Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](C3C=C(NC4C=CN=CN=4)C(=O)N(C)N=3)[C:16]=1[CH2:36][OH:37])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].Cl[C:39]1[CH:40]=[C:41]([NH:47][C:48]2[CH:52]=[CH:51][N:50]([CH:53]3[CH2:56][N:55]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:54]3)[N:49]=2)[C:42](=[O:46])[N:43]([CH3:45])[N:44]=1.C(OCC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N1CC2C(=CC=C(C(C)(C)C)C=2)C1=O)(=O)C>>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[C:16]([CH2:36][OH:37])=[C:17]([C:39]3[CH:40]=[C:41]([NH:47][C:48]4[CH:52]=[CH:51][N:50]([CH:53]5[CH2:56][N:55]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:54]5)[N:49]=4)[C:42](=[O:46])[N:43]([CH3:45])[N:44]=3)[CH:18]=[CH:19][CH:20]=1)[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccncn2)c1=O
Reactant: Cn1nc(Cl)cc(Nc2ccn(C3CN(C(=O)OC(C)(C)C)C3)n2)c1=O
Agent: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Product: Cn1nc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccn(C3CN(C(=O)OC(C)(C)C)C3)n2)c1=O

Procedure:
Using the same general procedure as described for the preparation of 103, reaction of 105c (150 mg, 0.394 mmol) with 102f (201 mg, 0.433 mmol) afforded a crude product 105d which was used in the next step without purification.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH:4]=[CH2:5].N1C=CC=CC=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:1]([O:6][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C=CCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCCCOS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An ice cold solution of 0.584 g (6.66 mmol) 4-penten-1-ol and 1.11 ml (14.0 mmol) pyridine in 5 ml DCM is treated with 0.866 ml (6.77 mmol) benzene sulfonyl chloride. After 30 minutes at 0° C. the mixture is stirred overnight at rt. The mixture is diluted with DCM, washed with 5% aqueous citric acid, water and 5% aqueous NaHCO3, dried with sodium sulfate and evaporated, yielding the benzenesulfonic acid pent-4-enyl ester as a colorless oil that is used without further purification.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[C:11](Br)[CH:10]=[C:9]([Br:14])[CH:8]=1.[CH3:15][S:16]SC.[Cl-].[Na+]>CCOCC.O1CCCC1.C(OCC)(=O)C>[Br:6][C:7]1[CH:12]=[C:11]([S:16][CH3:15])[CH:10]=[C:9]([Br:14])[CH:8]=1
Reactant: CSSC
Reactant: Brc1cc(Br)cc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CSc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2.5M solution of n-butyllithium (42 mL; 0.105M) was added over 25 mins. to a vigorously stirred suspension of 1,3,5-tribromobenzene (31.5 G; 0.1M) in 1.6 L of anhydrous ether and 400 mL of anhydrous tetrahydrofuran under nitrogen at -78°. After stirring the mixture 30 minutes, 2 equivalents of dimethyldisulfide was added dropwise. The resulting mixture was stirred at R.T. overnight. 150 mL of sat'd sodium chloride solution was cautiously added. 500 mL of ethyl acetate was added. The organic phase was separated, and dried over anhyd. magnesium sulfate. Solvent removal gave a crude product, which was purified on silica gel using hexane as solvent. The desired product was isolated and distilled at 107°-110°/~1 mm to give 18 G of 3,5-dibromothioanisole as a colorless liquid, which slowly solidified on standing.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([CH:8]=[C:9]2[C:13]3[O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:16]=4[C:17](=[O:18])[C:12]=3[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl>C(O)(=O)C.Cl>[NH2:1][C:4]1[CH:28]=[CH:27][C:7]([CH:8]=[C:9]2[C:13]3[O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:16]=4[C:17](=[O:18])[C:12]=3[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc2oc3c(c(=O)c2c1)CCC3=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2oc3c(c(=O)c2c1)CCC3=Cc1ccc(N)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
3-(4-nitro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, methyl ester (3.8 g), was reacted with SnCl2.2H2O (11.5 g) in acetic acid (130 ml) and 37% HCl (26.5 ml) under stirring at 60° C. for 3 hours: after cooling the precipitate was filtered and washed with 2N HCl and water finely dispersed in 2N NaOH. The precipitate was filtered and washed with water until neutral to give 3-(4-amino-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, methyl ester m.p. 265°-268° C. (2.9 g), which was treated with 37% HCl (60 ml) in acetic acid (120 ml) under stirring at 100° C. for 4 hours. After cooling the precipitate was filtered and then suspended under stirring in water containing Na2HPO4 : the precipitate was filtered and washed with water to give 2.1 g of 3-(4-amino-benzylidene)-1,2,3,9tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, m.p. 360° C. dec., NMR (DMSO d6) δppm: 2.90 (m) (4H, C-1 and C-2 protons), 3.30 (bs) (2H, NH2), 6.64 (d) (2H, C-3 and C-5 phenyl protons), 7.01 (bs) (1H=CH--), 7.31 (d) (2H, C-2 and C-6 phenyl protons, 7.69 (d) (1H, C-5 proton), 8.19 (dd) (1H, C-6 proton), 8.59 (d) (1H, C-8 proton).
