Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:7]=1[C:8](=[O:33])[N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:10]2)=[O:4].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.Cl>CC#N.CCOCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:7]2[C:11]=1[CH2:10][N:9]([C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:8]2=[O:33]
Reactant: C1COCCN1
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CCl)c3C2=O)ccc1OC
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(Cl)ccc(NC(=O)CN4CCOCC4)c3C2=O)ccc1OC
Temperature: 70 °C

Procedure:
To a solution of (1S)-2-chloro-N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (250 mg, 0.48 mmol) in CH3CN (10 ml) was added morpholine (0.17 ml, 1.94 mmol). The mixture was heated at 70° C. for 2 hrs. The reaction mixture was concentrated on rota-vap and extracted with water (50 ml) and EtOAc (50 ml). The organic layer was washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give an oil which was stirred with HCl in ether (3 ml) to give (1S)—N-{7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-morpholin-4-yl-acetamide; hydrochloride as a white solid (200 mg, 68% yield): mp, 198-200° C.; 1H NMR (CDCl3 with D2O added) δ 1.46 (t, J=7.0 Hz, 3H, OCH2CH3), 2.68 (broad, 4H, CH2NCH2 on morpholino ring), 2.99 (s, 3H, SCH3), 3.24 (broad, 2H, CH2NCO), 3.72 (dd, J=5, 15 Hz, 1H, CHHSO2), 3.87-3.92 (m, 7H, OCH3+OCH2OCH2 on morpholine ring), 4.05-4.23 (m, 4H, CHHSO2+CNHH+OCH2CH3), 4.40 (d, J=15 Hz, 1H, CHHN), 5.71-5.77 (m, 1H, NCH), 6.86-6.97 (m, 3H, Ar), 7.40d, J=8 Hz, 1H, Ar), 8.52 (d, J=8 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.75, 41.71, 47.09, 51.22, 51.59, 55.09, 56.02, 63.81, 64.10, 64.81, 105.68, 111.67, 112.28, 119.32, 120.0, 120.27, 124.03, 128.81, 133.20, 134.72, 139.41, 149.09, 150.01, 168.55. Anal Calcd for C26H33Cl2N3O7S+0.53H2O: C, 51.02; H, 5.61; N, 6.87. Found: C, 50.70; H, 5.38; N, 6.76; 0.98% H2O.
Reaction SMILES: [C:1]([C:9]1[CH:19]=[CH:18][C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][CH2:27][N:28]([CH2:31][CH2:32]Cl)[CH2:29][CH3:30]>C(#N)C>[C:1]([C:9]1[CH:19]=[CH:18][C:12]([N:13]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CCCl
Reactant: CS(=O)(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)CCN(c1ccc(C(=O)c2ccccc2)cc1)S(C)(=O)=O
Reaction time: 16 h
Yield: 95 %

Procedure:
4'-Benzoylmethanesulfonanilide (69.5 g., 0.252 mole) is dissolved in 1.4 1. of acetonitrile and heated to reflux. Potassium carbonate (35.0 g., 0.253 mole) is added followed by dropwise addition of 2-chlorotriethylamine (34.2 g., 0.252 mole) during 15 min. The reaction mixture is refluxed for 2 hrs. and then kept at room temperature for about 16 hrs. The mixture is filtered and the filtrate concentrated under vacuum. The resulting oil is dissolved in 3N HCl, the acidic solution washed with ethyl ether, and then basified with 50% aqueous NaOH to pH 11.0. The amine which separates is extracted into ethyl ether, and the ether solution is washed first with water, then with saturated sodium chloride, and dried (MgSO4). The ether is removed under reduced pressure to give 89.2 g. (95% yield) of oil which solidifies, m.p. 74°-76°C.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1B(O)O)=[O:6])([CH3:3])[CH3:2].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([O:4][C:5](=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1)([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(C)OC(=O)c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1ccccc1-c1ccc(C(F)(F)F)cn1
Yield: 70 %

Procedure:
2-(Isopropylcarboxy)-phenylboronic acid (S. Caron and J. M. Hawkins, J. Org. Chem. 1998, 63, 2054-2055) (2.2 g, 10.6 mmol) and 2-chloro-5-trifluoromethylpyridine (500 mg, 2.75 mmol) were dissolved in toluene. Tetrakis(triphenylphosphine)palladium (160 mg, 0.14 mmol) was added and the reaction vessel purged by alternating vacuum and nitrogen gas three times. 8 ml of a 10% sodium carbonate solution was added and the reaction mixture was heated at reflux for 1.5 h. The resulting mixture was extracted with ethyl acetate, the combined organic layers dried (magnesium sulfate), filtered and concentrated under vacuum. Purification of the residue by column chromatography eluting with 10% ethyl acetate in hexanes provided the title compound in approximately 70% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].I[CH3:13].[OH-].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([O:10][CH3:13])=[O:9]
Reactant: CI
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: [K+]
Agent: [OH-]
Product: COC(=O)c1c(N)cccc1Cl
Yield: 78.4 %

