Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([C:16]#[N:17])[CH:3]=1.IN1[C:23](=O)[CH2:22][CH2:21][C:20]1=[O:25]>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([C:16]#[N:17])[C:3]=1[C:23]1[O:25][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(Cl)c(-n2nc(C#N)cc2N)c(Cl)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1cc(Cl)c(-n2nc(C#N)c(-c3ccco3)c2N)c(Cl)c1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-methylphenyl)pyrazole (1 g) in acetonitrile (15 ml) at room temperature was added N-iodosuccinimide (0.845 g). Stirring was continued for 10 minutes and the mixture was then evaporated to dryness. The residue was taken up in dioxane (20 ml). Furan-2-boronic acid (0.845 g), tetrakis(triphenylphosphine)palladium(0) (0.35 g) and a solution of potassium carbonate (2.8 g) in water (8 ml) were added. The mixture was heated under reflux for 24 hours, then cooled and partitioned between ether and water. The separated aqueous layer was extracted with ether and the combined ether layers were washed with brine, dried and evaporated. The green oily residue was purified by column chromatography on silica gel eluted with hexane:dichloromethane (1:2). Combination and evaporation of suitable fractions followed by recrystallisation from toluene gave the title compound as a white solid, m.p. 191.5-192.5° C.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N+:9]([O-])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].P(Cl)(Cl)([Cl:18])=O.O.[OH-].[Li+]>O1CCCC1>[Cl:18][C:8]1[N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc[n+]([O-])c(C(F)(F)F)c1F
Reactant: O=P(Cl)(Cl)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-fluoro-2-(trifluoromethyl)isonicotinic acid 1-oxide (1.0 g, 4.4 mmol from Step A) in phosphoryl chloride (4 mL, 40 mmol) was heated to 110° C. for 2 hours, then was left to stir at ambient temperature overnight. The POCl3 was evaporated, the residue was treated with sodium bicarbonate solution, which was stirred for 1 hour. To this mixture was added tetrahydrofuran (20 mL) and lithium hydroxide monohydrate (0.24 g, 5.7 mmol). This was stirred for 3 hours. The pH of the mixture was then adjusted to the range of pH 4-5 by the addition of c.HCl. The product was extracted with three portions of ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. Yield: 0.54 g (50%); LC-MS: 244.1/245.9 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.07 (d, 1H).
Reaction SMILES: C([O:3][C:4](=[O:13])[CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)C.[OH-].[Li+].Cl>O1CCOCC1.O>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH2:5][C:4]([OH:13])=[O:3])[CH:8]=1
Reactant: CCOC(=O)COc1cccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)COc1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the compound from preparation 295, (pyridin-3-yloxy)-acetic acid ethyl ester, 300 mg (1.68 mmol) in 15 mL of dioxane was added a solution of 400 mg (16.8 mmol) of lithium hydroxide in 15 mL of water. The solution was stirred for three hours at rt. then acidified to pH=1.0 with 5 N HCl and concentrated to dryness to give a quantitative yield of the crude desired product. MS (ion spray) 154.1 (M+). Crude product was carried on without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)nc2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cn1