Reaction SMILES: C[O:2][C:3](=[O:43])[CH:4]([N:12]([CH:27]([C:34]1[O:42][C:38]2=[CH:39][CH:40]=[CH:41][C:37]2=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O[Li].O>C1COCC1.CO.O>[O:42]1[C:38]2=[CH:39][CH:40]=[CH:41][C:37]2=[CH:36][CH:35]=[C:34]1[CH:27]([N:12]([S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:14])=[O:15])[CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:43])=[O:2])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)C(Cc1ccccc1)N(C(c1ccccc1)c1ccc2cccc-2o1)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N(C(Cc2ccccc2)C(=O)O)C(c2ccccc2)c2ccc3cccc-3o2)c(C)c1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-[(4-Benzofuran-2-yl-benzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-3-phenyl-propionic acid methyl ester (40 mg, 0.067 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1) and then added 1N aqueous solution of LiOH.H2O (0.40 mL, 0.40 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and methanol (9:1) to obtain 2-[(4-Benzofuran-2-yl-benzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-3-phenyl-propionic acid. (29 mg, 75%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ7.59 (d, 2H), 7.48 (d, 2H), 7.42 (d, 2H), 7.19 (m, 4H), 7.06, 6.88 (2m, 6H), 6.37 (s, 1H), 4.55 (m, 3H), 3.70 (s, 3H), 3.19, 2.85 (2m, 2H), 2.56, 2.00, 1.98 (3s, 9H). ESI− (M−H): 582.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][S:7](=[O:10])(=[O:9])[CH2:8][C:4]=2[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+].[NH2:42][C:43]1[C:48]2[CH:49]=[C:50](Br)[S:51][C:47]=2[C:46]([C:53]([NH2:55])=[O:54])=[CH:45][N:44]=1>CS(C)=O.O>[NH2:42][C:43]1[C:48]2[CH:49]=[C:50]([C:2]3[CH:12]=[CH:11][CH:5]4[CH2:6][S:7](=[O:10])(=[O:9])[CH2:8][CH:4]4[CH:3]=3)[S:51][C:47]=2[C:46]([C:53]([NH2:55])=[O:54])=[CH:45][N:44]=1
Reactant: NC(=O)c1cnc(N)c2cc(Br)sc12
Reactant: O=S1(=O)Cc2ccc(Br)cc2C1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cnc(N)c2cc(C3=CC4CS(=O)(=O)CC4C=C3)sc12
Temperature: 85 °C
Reaction time: 12 h

Procedure:
To a stirred solution 5-bromo-1,3-dihydro-benzo[c]thiophene 2,2-dioxide (160 mg, 0.65 mmol) 67 (Salor, Milwaukee, Wis.) in DMSO (1 mL) was added bis(pinacolato)diboron (178 mg, 0.70 mmol), KOAc (159 mg, 1.6 mmol) and Pd(dppf)Cl2 DCM complex (22 mg, 0.027 mmol). The mixture was degassed with N2 and heated at 85° C. for 2 h then DMSO (2 mL), H2O (0.5 mL), K2CO3 (223 mg, 1.6 mmol) and 4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide H2SO4 salt 17 (200 mg, 0.54 mmol) were added. The mixture was stirred at 85° C. for a further 12 h then filtered. The residue was washed with DMSO (2 mL) and the filtrate purified by reverse phase preparative HPLC to yield 68 as a white solid. 1H-NMR (400 MHz, d6-DMSO) δ 8.31 (s, 1H), 8.24 (s, 1H), 8,19 (bs, 1H), 7.97-7.92 (m, 3H), 7.85 (d, 1H), 4.78 (s, 2H), 4.71 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[CH:30])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]1[O:8][C:5]2=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:30]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Oc1ncc(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2cc(Cl)cnc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3.07 g (12 mmol) sample of 5-chloro-3-iodo-2-pyridinol, from step 13a above, was dissolved in 10 mL of DMF, and (Ph3P)2PdCl2 (0.39 g, 0.5 mmol), CuI (0.38 g, 1.98 mmol) and triethylamine (1.7 mL, 12 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 1.95 g (10 mmol) of 1-BOC-2-(S)-ethynylpyrrolidine, from Example 1c above, dissolved in 5 mL of DMF, was added carefully. The reaction mixture was stirred at 60° C. for 16 hours, cooled to room temperature, diluted with ether and washed with 50% brine. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed on silica gel, eluting with 100:0 to 50:50 hexane:EtOAc to give 1.55 g of title compound: MS m/z: 323 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][NH2:5])([CH3:3])[CH3:2].[F:6][C:7]([F:18])([F:17])[C:8](=O)[CH:9]([CH3:15])[C:10]([O:12]CC)=O.Cl>C(O)C>[OH:12][C:10]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:8]([C:7]([F:6])([F:17])[F:18])[C:9]=1[CH3:15]
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Reactant: CC(C)NN
Agent: Cl
Solvent: CCO
Product: Cc1c(C(F)(F)F)nn(C(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 7.4 g (100.0 mmol) of isopropylhydrazine in 100 ml of ethanol was added dropwise under stirring 23.3 g (purity: 85.0%, 100.0 mmol) of ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate under ice-cooling so that the temperature in the reaction system did not exceed 10° C. After the dropwise addition, the whole was stirred at room temperature for 30 minutes. Then, 1 ml of concentrated hydrochloric acid was added into the reaction solution, followed by 2 days of stirring under refluxing. After the completion of the reaction was confirmed, the solvent was removed by evaporation under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was washed with n-hexane to obtain 18.1 g (yield: 87.0%) of 5-hydroxy-4-methyl-1-iso-propyl-3-trifluoromethyl-1H-pyrazole as white crystals (melting point: 150 to 153° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:28])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[NH:26][CH:25]=[N:24][C:23]=3[Cl:27])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH:29]#[C:30][CH2:31][CH3:32]>C1COCC1.[Cu]I>[C:29]([C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:28])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[NH:26][CH:25]=[N:24][C:23]=3[Cl:27])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1)#[C:30][CH2:31][CH3:32]
Reactant: C#CCC
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCC#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 27.6 %

Procedure:
To a solution of N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (65 mg, 0.134 mmol), Palladium dichlorobistriphenylphosphine(II) (7.01 mg, 0.013 mmol), copper(I)iodide (25.6 mg, 0.134 mmol) and TEA (0.019 ml, 0.134 mmol) in THF (5 ml) was bubbled 1-butyne (7.26 mg, 0.134 mmol) for 5 minutes and the reaction mixture was irradiated in a personal microwave reactor for 10 minutes at 120° C. The solvent was removed and the crude material was purified via reverse phase HPLC to give N-[(3-{[3-(1-butyn-1-yl)-5-cyanophenyl]oxy}-4-chloro-2-fluorophenyl)methyl]-4-chloro-1H-imidazole-5-carboxamide (17 mg, 0.037 mmol, 28% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.71 (br. s., 1H), 7.40 (s, 1H), 7.28-7.39 (m, 3H), 7.17 (s, 1H), 7.05 (s, 1H), 4.62 (s, 2H), 2.38 (q, 2H), 1.17 (t, 3H). LC-MS (ES+) m/z 457.14, [M+H].
