Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=O)[C:5]([F:21])([F:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)C.C(N(S(F)(F)F)CC)C.C([O:34][C:35](=[O:52])[C:36](C1C=CC(C2C=CC(OC)=CC=2)=CC=1)=O)C>ClCCl>[F:21][C:5]([F:20])([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[CH2:4][CH2:36][C:35]([OH:52])=[O:34]
Reactant: CCOC(=O)C(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)C(F)(F)c1ccc(-c2ccc(OC)cc2)cc1
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C(F)(F)CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Difluoro-(4′-methoxy-biphenyl-4-yl)-acetic acid ethyl ester. Diethylaminosulfur trifluoride (5 mL) is added directly to (4′-methoxy-biphenyl-4-yl)-oxo-acetic acid ethyl ester (3.77 g, 13.3 mmol), prepared as described by Neidlin, et. al., Arzneim.-Forsch. 1983, 33, 691-3. Dichloromethane (2 mL) is added and the mixture is stirred overnight at room temperature. The reaction is diluted with dichloromethane and slowly added to ice water. This mixture is extracted with ethyl acetate twice. The combined organic extracts are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified by column chromatography (silica gel, 5% EtOAc/hexanes) to give the desired product as a pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.Cl.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[CH:33]([CH3:35])[CH3:34])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(Cl)Cl>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:2][C:3]2[S:11][C:10]3[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:8][C:7]([Cl:18])=[N:6][C:5]=3[CH:4]=2)[CH2:29][C@H:28]1[CH:33]([CH3:35])[CH3:34])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CC(C)[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)[C@@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (100 mg, 0.29 mmol) in DMF (3 mL) were added (R)-2-isopropyl-piperazine-1-carboxylic acid tert-butyl ester hydrochloride (87 mg, 0.33 mmol) and potassium carbonate (124 mg, 0.90 mmol). The resulting mixture was stirred at RT for 18 h, then diluted with water and DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (139 mg, 97%).
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[C:29]1([CH2:35][CH2:36]C=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[C:21]=4[CH2:36][CH2:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Reactant: O=CCCc1ccccc1
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)ccc1c2CCc1ccccc1

Procedure:
The product of Example 84 is treated with 3-phenylpropanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[S:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[O:13]=[C:10]1[NH:9][C:8]2[CH:14]=[C:4]([CH2:3][CH2:2][O:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH:5]=[CH:6][C:7]=2[S:12][CH2:11]1
Reactant: O=C1CSc2ccc(CCO)cc2N1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc2c(c1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
A solution of (h) (0.34 g, 1.7 mmol) and triethylamine (0.25 ml, 0.19 g, 1.8 mmol) in dichloromethane (5 ml) was cooled to −15° C. and treated dropwise with methanesulfonyl chloride (0.14 ml, 1.75 mmol). The ice bath was removed and the mixture stirred 15 hours at room temperature. The organic phase was separated, washed with water, dried over magnesium sulfate and evaporated. The crude product was chromatographed on silica gel eluting with ethyl acetate/heptane (2/1) to give a white solid (0.36 g, 75%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1.O.[NH2:15][NH2:16]>>[NH:15]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1)[NH2:16]
Reactant: NN
Reactant: COCCNCc1ccc(Cl)nc1
Solvent: O
Product: COCCNCc1ccc(NN)nc1

Procedure:
3.6 g (17.7 mmol) of N-[(6-chloropyridin-3-yl)methyl]-2-methoxyethanamine [prepared analogously to WO 2004/081007] are initially charged in 4.3 ml (4.4 g, 88.5 mmol) of hydrazine hydrate and stirred at boiling point at a bath temperature of 150° C. for 16 h. The reaction solution is cooled and concentrated, and the residue is purified by column chromatography on silica gel (mobile phase: acetonitrile/water 9:1).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([CH:24]4[CH2:26][CH2:25]4)[CH:23]=2)[O:20][C:19]([CH3:28])([CH3:27])[CH2:18][C:17]3([CH3:30])[CH3:29])=[CH:8][C:7]=1[F:31])C.CO.[OH-].[Na+].O>C(#N)C>[CH:24]1([C:22]2[CH:23]=[C:14]([C:13]#[C:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:32])=[O:3])=[C:7]([F:31])[CH:8]=3)[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([CH3:27])([CH3:28])[CH2:18][C:17]3([CH3:30])[CH3:29])[CH2:25][CH2:26]1
Reactant: CCOC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)c(F)c3)cc(C3CC3)c2O1

