant: CI
Solvent: CC(C)=O
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1cc[n+](C)cc1
Product: [I-]
Yield: 96 %

Procedure:
Methyl iodide (90 μl, 1.5 mmol) was added to a solution of 1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-1) (0.30 g, 0.73 mmol) in acetone (1.5 ml) at room temperature, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure from the reaction mixture, and the precipitated crystals were filtered off with ethyl acetate to give 389 mg (96%) of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:44])=[C:13]([N+:41]([O-])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:44])=[C:13]([NH2:41])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc([N+](=O)[O-])c(O)cc2CN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc(N)c(O)cc2CN1C(=O)OC(C)(C)C
Yield: 101.4 %

Procedure:
(S)-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (5.1 mmol) was hydrolyzed and coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (5.85 mmol) according to general procedures B and A to provide (S)-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2.4 g). (S)-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.1 g) was dissolved in MeOH, Pd/C was added and the mixture stirred under balloon pressure of hydrogen for 1 h. Mixture was filtered through celite, washed with MeOH and EtOAc and concentrated to provide (S)-6-amino-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.06 g) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C@@H:9]1[CH2:11][C@H:10]1[C:12]1[C:13]2[C:17]([CH:18]=[CH:19][CH:20]=1)=[N:16][N:15]([CH3:21])[CH:14]=2)([CH3:4])([CH3:3])[CH3:2].CC(NCCC#N)CC1C=CC=CC=1.Cl.CCCCCC>C(O)C>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C@H:9]1[CH2:11][C@@H:10]1[C:12]1[C:13]2[C:17]([CH:18]=[CH:19][CH:20]=1)=[N:16][N:15]([CH3:21])[CH:14]=2)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cn1cc2c([C@@H]3C[C@H]3CNC(=O)OC(C)(C)C)cccc2n1
Agent: CC(Cc1ccccc1)NCCC#N
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Product: Cn1cc2c([C@H]3C[C@@H]3CNC(=O)OC(C)(C)C)cccc2n1
Yield: 49.5 %

Procedure:
Trans-tert-butyl{[2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}carbamate (5.90 g) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AD (50 mm ID×500 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: A) hexane 100%, B) ethanol 100%, mixing ratio: A/B=900/100, flow rate: 80 mL/min, column temperature: 30° C., sample injection amount: 200 mg (dissolved in 100 mL of mobile phase). A fraction solution containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give the title compound (2.92 g, 99.6% ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=900/100, flow rate: 1.0 mL/min, column temperature: 30° C., sample concentration: 0.5 mg/mL (mobile phase), injection volume: 10 μL).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:30]2[CH:42]=[CH:43][CH:44]=[CH:45][C:29]=2[S:28][CH2:27]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])C2=CC=CC=C2C1=O)=[O:5])[CH3:2].[OH2:46].NN>C(O)C>[C:38]([O:46][C:18]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[C:30]2[CH:42]=[CH:43][CH:44]=[CH:45][C:29]=2[S:28][CH2:27]1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:19])([CH3:41])([CH3:40])[CH3:39]
Reactant: O
Reactant: CCOC(=O)[C@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: NN
Solvent: CCO
Product: CCOC(=O)[C@H](CCCCCCCNC(=O)OC(C)(C)C)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 8 h
Yield: 184.2 %

