Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([O:24]CC)=[O:23].O.[OH-].[Li+].C(O)C.O.O1CCCC1>O>[C:22]([C:3]1[CH:4]=[C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:6]=[CH:7][C:2]=1[Cl:1])([OH:24])=[O:23]
Reactant: CCOC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)c(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A suspension of 4-[4-chloro-3-(ethoxycarbonyl)phenyl]hexahydro-1H-1,4-diazepine-1-carboxylic acid, 1,1-dimethylethyl ester (Example 5a, 0.21 g), lithium hydroxide monohydrate (1.05 ml of 3M solution in water) in 1:1 ethanol/water (7 ml) was stirred at room temperature for 14 h. More lithium hydroxide monohydrate (0.55 ml of 3M solution in water) was added followed by tetrahydrofuran (1 ml). The resulting solution was stirred for 4 h at room temperature then poured into water and extracted with diethyl ether. The aqueous phase was separated, acidified with 2M hydrochloric acid and then extracted with dichloromethane three times. The combined dichloromethane layers were dried over magnesium sulfate and evaporated under reduced pressure to yield the subtitle compound as a glass.
Reaction SMILES: [C:1]1([C:11]2[O:12][C:13]3[CH:19]=[C:18]([CH2:20][C:21]([O:23]C)=[O:22])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1>[C:1]1([C:11]2[O:12][C:13]3[CH:19]=[C:18]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccc2nc(-c3cccc4ccccc34)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc2nc(-c3cccc4ccccc34)oc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.4 %

Procedure:
To methyl (2-(1-naphthyl)-6-benzoxazolyl)acetate (223 mg, 0.70 mmol) were added THF (4 ml) and 0.5N NaOH (4.2 ml, 2.10 mmol). The resulting mixture was stirred at room temperature for 2 days. The reaction mixture was acidified 15 with ice-1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(1-naphthyl)-6-benzoxazolyl)acetic acid (194 mg, 91%) as a pale yellow solid.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:9]([C:13]([O:15]C)=O)=[CH:10][S:11][CH:12]=1)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:9]([C:13]([NH2:2])=[O:15])=[CH:10][S:11][CH:12]=1)[CH3:5]
Reactant: COC(=O)c1cscc1N=NN(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1cscc1C(N)=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 25 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (5 mL) was added a solution of methyl 4-[(dimethylamino)diazenyl]thiophene-3-carboxylate (110 mg) in THF (2 mL) for 5 min and stirred at rt for 36 h. The solution was poured into ice cooled water and extracted with chloroform. The combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product as a pale red color solid (25 mg, 25%), mp 168-172° C. IR (neat) νmax 3324, 3125, 2917, 2851, 1655, 1600, 1367, 1336, 1090 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.55 (1H, br s), 8.19 (1H, d, J=3.6 Hz), 7.15 (1H, d, J=3.6 Hz), 5.84 (1H, br s), 3.56 (3H, br s), 3.19 (3H, br s); LC-MS (positive ion mode): m/z 199 (M+H)+.
Reaction SMILES: C(OC(N1CCC[CH:10]([C:14]([S:28][CH2:29][CH3:30])([C:16](=[O:27])[NH:17][C:18]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=2)[CH3:15])C1)=O)(C)(C)C.Cl>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:23]([C:21]1[O:20][N:19]=[C:18]([NH:17][C:16](=[O:27])[C:14]([CH3:10])([S:28][CH2:29][CH:30]2[CH2:10][CH2:14][CH2:16][NH:17][CH2:18]2)[CH3:15])[CH:22]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CCSC(C)(C(=O)Nc1cc(C(C)(C)C)on1)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(SCC1CCCNC1)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 158.6 %