Procedure:
Using the procedure described above in Preparation 1, 5.0 g (0.029 mol) of 6-chloroanthranilic acid and 2.75 ml (0.044 mol) of iodomethane were reacted in the presence of 4.08 g (0.073 mol) of powdered potassium hydroxide to give 4.22 g (78%) of methyl 6-chloroanthranilate as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1Cl.[O:10]1CC[CH2:12][CH2:11]1.[OH-].[Na+]>[C].[Pd].C(O)C>[CH2:11]([O:10][C:3]1[C:2]([NH2:1])=[CH:7][N:6]=[CH:5][N:4]=1)[CH3:12]
Reactant: C1CCOC1
Reactant: Nc1c(Cl)ncnc1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ncncc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
A mixture of 5-amino-4,6-dichloropyrimidine (5.00 g, 30.5 mmol), tetrahydrofuran (100 ml), sodium hydroxide (2.44 g, 61.0 mmol), ethanol (100 ml) and 10% palladium-carbon (500 mg) was stirred under a hydrogen atmosphere at room temperature for 1 day, insolubles were filtered off and an organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (4.00 g, 94.3%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]#N)=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].CC(C[AlH]CC(C)C)C.[O:30]1CCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[O:30])=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: C1CCOC1
Reactant: N#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Agent: CC(C)C[AlH]CC(C)C
Product: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-2-pyridinecarbonitrile (0.876 g, 2.93 mmol) in anhydrous tetrahydrofuran (30 mL), was added DIBAL-H (5.87 mL, 5.87 mmol) dropwise at −78° C. The reaction mixture was stirred for 1 h at −78° C., then quenched with 1N HCl solution, concentrated. Purification via ISCO afforded the title product (350 mg) as an off white solid. LC-MS (ESI): m/z 302 [M+H]+; 3.47 min (ret time).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:27])=O>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1[nH]c(=O)c2cc(OCCCC)ccc2c1O
Product: CCCCOC(=O)c1nc(Br)c2cc(OCCCC)ccc2c1O

Procedure:
0.150 g of 7-butoxy-4-hydroxy-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester, were allowed to react with phosphorous oxybromide analogously to Example D-46 b) to give 0.105 g of an off-white solid: Proton NMR (200 MHz, chloroform-d): δ 11.82 (s, 1H), 8.68 (s, 1H), 8.26 (d, 1H), 7.35 (dd, 1H), 7.19 (d, 1H), 4.49 (t, J=7 Hz, 2H), 4.12 (t, J=7 Hz, 2H), 1.95-1.75 (m, 4H), 1.70-1.40 (m, 4H), 1.05-0.95 (m, 6H).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3].Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3]
Reactant: NC(=O)Nc1cc(-c2cccc(O)c2)sc1C(N)=O
Reactant: ClCCN1CCCC1
Product: NC(=O)Nc1cc(-c2cccc(OCCN3CCCC3)c2)sc1C(N)=O

Procedure:
Prepared by the method of Example 9(b) using the product of Example 6 and N-(2-chloroethyl)pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:15][CH:16]=O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:15]=[CH:16][N:8]=[C:4]2[CH:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Clc1ccn2ccnc2c1
Yield: 86.5 %