Procedure:
In 10 ml of ethanol is dissolved 0.9 g of tert-butyl 3(R)-[1(S)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 0.35 g of hydrazine hydrate is added to the solution. After the mixture is left standing at room temperature overnight, the mixture is concentrated under reduced pressure, diluted with water and extracted four times with 50 ml of ethyl acetate. Water (50 ml) and 1.0 g of sodium bicarbonate are added to the ethyl acetate layer, and 0.46 g of di-tertbutyl dicarbonate is added to the resulting mixture with stirring. After the mixture is stirred at room temperature for 30 minutes, the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to give 0.79 g of tert-butyl 3(R)-[8-tert-butoxycarbonylamino-1(S)-ethoxycarbonyloctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].[CH:20]1([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][C:24]=2I)[CH2:22][CH2:21]1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.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]>[CH:20]1([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][C:24]=2[C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[CH:11]=[C:10]([C:12]4[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=4)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=23)[CH2:22][CH2:21]1
Reactant: Ic1cnn(-c2ccccc2)c1C1CC1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cnn(-c4ccccc4)c3C3CC3)c12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (40 mg, 0.160 mmol), 5-cyclopropyl-4-iodo-1-phenyl-1H-pyrazole (62 mg, 0.20 mmol), copper (I) iodide (9.1 mg, 0.048 mmol), and tetrakis(triphenylphosphine)palladium (0) (18.3 mg, 0.016 mmol) in N,N-dimethylformamide (2 ml), was added triethylamine (0.044 ml, 0.32 mmol). The mixture was sparged with argon for 3 minutes and heated to 70° C. After 1 h, reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 3-[(5-cyclopropyl-1-phenyl-1H-pyrazol-4-yl)ethynyl]-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH2:17][NH2:18].[NH2:25][CH2:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[CH:30][NH:31]2>>[CH3:24][O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:15]([O:14][CH3:13])[C:16]=1[CH2:17][NH:18][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([NH:25][CH2:26][C:27]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:28]=3[CH:29]=[CH:30][NH:31]4)=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: COc1cccc(OC)c1CN
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: NCc1cccc2[nH]ccc12
Product: COc1cccc(OC)c1CNc1ccc2c(NCc3cccc4[nH]ccc34)cccc2n1

Procedure:
The title compound, MS: m/e=439.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, 2,6-dimethoxybenzylamine and 4-aminomethylindole.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[ClH:16]>O>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:1][CH2:2][CH2:3][Cl:16])=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: Cl
Reactant: Nc1ccc(C(=O)C2CC2)cc1[N+](=O)[O-]
Solvent: O
Product: Nc1ccc(C(=O)CCCCl)cc1[N+](=O)[O-]
Yield: 84.5 %

Procedure:
A mixture of cyclopropyl (4-amino-3-nitrophenyl)methanone (80 g), prepared as described in U.S. Pat. No. 3,657,267, and concentrated HCl (420 ml) was stirred and refluxed for 30 minutes. The reaction mixture was cooled and water was added. The precipitate was filtered off, washed with water and dried, yielding 80 g (84.5%) of 1-(4-amino-3-nitrophenyl)-4-chloro-1-butanone; mp. 150° C. (intermediate 10).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].[CH3:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:34]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:26])[NH:42][C:39]2([C:35]3[N:34]=[C:33]([CH3:32])[CH:38]=[CH:37][N:36]=3)[CH2:40][CH2:41]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Reactant: Cc1ccnc(C2(N)CC2)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nccc(C)n5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(4-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.064 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.024 g (46%). 1H NMR (400 MHz, CDCl3): δ 8.63 (d, J=6.0 Hz, 1H), 8.39 (bs, 1H), 7.99-7.95 (m, 2H), 7.82 (dd, J=2.0, 8.0 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.41-7.36 (m, 2H), 7.34 (d, J=5.6 Hz, 1H), 7.21-7.15 (m, 3H), 6.39 (bs, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.71 (s, 3H), 2.24 (s, 3H), 2.06-2.03 (m, 2H), 1.74-1.71 (m, 2H). 19F NMR (376.47 MHz, CDCl3) δ−75.92 (TFA), −109.79, −119.33. LCMS: (ES+) m/z=553.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1)[CH:6]=[C:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].[Cl-:18].[CH3:19][N+:20](=[CH2:22])[CH3:21]>C(#N)C>[ClH:18].[CH3:17][O:16][C:14]1[CH:13]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:15]=1)[CH:6]=[C:7]1[CH2:11][CH2:10][CH:9]([CH2:19][N:20]([CH3:22])[CH3:21])[C:8]1=[O:12]
Reactant: [Cl-]
Reactant: C=[N+](C)C
Reactant: COc1cc(C=C2CCCC2=O)cc(OC)c1
Solvent: CC#N
Product: COc1cc(C=C2CCC(CN(C)C)C2=O)cc(OC)c1
Product: Cl
Yield: 89.3 %