Procedure:
Following general procedure L and using [4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-2-fluorophenyl]acetic acid ethyl ester (Compound 37, 0.14 g, 0.323 mmol), 5 mL of methanol and 1M sodium hydroxide solution (2 mL) followed by reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a solid (0.11 g, 80%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][N:6]([C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)[C:7]([C@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[O:8])[CH2:4][CH2:3]1.[Cl:22][C:23]1[C:24]([CH3:33])=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C>C(#N)C>[Cl:22][C:23]1[C:24]([CH3:33])=[C:25]([S:29]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([C:7]([N:6]([CH2:5][CH:2]3[CH2:3][CH2:4]3)[C@H:15]3[CH2:16][CH2:17][C@H:18]([OH:21])[CH2:19][CH2:20]3)=[O:8])[CH2:10]2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: O=C([C@H]1CCCNC1)N(CC1CC1)[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](C(=O)N(CC2CC2)[C@H]2CC[C@H](O)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (3S)-N-(cyclopropylmethyl)-N-(trans-4-hydroxycyclohexyl)piperidine-3-carboxamide hydrochloride (10 mg, 0.03 mmol), 3-chloro-2-methylbenzenesulfonyl chloride (7.1 mg, 0.03 mmol), triethylamine (11 μL, 0.08 mmol) in acetonitrile (0.2 mL) was stirred at r.t. for 1 hour, then purified with flash column. 5.1 mg (yield: 34%) final product was obtained. LCMS: m/z 468.9 (M+H)+.
Reaction SMILES: CS(N)(=O)=O.[OH2:6].[CH:7](/[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8]/[CH3:9].S([O-])([O-])(=[O:27])=S.[Na+].[Na+]>C(O)(C)(C)C>[OH:6][C@@H:7]([C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[C@H:8]([OH:27])[CH3:9]
Reactant: C/C=C\c1ccccc1CNC(=O)OC(C)(C)C
Reactant: O=S([O-])([O-])=S
Reactant: O
Agent: CS(N)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: C[C@@H](O)[C@@H](O)c1ccccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3.30 g of AD mix-α, 200 mg of methanesulfonamide, 12.5 ml of tert-butyl alcohol, and 12.5 ml of water was added a solution of 500 mg of tert-butyl {2-[(1Z)-prop-1-en-1-yl]benzyl}carbamate in 5 ml of tert-butyl alcohol, followed by stirring at room temperature for 12 hours. To the reaction mixture was added sodium thiosulfate, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 449 mg of tert-butyl {2-[(1S,2R)-1,2-dihydroxypropyl]benzyl}carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:30][C:31](=[NH:50])[C:32]1[CH:49]=[CH:48][C:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40][C:34]=2[CH:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:30]=[C:31]([C:32]3[CH:49]=[CH:48][C:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH2:40][C:34]=4[CH:33]=3)[N:50]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=N)NO)cc2CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)no2)cc1Cl
Temperature: 80 °C
Yield: 28.5 %

Procedure:
To a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (Preparation 6) (1.406 g, 6.55 mmol) in DMF was added HOBT (1.103 g, 7.20 mmol) and EDC (1.381 g, 7.20 mmol), the resultant solution was stirred under argon for 10 mins at room temp. 1,1-dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 41)(2 g, 6.55 mmol) was then added to the reaction mixture and the solution heated at 80° C. overnight. The solvent was removed in vacuo and the residue dissolved in methanol for purification by Biotage Horizon, reverse phase cartridge, eluting 5-100% acetonitrile in water. The product containing fractions (last 5) were concentrated in vacuo to yield the title compound as a yellow oil (950 mg, 1.87 mmol, 29% yield). δH (d6DMSO, 400 MHz): 8.19 (1H, d), 8.11 (1H, dd), 7.83-7.89 (2H, m), 7.45 (1H, d), 7.37 (1H, d), 4.89 (1H, sept), 3.50 (4H, br.s), 2.96 (4H, br.s), 1.41 (9H, s), 1.36 (6H, d). MS (ES): C26H3035ClN3O4 requires 483; found 384 [M+H−100]+.
Reaction SMILES: [C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11](COCC[Si](C)(C)C)[C:12]([O:16][C@@H:17]4[CH2:21][O:20][C@@H:19]5[C@H:22]([O:25][Si](C(C)(C)C)(C)C)[CH2:23][O:24][C@H:18]45)=[N:13]3)=[CH:9][N:8]=2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+].CCOC(C)=O>C(Cl)Cl>[C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:15]=[C:14]3[C:10]([NH:11][C:12]([O:16][C@H:17]4[C@H:18]5[O:24][CH2:23][C@@H:22]([OH:25])[C@H:19]5[O:20][CH2:21]4)=[N:13]3)=[CH:9][N:8]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)ncc2n1COCC[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)ncc2[nH]1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To 2-([1,1′-biphenyl]-4-yl)-8-(((3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine (38.0 mg, 0.057 mmol) in anhydrous DCM (1.8 mL) was added TFA (1.33 mL, 17.25 mmol). The solution stirred at RT for 22 h. The reaction solution cooled to 0° C. and 1N NaOH (18.2 mL, 18.2 mmol) and EtOAc (60 mL) added. The organic layer washed with brine (20 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. Flash chromatography utilizing a 12 g silica RediSep Rf® Gold column and employing a 0-15% MeOH/DCM gradient afforded the title compound. LC-MS: calculated for C23H20N4O4 416.15 observed m/e: 417.36 (M+H)+ (Rt 0.93/2.0 min).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@H:34]([O:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>ClCCl.CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][C@H:34]([O:37][C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:40][CH:39]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(N)cc2)C1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)C1
Reaction time: 1 h
Yield: 85 %