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH:13]([C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([OH:23])=O)[C:16]=1[CH3:24])=[O:14].ON1C2C=CC=CC=2N=N1.[CH2:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][NH2:43])[CH3:36]>O.CN(C=O)C.C(N(CC)CC)C>[CH2:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][NH:43][C:21]([C:17]1[C:16]([CH3:24])=[C:15]([CH:13]=[O:14])[NH:19][C:18]=1[CH3:20])=[O:23])[CH3:36]
Reactant: CCN1CCCC1CN
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCN1CCCC1CNC(=O)c1c(C)[nH]c(C=O)c1C
Temperature: 0 °C
Yield: 47.6 %

Procedure:
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1 g, 1.4 mol), triethylamine (280.0 mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0 g, 1.0 mol) and 1-hydroxybenzotriazole (189.2 g, 1.4 mol) were added to DMF (500 mL) with stirring at about 0° C. and allowed to stir for 1.5 hrs, and then (1-ethylpyrrolidin-2-yl)methylamine (1.2 mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/dichloromethane (300 mL×3). The combined organic phase was washed with saturated salt water (300 mL×3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (eluted with methanol/ethyl acetate=1/1) to afford 131.86 g (476 mmol) of N-[(1-ethylpyrrolidin-2-yl) methyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 47.6%, m.p. 166-169° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)([C@@H]2CCCN2)O)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:34])[CH2:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:20][O:21][C:22](=[O:34])[CH2:23][CH:24]([OH:33])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)CC(=O)CCc1ccccc1
Agent: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Solvent: C1CCOC1
Product: COC(=O)CC(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a stirred solution of (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (770 mg, 3 mmol) in dry THF (100 mL) was added 2 M THF solution of borane-dimethylsulfide complex (11 mL, 22 mmol) at rt under N2. After being stirred at rt for 16 h, a solution of 3-Oxo-5-phenyl-pentanoic acid methyl ester (JACS, 1974, 1082-1087) (6.5 g, 31.5 mmol) in dry THF (20 mL) was added dropwise at rt over a period of 1 h. The resultant clear solution was stirred at rt for another 30 min and was then cooled to 0° C. in an ice bath. The reaction was quenched by the addition of MeOH (90 mL) and the reaction pot was concentrated under reduced pressure. The residue was taken up with EtOAc (200 mL) and washed successively with H2O (100 mL), citric acid (100 mL), 5% NaHCO3 (100 mL) and brine (100 mL). After being dried over Na2SO4, the solvent was removed to afford an oil. Flush column chromatography purification on silica gel gave 3-Hydroxy-5-phenyl-pentanoic acid methyl ester as an oil (3.3 g, 51%) with 92% e.e. (judged from the corresponding Mosher's ester). 1H NMR (300 MHz, CDCl3) δ1.6-1.9 (m, 2H), 2.4-2.6 (m, 2H), 2.65-2.9 (m, 2H), 3.05 (d, 1H, J=6), 3.7 (s, 3H), 3.95-4.10 (m, 1H), 7.10-7.35 (m, 5H). ESMS calcd (C12H16O3): 208.1; found: 209.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:10]1.F[C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:31]2[CH:36]=[N:35][CH:34]=[CH:33][N:32]=2)=[CH:4][C:3]=1[C@:9]1([CH2:28][F:29])[CH2:14][C@@H:13]([C:15]([F:18])([F:16])[F:17])[O:12][C:11]([NH:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:10]1
Reactant: O=C(NC1=N[C@](CF)(c2cc(O)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Reactant: Fc1cnccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(NC1=N[C@](CF)(c2cc(Oc3cnccn3)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
To a microwave vial were added N-((4S,6S)-4-(2-fluoro-5-hydroxyphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (95 mg, 0.229 mmol), 2-fluoro-pyrazine (24.74 mg, 0.252 mmol), cesium carbonate (90 mg, 0.275 mmol) in DMSO (459 μL). The vial was heated in microwave instrument at 100° C. for 30 min. After cooling to room temperature, water was added to the reaction mixture and precipitate was observed. After stirring for 10 min, the precipitate was collected by filtration, washed with water and hexane, dried in vacuum oven at 60° C. for 1 h to provide N-((4S,6S)-4-(2-fluoro-5-(pyrazin-2-yloxy)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (85 mg, 0.173 mmol, 75% yield) as off-white solid. MS m/z=493 [M]+. Calculated for C23H17F5N4O3: 492.4.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:14][C:15]([NH:17][CH2:18][CH:19]([CH2:23][NH:24][C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH:20]([OH:22])[CH3:21])=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>ClCCl>[CH2:28]([O:27][C:25]([NH:24][CH2:23][CH:19]([CH2:18][NH:17][C:15]([O:14][CH2:11][CH:12]=[CH2:13])=[O:16])[C:20](=[O:22])[CH3:21])=[O:26])[CH:29]=[CH2:30]