Procedure:
To a solution of 288 mg (0.65 mmol) of 3-[1-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-1-methyl-ethylsulfanylmethyl]-piperidine-1-carboxylic acid tert-butyl ester (synthesized according to Method H, step 1) in DCM (5 mL) were added 1.1 mL of HCl (2M solution in dioxane). The reaction was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO3 solution (5 mL), the organic layer was separated and dried over Na2SO4. Filtration and concentration of the filtrate under reduced pressure afforded 175 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(piperidin-3-ylmethylsulfanyl)-propionamide.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:34])[CH3:33]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A159) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: COC1C=C([N+]([O-])=O)C=CC=1O.[OH:13][C:14]([CH3:34])([CH3:33])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:28]=[CH:27][NH:26][C:25](=O)[C:24]2=[O:30])=[CH:19][C:18]=1[O:31][CH3:32].C(N(C(C)C)C(C)C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[N:77]1[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[CH2:83][CH2:84][SH:85]>CN(C=O)C>[OH:13][C:14]([CH3:34])([CH3:33])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:28]=[CH:27][N:26]=[C:25]([S:85][CH2:84][CH2:83][C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][N:77]=3)[C:24]2=[O:30])=[CH:19][C:18]=1[O:31][CH3:32]
Reactant: SCCc1ccccn1
Reactant: COc1cc(-n2cc[nH]c(=O)c2=O)ccc1OCC(C)(C)O
Agent: COc1cc([N+](=O)[O-])ccc1O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-n2ccnc(SCCc3ccccn3)c2=O)ccc1OCC(C)(C)O
Temperature: 25 °C
Yield: 68 %

Procedure:
Following the procedures described in parts A-D of example 134, 2-methoxy-4-nitrophenol was converted to 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrazine-2,3(1H,4H)-dione. A solution of 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrazine-2,3(1H,4H)-dione prepared in Part ? (2.28 g, 7.44 mmol), EtN(iPr)2 (3.9 mL, 22.3 mmol), PyBOP (6.78 g, 13.0 mmol) in DMF (35 mL) was stirred at ambient temperature for 1.5 h. After addition of 2-pyridylethyl mercaptan (1.24 g, 8.93 mmol), the reaction was stirred at ambient temperature. After stirring overnight the reaction mixture was partially concentrated under reduced pressure, quenching by addition of aq. NaHCO3 and extracted with EtOAc. The EtOAc extracts were washed with brine, dried over MgSO4 and concentrated. Chromatography on silica employing a gradient elution with 2.5-10% methanol/methylene chloride, followed by chromatography on silica eluting with EtOAc, and trituration with EtOAc/Hexanes afforded the desired product 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-3-(2-(pyridin-2-yl)ethylthio)pyrazin-2(1H)-one (2.15 g, 68% yield).
Reaction SMILES: [C@H:1]1([NH2:13])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.Cl.C(=O)([O-])[O-].[K+].[K+].[C@H]1(N)C2=C3C(=CC=C2)C=CC=C3C1.[I-].C([N+]1(C)[CH2:42][CH2:41][C:40](=[O:43])[CH2:39][CH2:38]1)C>O.C(O)C>[C@H:1]1([N:13]2[CH2:42][CH2:41][C:40](=[O:43])[CH2:39][CH2:38]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: N[C@@H]1Cc2cccc3cccc1c23
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CCO
Product: O=C1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Yield: 72 %