Procedure:
A solution of 81.7 mg (0.194 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-methyl-5-pyridyl)-2-naphthalenyl)ethynyl]benzoate (Compound 12) and 40.7 mg (0.969 mmol) of LiOH—H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ8.41 (1H, d, J=1.9 Hz), 7.90 (2H, d, J=8.3 Hz), 7.63 (1H, dd, J=2.3, 7.9 Hz), 7.59 (2H, d, J=8.3 Hz), 7.49 (2H, m), 7.33 (1H, d, J=7.8 Hz), 6.95 (1H, s), 6.11 (1H, t, J=4.5 Hz), 2.52 (3H, s), 2.37 (2H, d, J=4.6 Hz), 1.31 (6H, s).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:13][C@@H:12]([OH:23])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>[Pd]>[CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:21])([CH3:20])[CH3:22])([CH3:18])[CH3:17])[CH2:13][C@@H:12]([OH:23])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](O)C=C1COCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](O)C[C@H]1COCc1ccccc1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A suspension of (1R,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]-oxy}cyclopent-2-en-1-ol (1.47 g, 0.00439 mol), sodium carbonate (1.1 g, 0.010 mol) and 10% Pd/C (0.3 g, 0.0003 mol) in EtOAc (20 mL, 0.2 mol) was stirred under an atmosphere of Hydrogen overnight. The reaction was purged with nitrogen and filtered through celite with EtOAc. The filtrate was concentrated to obtain 1.45 g (98%) of the title compound as a 5:1 mixture of diastereomers (desired:undesired).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][CH3:17])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][CH3:17])[C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(F)(F)F)cc(OC)c1C(=O)O
Solvent: Cc1ccccc1
Product: COc1cc(C(F)(F)F)cc(OC)c1C(=O)Cl
Temperature: 85 °C
Yield: 98.9 %

Procedure:
To a suspension of 14.47 g (57.84 mmol) 2,6-dimethoxy-4-trifluoromethyl-benzoic acid (intermediate AJ) in 160 ml toluene containing four drops DMF under nitrogen at room temperature, was added 42 ml (578.4 mmol) thionyl chloride. The mixture was heated in an 85° C. oil bath for 3 hours. The solvent was removed in vacuo to provide 15.37 g (yield: 98.9%) of the title compound as an off-white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[C:14]([O:22][CH3:23])[N:13]=1.O>CN(C)C=O>[CH3:23][O:22][C:14]1[N:13]=[C:12]([S:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1ccc(OC)nc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)nc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a stirred mixture of 0.8 g (0.0161 mol) of 50% sodium hydride (in mineral oil), which had been washed with hexanes, in 20 mL dry dimethylformamide cooled to -5° under nitrogen was added dropwise 1.9 mL (0.0161 mol) benzyl mercaptan The suspension was stirred at room temperature for 1 hour, cooled to 0°, and a solution of 3.2 g (0.0147 mol) of the product of Example 2 in 20 mL dry dimethylformamide was added dropwise. After warming to room temperature, the solution was poured into water and extracted with ether. The combined organic layers were washed with water and with brine, dried over magnesium sulfate, and evaporated to an oil which was purified by flash chromatography to afford 3.0 g (64%) of a yellow solid: m.p. 67°-71°; NMR (CDCl3, 200 MHz) 3.88 (3H, s), 3.96 (3H, s), 4.46 (2H, s), 6.44 (1 H, d, J=9 Hz), 7.2-7.5 (5H, m), 8.1 (1H, d, J=9 Hz); IR (nujol) 1700, 1580, 1305, 1255 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([C:11]=1[O:12][CH3:13])=[N:7]O[N+:9]=2[O-]>CCOC(C)=O.[Pd]>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[C:6]([NH2:7])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: COc1c(Br)ccc2c1no[n+]2[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1c(Br)ccc(N)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A 2 L Parr shaker bottle was dried and cooled under a stream of nitrogen then charged with 5-bromo-4-methoxybenzofurazanoxide (100 g, 0.44 mol, 1.0 equiv.) in EtOAc (1 L) and 10% Pd/C (10% w/w, 10.0 g) was added. The reaction was then stirred at RT overnight under hydrogen. The reaction mixture was filtered through a Celite® pad and concentrated in vacuo to afford 4-bromo-3-methoxy-benzene-1,2-diamine (61.0 g, crude) as a dark brown semi solid. The crude material was taken directly to the next step.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]([CH3:42])[C:25]([C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)=[O:26]>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:25]([N:24]([CH3:42])[CH3:23])=[O:26])=[N:28][CH:29]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(C(=O)N(C)C)nc4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (from PepTech Corp. Encyclopedia of Amino Acid Analogs and Boronic Acids). LCMS calculated for C24H26N5O3 (M+H)+: m/z=432.2. Found 432.1.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[F:28][C@@H:29]1[CH2:33][NH:32][C@@H:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:30]1>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:32]1[CH2:33][C@@H:29]([F:28])[CH2:30][C@@H:31]1[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@H]1C[C@H](F)CN1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N2C[C@@H](F)C[C@@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 2.36 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 3.30 g of the compound obtained in Step 13-3 as starting materials, respectively 874 mg (Isomer A: colorless solid) and 1.80 g (Isomer B: colorless solid) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[NH2:16])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.C(N(CC)CC)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:2][C:3]1[C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[NH:16][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[C:25]([F:24])([F:35])[F:36])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: NC1CCCCC1c1ncc(Cl)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Yield: 34.9 %