Procedure:
To a solution of 4-Chloro-pyridin-2-ylamine (12.8 g, 100 mmol, 1.0 equiv) in EtOH (170 ml) was added NaHCO3 (16.8 g, 200 mmol, 2.0 equiv) followed by chloroacetaldehyde (19.0 ml, 150 mmol, 1.5 equiv). The mixture was refluxed for 6 h. Solvents removed under reduced pressure and the crude mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by column chromatography (SiO2, eluted with 50% EtOAC-petrol) to afford 13.2 g of product. MS: [M+H]+=153.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:42]([O:49][C:50]1[CH:77]=[CH:76][C:75](O)=[CH:74][C:51]=1[C:52]([NH:54][C:55]1[CH:67]=[C:66]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH:65]=[CH:64][C:56]=1[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[O:53])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1>[CH2:42]([O:49][C:50]1[CH:77]=[CH:76][C:75]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)=[CH:74][C:51]=1[C:52]([NH:54][C:55]1[CH:67]=[C:66]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH:65]=[CH:64][C:56]=1[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[O:53])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CN1CCC(O)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(O)ccc1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Hydroxy-1-methylpiperidine (0.17 g), triphenylphosphine (0.39 g), and diisopropyl azodicarboxylate (0.30 mL) were added to a tetrahydrofuran (3.0 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-hydroxybenzamido)-4-phenylbenzoate (0.15 g), followed by stirring at room temperature for 3 hours and 20 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: 60-50% hexane/ethyl acetate to 100-90% chloroform/methanol] to obtain tert-butyl 2-(2-(benzyloxy)-5-((1-methylpiperidin-4-yl)oxy)benzamido)-4-phenylbenzoate.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[C:13]12([CH2:23][NH:24][CH2:25][CH2:26][CH:27]([OH:32])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.CCN(CC)CC>C(Cl)Cl>[C:13]12([CH2:23][N:24]3[CH2:25][CH2:26][CH:27]([CH2:28][CH:29]([CH3:30])[CH3:31])[O:32][C:2]3=[O:4])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: CC(C)CC(O)CCNCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC1CCN(CC23CC4CC(CC(C4)C2)C3)C(=O)O1
Reaction time: 1 h
Yield: 218.3 %

Procedure:
A solution of triphosgene (35 mg, 0.12 mmol) in anhydrous CH2Cl2 (500 μL) was added slowly to a solution of 1-(1-adamantylmethylamino)-5-methylhexan-3-ol (100 mg, 0.36 mmol) and Et3N (50 μl, 0.257 mmol) in anhydrous CH2Cl2 (2 mL) at 0° C. The reaction mixture was stirred for 1 h. Solvent was removed and the residue was purified by preparative TLC to give 3-((1-adamantyl)methyl)-6-isobutyl-1,3-oxazinan-2-one (80 mg, 74%). 1H NMR (MeOD, 400 MHZ): δ=0.93-0.98 (q, 6H), 1.35-1.44 (m, 1H), 1.50-2.08 (m, 18H), 2.87-2.94 (d, 1H), 3.12-3.20 (d, 1H), 3.30-3.40 (m, 1H), 3.49-3.61 (m, 1H), 4.35-4.45 (m, 1H); MS m/z=306.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3C=CC=C(OC)C=3)=[CH:29][CH:28]=2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.[F:41][C:42]1[C:43](=O)[NH:44][C:45]2[C:50]([CH:51]=1)=[CH:49][C:48](B1OC(C)(C)C(C)(C)O1)=[CH:47][CH:46]=2>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:48]3[CH:49]=[C:50]4[C:45](=[CH:46][CH:47]=3)[N:44]=[CH:43][C:42]([F:41])=[CH:51]4)=[CH:33][C:28]=2[CH3:29])[C:23]([F:24])([F:25])[F:26])[N:3]=1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)c(F)cc3c2)OC1(C)C
Reactant: COc1cccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)cc2)c1
Product: Cc1cc(-c2ccc3ncc(F)cc3c2)ccc1[C@@H](Oc1cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)nc(N)n1)C(F)(F)F

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 55an) Steps 4-5. 3-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolone was used as the Suzuki coupling partner (CAS#1251731-31-3).
Reaction SMILES: [O-2].[Zn+2:2].[C:3]1([P:9](=[O:12])([OH:11])[OH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O>[C:3]1([P:9](=[O:10])([O-:12])[O-:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Zn+2:2]
Reactant: O=P(O)(O)c1ccccc1
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: O=P([O-])([O-])c1ccccc1

Procedure:
In Loedige mixer (M-20 type (total volume: 20 L) available from Loedige), 8.51 kg (105 mol) of zinc oxide powder (JIS grade 2, available from HakusuiTech Ltd.) was placed. An aqueous solution of 1.67 kg (10.5 mol) of phenylphosphonic acid powder (Nissan Chemical Industries, Ltd.) dissolved in 9.43 kg of water was added thereinto (solid concentration in total mixture: 52% by mass). The resulting mixture was mixed for 5 minutes. Then, the mixture was dried for 60 minutes with mixing by flowing steam at 150° C. in the jacket provided with the apparatus surface and further dried for 70 minutes under reduced pressure, yielding a white powder of zinc phenylphosphonate-containing zinc oxide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]([F:44])([F:43])[F:42])=[C:6]([CH:40]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:39])[CH2:16][NH:17][C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31]CC3C=CC=CC=3)[NH:22][N:21]=2)=[O:19])[CH2:11][CH2:10]1)=[O:8]>CO.C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]([F:44])([F:42])[F:43])=[C:6]([CH:40]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:39])[CH2:16][NH:17][C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[NH:22][N:21]=2)=[O:19])[CH2:11][CH2:10]1)=[O:8]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2O)[nH]n1
Yield: 46.2 %