Reactant: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.5 %

Procedure:
To a solution of 0.32 ml of oxalyl chloride in 10 ml of dichloromethane was added 0.54 ml of dimethyl sulfoxide at -78° C. under nitrogen. After stirring for 5 minutes, a solution of 1.00 g of 1-allyloxycarbonylamino-2-(N-allyloxycarbonylaminomethyl)butan-3-ol in 2 ml of dichloromethane was added. After stirring for 30 minutes, 2.43 ml of triethylamine was added to the mixture and then the temperature of the mixture was raised to room temperature. The mixture was extracted with chloroform and the organic layer was washed in turn with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by a column chromatography on silica gel (hexane:ethyl acetate=1:1) gave 0.77 g of 1-allyloxycarbonylamino-2-(N-allyloxycarbonylaminomethyl)butan-3-one.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[NH2:36][C:37]1[CH:41]=[CH:40][N:39]([CH2:42][C:43]([CH3:46])([OH:45])[CH3:44])[N:38]=1>C1C=CC=CC=1.CN(C=O)C.C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)[C:8]([NH:36][C:37]2[CH:41]=[CH:40][N:39]([CH2:42][C:43]([OH:45])([CH3:44])[CH3:46])[N:38]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1cccc([C@@H](CC2CCCC2)C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2cccc(S(C)(=O)=O)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
To a stirred solution of (R)-3-cyclopentyl-2-(3-methylsulfonyl-phenyl)-propionic acid (200 mg, 0.65 mmol) in benzene (10 mL) was added oxalyl chloride (123 mg, 0.97 mmol) and DMF (1 drop) and the reaction was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure and the residue was dissolved into methylene chloride (10 mL) under a nitrogen atmosphere. To this stirred solution was added N,N′-diisopropylethylamine (125 mg, 0.97 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 130 mg, 0.84 mmol). The reaction was stirred at 25° C. for 18 h and then diluted with methylene chloride (30 mL). The methylene chloride was washed with water, 2 N aqueous hydrochloric acid solution, saturated sodium bicarbonate and saturated sodium chloride solution and then dried over magnesium sulfate. Filtration and concentration afforded the crude product which was purified by flash column chromatography (Biotage 40S Flash Column; 80% ethyl acetate/hexanes) to yield (R)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(3-methanesulfonyl-phenyl)-propionamide (92 mg, 32%) as a white solid: [α]28589=−8.9° (c=0.1, methanol); ES-HRMS m/e calcd for C22H31N3O4S (M+H)+ 434.2108, observed 434.2108; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.12 (m, 2H, CH2), 1.37-1.79 (m, 8H, 4×CH2), 2.13 m, 1H, CH), 3.21 (s, 3H, SO2CH3), 3.86 (s, 2H, NCH2), 3.93 (m, 1H, ArCHCO), 4.64 (s, 1H, OH), 6.46 (d, J=2.2 Hz, 1H, Ar), 7.50 (d, J=2.2 Hz, 1H, Ar), 7.61 (t, J=7.7 Hz, 1H, Ar), 7.73 (d, J=7.7 Hz, 1H, Ar), 7.82 (d, J=7.7 Hz, 1H, Ar), 7.93 (s, 1H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][OH:20])=[O:12])=[C:4]([F:21])[CH:3]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][O:20][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:12])=[C:4]([F:21])[CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cc(NC(=O)N2CCCCC2CO)c(F)cc1Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)N2CCCCC2COC(=O)C(C)(C)C)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
15.9 g (0.05 mol) of 1-[N-(4-chloro-2-fluoro-5-methoxyphenyl)-carbamoyl]-2-hydroxymethylpiperidine (Example 1) and 4.7 g (0.06 mol) of pyridine are dissolved in 200 ml of toluene, and 6.0 g (0.05mol) of pivaloyl chloride are added dropwise at 20° C. The mixture is stirred for 3 hours at 50° C. and washed with twice 100 ml of water, and the toluene phase is dried over sodium sulfate. After the solvent as been removed, 18.4 g (92% of theory) of 1-[N-(4-chloro-2-fluoro-5-methoxyphenyl)-carbamoyl]-2-pivaloyloxymethylpiperidine are obtained in the form of a colorless viscous oil.