Procedure:
0.70 g of 2-[3,5-dichloro-2-pyridinyl]cyclohexanamine hydrochloride (0.00022 mol), 0.07 ml of triethylamine, 49 mg (0.00023 mol) of 2-trifluoromethylbenzoyl chloride are stirred in 3 ml of dichloromethane at room temperature overnight. Dichloromethane is added (5 ml) to the reaction mixture, which is washed twice with water (5 ml). After separation, the organic phase is dried over magnesium sulfate, filtered, concentrated to dryness and purified on silica to yield to 32 mg of N-{2-[3,5-dichloro-2-pyridinyl]-cyclohexyl}-2-(trifluoromethyl)benzamide (31%).
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]2[O:13][CH2:12]2)[C:5]=1[OH:14].[OH-].[Na+].F[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>CC(N(C)C)=O.C(OCC)(=O)C>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([O:14][C:5]2[C:4]([CH2:3][CH:2]3[O:1][CH2:15]3)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:20][CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(F)cc1
Reactant: Oc1c(CC2CO2)cccc1CC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2c(CC3CO3)cccc2CC2CO2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2,6-Diallylphenol (3.8 gm, 0.02 mol) was oxidized with m-chloroperbenzoic acid as described in Example 1 to give 2,6-di(2,3-epoxypropyl)phenol. MS m/z 206 (M+ calcd for C12H14O3=206). H NMR (300 MHz, CDCl3) d 2.65 (d, 2, CH2 epoxypropyl) 2.75–2.96 (CH2 epoxypropyl), 3.12 (d, 2, CH epoxypropyl), 3.25–3.35(m, 2, CH epoxypropyl), 6.80 (t, 1, aromatic), 7.10 (d, 2, aromatic). The product 2,6-di(2,3-epoxypropyl)phenol was diluted with dimethylacetamide (50 ml) and neutralized with sodium hydroxide. 4-Fluorobenzonitrile (1 equivalent of the phenol) was added and the mixture heated and stirred overnight at 50° C. After cooling, the reaction was diluted with ethyl acetate and washed with water (4×), dried over MgSO4 and evaporated to give 2,6-di(2,3epoxypropyl)phenyl 4-cyanophenyl ether. MS m/z 307 (M+ calcd for C19H17O3N=307). H NMR (300 MHz, CDCl3) d 2.50, (d, 2, CH2 epoxypropyl CH2), 2.65–2.90 (m, 4, CH2 epoxypropyl), 3.15–3.30 (m, 2, CH2 epoxypropyl), 3.45–3.75 (m, 2, epoxypropyl CH), 6.75–7.06 (m, 3, aromatic), 7.00–7.75 (m, 4, aromatic).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][CH2:8][CH2:9][CH2:10][OH:11].[Br:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>C(#N)C>[Br:12][C:13]1[CH:14]=[C:15]([S:19]([NH:7][CH2:8][CH2:9][CH2:10][OH:11])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: NCCCO
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(=O)(NCCCO)c1cccc(Br)c1