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (2.57 g, 10 mmol) was suspended in dichloromethane (20 mL). Oxalyl chloride (2M in dichloromethane, 10 mL) was added followed by DMF (0.028 mL). The mixture was stirred for 1 hr and solvents were evaporated. The residue was treated with benzene (20 mL) and solvents were evaporated. The residue was dissolved in dichloromethane (30 mL) and treated with a mixture of (S)-3-(4-amino-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.78 g, 10 mmol) and triethylamine (3.6 mL, 25 mmol) under ice bath. The mixture was stirred for 30 minutes and ice bath was removed. The solution was further stirred for 2 hrs. Solvents were evaporated and the residue was extracted with 0.1N hydrochloric acid and ethyl acetate. The organic layer was washed with water, concentrated sodium bicarbonate solution and brine. Solvents were evaporated and the residue was purified through ISCO column chromatography (silica gel, ethyl acetate in hexanes, 10% to 80% linear gradient) to give (S)-3-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid tert-butyl ester (4.4 g, 85.1% yield). LC-MS for C26H26F3N3O5 (m/e) calcd 517, obsd 516 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1N.[CH3:9][C:10]([CH:12]=[CH2:13])=O.ClC(Cl)=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:32][C:33]([NH2:35])=[S:34])[CH:23]=[CH:24][C:25]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[CH2:9][C:10]1[S:34][C:33]([NH:32][C:22]2[CH:23]=[CH:24][C:25]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:20]([O:19][CH3:18])[CH:21]=2)=[N:35][C:12]=1[CH3:13]
Reactant: Nc1ccccc1Cl
Reactant: C=CC(C)=O
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Agent: O=C(Cl)Cl
Product: COc1cc(Nc2nc(C)c(Cc3ccccc3Cl)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 6 without purification of the intermediate from 128 mg (1 mmol) 2-chloroaniline and 421 mg (6 mmol) methyl vinylketone. The crude chloroketone was used without further purification in the next step with 53 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 40 mg (47%) [5-(2-chloro-benzyl)-4-methyl-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a brown solid. MS ISP (m/e): 425.1/427.2 (100/44) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.15 (s, 1H), 7.63 (s, 1H), 7.53 (s, 1H), 7.47-7.22 (m, 6H), 7.01 (s, 1H), 4.07 (s, 2H), 3.77 (s, 3H), 2.25 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[CH:28]=[CH:27][N:26]2[N:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[C:25]2[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:59]1[CH2:63][CH2:62][C@H:61]([OH:64])[CH2:60]1>CN(C=O)C.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[CH:28]=[CH:27][N:26]2[N:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[C:25]2[CH:24]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]1[CH:28]=[CH:27][N:26]2[N:29]=[CH:30][C:31]([C:32]([N:59]3[CH2:63][CH2:62][C@H:61]([OH:64])[CH2:60]3)=[O:34])=[C:25]2[CH:24]=1
Reactant: O[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cnn2ccc(N3CCCC3c3cc(F)ccc3F)cc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1cnn2ccc(N3CCCC3c3cc(F)ccc3F)cc12)N1CC[C@H](O)C1
Reaction time: 0.03 h

Procedure:
5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (100 mg, 0.29 mmol) was prepared by the method mentioned in Example-3. DIPEA (93.6 mg, 0.72 mmol) was added to a stirred solution of 5-(2-(2,5-difluorophenyl) pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (100 mg, 0.29 mmol) in DMF (1.5 mL) followed by addition of HATU (165 mg, 0.437 mmol) to the reaction mixture. After 2 minutes of stirring, (S)-pyrrolidin-3-ol (81.8 mg, 0.43 mmol) was added and the resulting mixture was stirred at 20-35° C. for 2 h. The reaction mixture was diluted with cold water; extracted with ethyl acetate; dried over sodium sulfate; and concentrated under reduced pressure to get a residue. The residue thus obtained was purified by column chromatography (60-120 silica gel and 3% EtOAc in Hexane as eluent) to afford (5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridin-3-yl)((S)-3-hydroxypyrrolidin-1-yl)methanone
Reaction SMILES: C([O:9][C@H:10]([C@@:12]1([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:14][O:13]1)[CH3:11])(=O)C1C=CC=CC=1.Cl>CO.C[O-].[Na+].CO>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C@:12]1([C@@H:10]([OH:9])[CH3:11])[CH2:14][O:13]1
Reactant: C[C@H](OC(=O)c1ccccc1)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.7 %