Procedure:
10% Pd/c (25 mg) was added to a stirred solution of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide (94 mg, 0.15 mmol) in a mixture of MeOH (60 mL) and THF (10 mL) and stirred under hydrogen atmosphere. The reaction mixture was then stirred for 1 hrs at room temperature. The mixture was filtered over a bed of celite. The celite was washed with MeOH and the filtrate was concentrated under reduced pressure. The crude was washed with ethyl acetate, filtered and dried to afford 36 mg (45% yield) of 5-(2-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 94.89%. 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 10.4 (s, 1H), 7.9 (m, 2H), 7.5 (m, 2H), 6.9 (m, 3H), 4.1 (d, 2H), 3.4 (m, 6H), 3.1 (m, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C@@H:10]1[NH:15][C:14](=O)[CH2:13][O:12][CH2:11]1)[CH2:8][CH3:9]>C1COCC1>[CH2:7]([C@H:10]1[CH2:11][O:12][CH2:13][CH2:14][NH:15]1)[CH2:8][CH3:9]
Reactant: CCC[C@H]1COCC(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC[C@H]1COCCN1
Temperature: 0 °C
Yield: 98 %

Procedure:
To an ice cold, stirred suspension of NaH (60% in oil, 1.9 g, 46.0 mmol) in toluene (62 mL) was added dropwise a solution of (S)-2-aminopentan-1-ol (2.1 g, 20.0 mmol) in toluene (44 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.7 g, 22.0 mmol) in toluene (12 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.5 g, 46.0 mmol) was added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 98:2 CH2Cl2/CH3OH to 95:5 CH2Cl2/CH3OH) to give (S)-5-propylmorpholin-3-one (2.2 g, 76%) as a yellow oil. To ice-cold THF (10 mL) was added lithium aluminum hydride (1.0 M solution in THF, 30 mL, 30 mmol). Once the addition was complete, a solution of (S)-5-propylmorpholin-3-one (2.2 g, 15 mmol) in THF (10 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added H2O (1.2 mL), then 15% aqueous solution of sodium hydroxide (1.2 mL), and then H2O (1.2 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solid with EtOAc (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (S)-3-propylmorpholine (1.9 g, 98%) as a light yellow oil. 1H NMR and MS consistent.
Reaction SMILES: Br[C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8].[F:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1>>[F:30][C:31]1[CH:36]=[C:35]([C:2]2[C:3]([N:24]3[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:22])([F:21])[CH:18]([F:19])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:23]=2)[CH:34]=[N:33][CH:32]=1
Reactant: O=C(Nc1ccc(OC(F)(F)C(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)C(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)nicotinamide (Stage 212.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford a solid. UPLC-MS (Condition 3), tR=0.96 min, m/z=495.3; 1H-NMR (400 MHz, DMSO-d6), δ ppm 1.75 (br. s, 1H) 1.86 (d, J=8.21 Hz, 1H) 2.88 (d, J=12.12 Hz, 1H) 3.17-3.29 (m, 3H) 3.35-3.46 (m, 1H) 4.21 (br. s, 1H) 4.88 (br. s, 1H) 6.79 (m, 1H) 7.26 (d, J=8.99 Hz, 2H) 7.83 (d, J=9.38 Hz, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.51 (s, 1H) 8.60 (d, J=2.74 Hz, 1H) 8.76-8.81 (m, 1H) 10.15 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[S:41](Cl)(=[O:43])=[O:42]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:35]4[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=4[O:33][CH3:32])(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(C)ccc4OC)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-methoxy-5-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=605.7)=94%.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][NH:27][CH2:28][CH:29]([CH3:31])[CH3:30]>C(Cl)Cl>[CH2:28]([N:27]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:26])[CH:29]([CH3:31])[CH3:30]
Reactant: CNCC(C)C
Reactant: COC(=O)c1cc(C)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(C)cc(CN(C)CC(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. N-Methylisobutylamine (287 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.36 (s, 1H), 3.90 (s, 3H), 3.44 (s, 2H), 2.38 (s, 3H), 2.14 (s, 3H), 2.10 (d, J=8 Hz, 2H), 1.81 (m, 1H), 0.90 (d, J=7 Hz, 6H).