Procedure:
3-Bromo-N-(3-hydroxy-propyl)-benzenesulfonamide (266 mg) obtained from the reaction of pyridine, 3-aminopropanol and 3-bromobenzenesulfonyl chloride in acetonitrile was left to act in di-tert-butyl carbonate (226 mg) and acetonitrile (5 ml) in the presence of DMAP (10 mg), to obtain 3-bromo-N-Boc-N-(3-hydroxy-propyl)-benzenesulfonamide as a colorless oil (267 mg, 72%).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([S:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:24]([Cl:34])[CH:23]=2)[C:8](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:36]>O1CCOCC1.O>[Cl:34][C:24]1[CH:23]=[C:22]([C@@H:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([OH:9])=[O:36])[CH:27]=[CH:26][C:25]=1[S:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@H](CC1CCCC1)c1ccc(SC2CCCC2)c(Cl)c1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@H](CC1CCCC1)c1ccc(SC2CCCC2)c(Cl)c1
Temperature: 105 °C

Procedure:
A solution of (R)-3-cyclopentyl-2-(3-chloro-4-cyclopentylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (1.5 mmol) in dioxane (5 mL) is treated with a 9 N aqueous sulfuric acid solution (1.5 mL). The resulting solution is then heated at 105° C. for 16 h. The reaction is then cooled and diluted with water (13 mL) and extracted with a chloroform/methanol solution (3:2, 3×20 mL) and then combined the organic extracts and dried over magnesium sulfate, filtered and concentrated. Purification on an AnaLogix Intelliflash system (silica gel column) will afford (R)-2-(3-chloro-4-cyclopentylsulfanyl-phenyl)-3-cyclopentyl-propionic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:21]([CH3:24])=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=5)[CH:23]=[CH:22][C:21]=4[CH3:24])=[CH:11][N:10]3[N:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 65.3 %

Procedure:
To a solution of N-[6-(3-amino-6-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.309 mmol) in 1-methylpyrrolidin-2-one (2.0 mL) was added 3-(trifluoromethyl)benzoyl chloride (78 mg, 0.371 mmol), and the mixture was stirred at room temperature for 10 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained oil was triturated with ethyl acetate and hexane to give the title compound (100 mg, 65%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([C@@H:15]([CH3:26])[CH2:16][NH:17][C:18]([C:20]3[N:21]=[C:22]([CH3:25])[NH:23][CH:24]=3)=[O:19])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].I[CH:28]([CH3:30])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([C@@H:15]([CH3:26])[CH2:16][NH:17][C:18]([C:20]3[N:21]=[C:22]([CH3:25])[N:23]([CH:28]([CH3:30])[CH3:29])[CH:24]=3)=[O:19])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)I
Reactant: Cc1nc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Product: Cc1nc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1C(C)C

Procedure:
The title compound was prepared using the method of Example 253 starting from (S)—N-{2-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propyl}-2-methyl-1H-imidazole-4-carboxamide and 2-iodopropane. 1H NMR (400 MHz, CDCl3): 1.42 (31-1, d), 1.43 (3H, d), 1.60 (3H, d), 2.37 (3H, s), 3.77 (1H, m), 3.88 (1H, m), 4.28 (1H, m), 4.63 (1H, m), 6.58 (1H, d), 7.50 (1H, d), 7.51 (1H, t), 7.59 (1H, s), 7.66 (1H, d), 7.84 (1H, dd), 8.00 (1H, d).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([C:8]2[CH:9](C)[NH:10][CH2:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.Cl.CC([OH:18])C>>[OH:18][C:7]1[CH:6]=[CH:5][C:4]([C:8]2[CH2:9][NH:10][CH2:11][CH:12]=2)=[CH:3][CH:2]=1
Reactant: CC1NCC=C1c1cccc(O)c1
Reactant: CC(C)O
Agent: Cl
Product: Oc1ccc(C2=CCNC2)cc1