Procedure:
[(1S)-1-[(2R)-2-(2,4-Difluorophenyl)-2-oxiranyl]-ethyl] benzoate (15.9 g) was dissolved in methanol (800 ml), to which 28% sodium methylate-methanol solution (12.9 ml) was added at ice-bath temperature and stirred at room temperature for 6 hours. After 1N-hydrochloric acid (63.2 ml) was added thereto, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=6/1 to 2/1) to give (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (9.7 g) as a colorless oily substance.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[C:17]2[C:18]3[CH:27]=[CH:26][NH:25][C:19]=3[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2C=CC=CC=2)C2C=CNC=2C1=O>>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[C:9]([C:17]2[C:18]3[CH:27]=[CH:26][NH:25][C:19]=3[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[CH:10]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2OC2CCCCC2)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: Cn1cc(-c2cc(N)ccc2OC2CCCCC2)c2cc[nH]c2c1=O

Procedure:
Example 57b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 57a for the product of Example 2b, to provide the title compound.
Reaction SMILES: [CH:1]1([C:4](Cl)=O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]2)[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl.CCOCC>[CH:1]1([CH2:4][NH:29][CH2:28][CH2:27][C:21]2([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=3)[CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]2)[CH2:3][CH2:2]1
Reactant: COc1cccc(C2(CCN)C=CCCC2)c1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cccc(C2(CCNCC3CC3)C=CCCC2)c1

Procedure:
3.45 g of cyclopropanecarboxylic acid chloride are placed in 50 ml of methylene chloride, whereafter 5.0 g of potassium carbonate are added, and then a solution of 7.0 g of 1-(m-methoxyphenyl)-2-cyclohexene-1-ethylamine in 10 ml of methylene chloride is added dropwise while stirring. The mixture is stirred at room temperature overnight and subsequently at reflux for 30 minutes and cooled. Then, the precipitate is removed by filtration under suction, the filtrate is evaporated, and the oil obtained is taken up in ether. The ethereal solution is washed with 1 N hydrochloric acid and subsequently with water, dried over magnesium sulfate and evaporated, and N-[2-[1-(m-methoxyphenyl)-2-cyclohexen-1-yl]ethyl]-cyclopropanecarboxamide remains as the residue. 6.5 g of this compound, dissolved in 30 ml of absolute tetrahydrofuran, are added dropwise to a dispersion of 6 g of lithium aluminum hydride in 100 ml of absolute tetrahydrofuran. The mixture is boiled at reflux for 3 hours, cooled and worked-up in the usual manner, and there is obtained N-(cyclopropylmethyl)-1-(m-methoxyphenyl)-2-cyclohexene-1-ethylamine, the hydrochloride of which melts at 141°-142° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[CH2:30]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH3:31]>[Zn].C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:36][C:35]1[CH:38]=[CH:39][C:32]([CH2:30][CH3:31])=[CH:33][CH:34]=1
Reactant: CCc1ccc(C=O)cc1
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1ccc(C=C(Br)Br)cc1
Reaction time: 2 h

Procedure:
A mixture of 4.94 g. (0.015 mol.) of carbon tetrabromide, 3.90 g. (0.015 mol.) of triphenylphosphine and 0.975 g. (0.015 g.-atom) of zinc in 25 ml. of carbon tetrachloride is stirred at 25° for 24 hours. A solution of 1.0 g. (7.45 mmol.) of p-ethylbenzaldehyde in 10 ml. of methylene chloride is added and the reaction mixture is stirred an additional 2 hours. Petroleum ether (140 ml.) is added to the mixture, the organic layer is decanted and the residue is extracted with 1:4 methylene chloride-petroleum ether. The combined organic solutions are concentrated under reduced pressure to give 1,1-dibromo-2-(4-ethylphenyl)ethylene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH:33]=[CH2:34].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](/[CH:34]=[CH:33]/[C:32]([O:36][CH2:37][CH3:38])=[O:35])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 100 °C

Procedure:
A mixture of the title compound of Example 5 (1.05 g), triethylamine (6 mL), ethyl acrylate (0.3 mL), palladium acetate (5.1 mg) and tris(o-tolyl)phosphine (42 mg) in DMF (5 mL) is heated to 100° C. for 24 h in a pressure-safe tube. The reaction is partitioned between CH2Cl2 and water. The aqueous layer is extracted with CH2Cl2 (3×). The combined organic layers are filtered, dried over Na2SO4, filtered and condensed. The crude product is purified by trituration with hot EtOAc to yield 0.461 g of the desired product as a tan solid.