Procedure:
0.03 mol of 2-(3,5-dimethoxybenzylidene)cyclopentanone was dissolved in 30 mL anhydrous acetonitrile, treated with 8.4 g (0.09 mol) of N,N-dimethyl-methylene ammonium chloride under refluxing, refluxed for 12 h to yield a solid product which was then suction filtered, dried and recrystallized in acetonitrile/chloroform to yield 2-(3,5-dimethoxy-benzylidene)-5-dimethylaminomethyl cyclopentanone hydrochloride with a yield of 89.3%.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:12])[CH:8]=[CH:9][CH2:10][OH:11].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.O1CCCC1>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:11][CH2:10]/[CH:9]=[CH:8]\[CH2:7][OH:12]
Reactant: C1=COCCC1
Reactant: OCC=CCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: OC/C=C\COC1CCCCO1
Temperature: 0 °C
Reaction time: 48 h
Yield: 481.9 %

Procedure:
Dihydropyran (9.1 ml, 100 mmol) was added dropwise to a cooled (0° C.) solution of 2-butene-1,4-diol (8.8 g, 10 mmol) and pyridinium paratoluenesulfonate (0.25 g, 10 mmol) in anhydrous dichloromethane:tetrahydrofuran (2:1). The mixture was stirred two days at 0° C. then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (ethyl acetate:hexane 3:7) to give 8.3 g of the title compound (49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[CH2:9][CH2:10][I:11])[CH:5]=[CH:6][CH:7]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:12])[CH2:9][CH2:10][I:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCI)c1cccc(Cl)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O[C@H](CCI)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
1-(3-Chlorophenyl)-3-iodopropan-1-one: Intermediate 12A (2.415 g, 8.14 mmol) was dissolved in acetone (40.7 mL) and the above solution was cooled to 0° C. and Jones Reagent (6.08 ml, 16.29 mmol) was added dropwise. The reaction mixture turned orange/brown and was allowed to stir at 0° C. for 30 min. To the mixture was added 10 mL of isoproponal (reaction mixture turned green) and was then allowed to stir at rt for 10 min. The reaction mixture was then diluted with EtOAc and water. The organic layer was washed with water (3×) and brine, dried with magnesium sulfate, filtered and concentrated to yield a light yellow oil (which solidified into long yellow needles). The crude product was then purified using silica gel chromatography to yield the desired product as a white solid (2.16 g, 90%). MS (ESI) m/z: 294.8 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.93 (t, J=1.6 Hz, 1H), 7.85-7.81 (m, 1H), 7.59-7.56 (m, 1H), 7.47-7.42 (m, 1H), 3.65-3.60 (m, 2H), 3.49-3.43 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[C:4]2[C:5]([N:7]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:8](=[O:9])[C:3]=12)=[O:6].O>CO.[BH4-].[K+]>[F:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[C:4]2[C:3]=1[CH:8]([OH:9])[N:7]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:5]2=[O:6]
Reactant: CC(C)CN1C(=O)c2c(F)ccc(F)c2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)CN1C(=O)c2c(F)ccc(F)c2C1O
Temperature: 20 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
4,7-Difluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 6.41 g of 3,6-difluoro-N-isobutylphthalimide in 70 cm3 of methanol and 1.44 g of potassium borohydride. The reaction mixture is: stirred at a temperature in the region of 20° C. for 3 hours and is then cooled to a temperature in the region of 0° C. and 45 cm3 of distilled water are added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 30° C., followed by addition of 80 cm3 of dichloromethane. After separation of the phases by settling, the aqueous phase is extracted twice with 80 cm3 of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 5.68 g of 4,7-difluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a yellow solid melting at 129.5° C. (Rf=0.48, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:27][C:28]1([CH3:35])[CH2:32][C:31](=[O:33])[O:30][C:29]1=[O:34]>C1COCC1>[C:2]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:31](=[O:33])[CH2:32][C:28]([CH3:35])([CH3:27])[C:29]([OH:34])=[O:30])[CH2:12][CH2:11]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccccc1OCC1CCNCC1
Reactant: CC1(C)CC(=O)OC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CC(=O)N1CCC(COc2ccccc2C(C)(C)C)CC1)C(=O)O
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To an ice-cold stirred solution of 4-[(2-tert-butylphenoxy)methyl]piperidine hydrochloride (0.20 g, 0.71 mmol) and triethylamine (0.10 g, 1.0 mmol) in THF (20.0 mL) was added 3,3-dimethyldihydrofuran-2,5-dione (0.11 g, 0.87 mmol) and the resulting mixture was warmed to room temperature. After 16 h the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 1N hydrochloric acid and separated. The organic layer was washed with saturated sodium chloride, dried (MgSO4), filtered and concentrated under reduced pressure to give a white solid. The solid was recrystallized from hexane/ethyl acetate to provide 4-{4-[(2-tert-butylphenoxy)methyl]piperidin-1-yl}-2,2-dimethyl-4-oxobutanoic acid (0.19 g, 72%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN(C)C(=O)C>[CH:21]1([C:19]([NH:18][C:16]2[N:17]=[C:12]3[CH:11]=[CH:10][C:9]([S:8][C:4]4[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)[CH:7]=[CH:6][CH:5]=4)=[N:14][N:13]3[CH:15]=2)=[O:20])[CH2:22][CH2:23]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Yield: 69.2 %