Procedure:
(±)-3-(3-hydroxyphenyl)-2-methyl-3-pyrroline·HCl (3n), mp 202° C. (from propanol-2).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]([NH2:10])=[O:9].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[C:11]([NH:19][C:20]([NH:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]([NH2:10])=[O:9])=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cn1cnc(C(N)=O)c1N
Solvent: CC(C)=O
Product: Cn1cnc(C(N)=O)c1NC(=S)NC(=O)c1ccccc1
Yield: 92.4 %

Procedure:
5-Amino-1-methyl-1H-imidazole-4-carboxamide (6.5 g, 45 mM) and benzoylisothiocyanate (7.7 g, 47 mM) were refluxed in acetone (90 ml) for 4 hours under N2. After cooling in an ice bath the formed product was filtered off, washed with acetone and dried. Hereby was isolated 13.0 g (95%) of the title compound as a white powder, mp 194°-196° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[N:11]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:26]([O:25][CH2:24][C:10]1([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:14][CH2:13][CH:12]([CH2:15][O:16][S:39]([C:36]2[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=2)(=[O:41])=[O:40])[N:11]1[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C(CO)CCC1(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.6 %

Procedure:
To a mixture of tert-butyl 2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(hydroxymethyl)pyrrolidine-1-carboxylate (400 mg, 0.82 mmol) and 4-dimethylaminopyridine (300 mg, 2.45 mmol) in DCM (20 mL) was added 4-toluenesulfonyl chloride (312 mg, 1.64 mmol) at 0° C. The mixture was stirred at 25° C. for 16 h. Then the mixture was diluted with DCM (50 mL) and washed with saturated NH4Cl (50 mL) three times, saturated NaHCO3 (50 mL) three times and water (50 mL) three times, dried over anhydrous sodium sulfate and concentrated in vacuo to afford tert-butyl 2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(p-tolylsulfonyloxymethyl)pyrrolidine-1-carboxylate 81i (410 mg, 77%) which was used for next step without further purification. MS: calc'd (MH+) 644, measured (MH+) 644.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:33])[C:7]=1[CH2:8][CH2:9][C@H:10]1[O:15][CH2:14][C@H:13]([CH2:16][O:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11]1.[F:34][C:35]1[CH:36]=[C:37]([C@H:42]([C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[CH2:43][C:44](O)=[O:45])[CH:38]=[C:39]([F:41])[CH:40]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[F:53][C:50]1[CH:49]=[CH:48][C:47]([C@@H:42]([C:37]2[CH:38]=[C:39]([F:41])[CH:40]=[C:35]([F:34])[CH:36]=2)[CH2:43][C:44]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([F:33])[C:7]=2[CH2:8][CH2:9][C@H:10]2[O:15][CH2:14][C@H:13]([CH2:16][O:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[O:19])[N:12]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:11]2)=[O:45])=[CH:52][CH:51]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Reactant: O=C(O)C[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)C[C@@H](c2ccc(F)cc2)c2cc(F)cc(F)c2)OC[C@@H]1COC(=O)NCC(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (2R,5R)-2-(2-(3-amino-5-fluoropyridin-4-yl)ethyl)-5-(2,2,2-trifluoroethylaminocarbonyloxymethyl)morpholine-4-carboxylate (75 mg, 0.16 mmol) and (3S)-3-(3,5-difluorophenyl)-3-(4-fluorophenyl)propanoic acid (44 mg, 0.16 mmol) in pyridine (1.0 mL) was cooled to −10° C. in an ice-acetone bath. To the stirred solution was added POCl3 (0.016 mL, 0.17 mmol) and the mixture was stirred for 30 min. The reaction was quenched by the addition of aqueous NaHCO3 solution and the resulting mixture was extracted with two portions of EtOAc. The combined EtOAc layers were dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-70% EtOAc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give a gum. LC MS: RT=1.41 min, M+H=743 (2 min gradient)