Procedure:
Using N-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (140 mg, 0.430 mmol), 3-(trifluoromethyl)benzoic acid (98 mg, 0.516 mmol), oxalyl chloride (75 μL, 0.860 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3 mL) and N,N-dimethylacetamide (3 mL) as starting materials and in the same manner as in Example 412, the title compound (148 mg, 75%) was obtained as a white powder.
Reaction SMILES: [O:1]=[C:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[BH4-].[Na+]>>[OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1
Reactant: O=C(CCC1CCC(=O)N1)Cc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CCC(CCC(O)Cc2cccc(C(F)(F)F)c2)N1
Yield: 86 %

Procedure:
Analogous to the procedure described for Example 1A, Step B, 5-[3-oxo-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one (1.37 g, 4.59 mmol) was reduced with NaBH4 (174 mg) at 0° C. over 2 h. Purification by medium pressure chromatography (2% MeOH in CH2Cl2) provided 5-[3-hydroxy-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one (1.19 g). 1H NMR (CDCl3) δ7.42 (m, 4H), 6.26 (m, 1H), 3.82 (m, 1H), 3.65 (m, 1H), 2.84 (m, 1H), 2.72 (m, 1H), 2.27 (m, 3H), 1.86 (m, 1H), 1.75-1.42 (m, 5H); MS 302.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[N:10]([C:11]([S:17][CH3:18])=[N:12][CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].B(F)(F)F.CCOCC.C(#N)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]([C:19](=[O:21])[CH3:20])=[C:15]3[N:10]([C:11]([S:17][CH3:18])=[N:12][CH:13]=[CH:14]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1nccc2cc(-c3ccc(F)cc3)nn12
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CSc1nccc2c(C(C)=O)c(-c3ccc(F)cc3)nn12
Temperature: 90 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a solution of 2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidine (150 mg, 0.58 mmol) in toluene (10 mL) was added acetic anhydride (0.065 mL, 0.69 mmol), followed by boron trifluoride diethyl etherate (0.080 ml, 0.64 mmol). An additional 10 mL of toluene was added and the mixture heated to 90° C. Acetonitrile (10 mL) was added to the reaction and the mixture heated at 70° C. for additional 16 hours. Additional acetic anhydride (0.11 mL, 1.1 mmol) and boron trifluoride diethyl etherate (0.15 ml, 1.2 mmol) were added dropwise to the reaction mixture at 90° C. The reaction was stirred for 1 hour, cooled to room temperature, stirred for 16 hours, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered, concentrated, and the residue purified by silica gel chromatography eluting with 10% ethyl acetate in hexanes to yield 110 mg (63%) of 1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone. 1H NMR (CDCl3): δ 8.13 (d, 1H), 7.98 (d, 1H), 7.65 (dd, 2H), 7.27 (m, 2H), 2.77 (s, 3H), 2.23 (s, 3H). MS m/z 302 (M+1).