Procedure:
(R)-Acenaphthen-1-yl-amine•hydrochloride (25 g) was dissolved in water (200 ml) and the mixture was alkalified with potassium carbonate and extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained (R)-acenaphthen-1-yl-amine (21 g, 124 mmol) was dissolved in ethanol (200 ml). Potassium carbonate (2.5 g, 18 mmol) and 1-ethyl-1-methyl-4-oxopiperidinium iodide (40 g) dissolved in water (100 ml) was added and the mixture was heated under reflux for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give (R)-1-(acenaphthen-1-yl)-piperidin-4-one (22 g) as a red-yellow oil. (4) A solution of (R)-1-(acenaphthen-1-yl)-piperidin-4-one (12.6 g, 50 mmol) and 1,2-phenylenediamine (10.8 g, 100 mmol) in THF (100 ml) was cooled to (0° C.), sodium triacetoxy borohydride (30 g) and acetic acid (12 ml) were added thereto, and the mixture was stirred at room temperature for 24 hr. The reaction mixture was poured into water, and potassium carbonate was added for neutralization. The mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give (R)—N-[1-(acenaphthen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (9 g) as yellow crystals. (5) (R)—N-[1-(Acenaphthen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (9 g, 26 mmol) was dissolved in THF (100 ml), and carbonyldiimidazole (5 g, 30 mmol) was added. The mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (8.8 g) as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C@@H:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9].[CH3:17]O>>[NH2:6][C@@H:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([O:10][CH3:17])=[O:9]
Reactant: CO
Reactant: N[C@H](C(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H](N)c1ccccc1
Temperature: 65 °C
Yield: 74 %

Procedure:
A catalytic amount of concentrated sulfuric acid (0.1 mL) was added to a 50 mL round bottom flask containing a solution of (S)-2-amino-2-phenylacetic acid (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (1.0 g, 6.6 mmol) in MeOH (10 mL). The resulting mixture was heated at 65° C. for 6 hours. The solvent was removed under reduced pressure, and the mixture was quenched with aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to afford (S)-methyl 2-amino-2-phenylacetate (0.8 g, 74.0%) as a white solid. 1H NMR (300 MHz, CDCl3) δ: 7.37-7.32 (m, 5H), 4.62 (s, 1H), 3.70 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])=[CH:4][CH:3]=1.[CH2:33]([O:35][C:36]([C:38]1([C:41]2[CH:46]=[CH:45][C:44](B3OC(C)(C)C(C)(C)O3)=[CH:43][CH:42]=2)[CH2:40][CH2:39]1)=[O:37])[CH3:34]>>[CH2:33]([O:35][C:36]([C:38]1([C:41]2[CH:46]=[CH:45][C:44]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14]([N:16]4[CH2:21][CH2:20][N:19]([S:22]([C:25]5[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=5)(=[O:23])=[O:24])[CH2:18][CH2:17]4)=[O:15])=[CH:4][CH:3]=3)=[CH:43][CH:42]=2)[CH2:39][CH2:40]1)=[O:37])[CH3:34]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)N1CCN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)N4CCN(S(=O)(=O)c5ccc(Cl)c(Cl)c5)CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 2, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[4-(3,4-dichloro-benzenesulfonyl)-piperazin-1-yl]-methanone and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1.[H-].[Na+].[CH3:17]I>CN(C=O)C.Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:17])[S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1
Reactant: COc1ccc(NS(C)(=O)=O)c(C)c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)S(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 860 mg (4.0 mmol) N-(4-methoxy-2-methyl-phenyl)-methanesulfonamide in 15 ml DMF at ambient temperature was added 192 mg (48 mmol) 60% sodium hydride dispersion and the resulting mixture was treated with 1.14 gm, 0.5 ml (8.0 mmol) methyl iodide. The reaction mixture was stirred at room temperature for 2 hours and 0.5 ml of methyl iodide was introduced and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 1N HCl and then extracted with ethyl acetate. The organics were washed with brine, dried with sodium sulfate and then evaporated in vacuo to afford 293 mg (X %) of a light purple solid. Mass spectrum APCI (m/z) 230 (p+1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7](C(Cl)(Cl)Cl)[O:6][N:5]=1)[CH3:3].[NH:13]1[CH2:18][CH2:17][CH:16]([C@H:19]([OH:21])[CH3:20])[CH2:15][CH2:14]1.[OH-].[Na+]>CO>[CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:13]2[CH2:18][CH2:17][CH:16]([C@H:19]([OH:21])[CH3:20])[CH2:15][CH2:14]2)[O:6][N:5]=1)[CH3:3]
Reactant: CC(C)c1noc(C(Cl)(Cl)Cl)n1
Reactant: C[C@@H](O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1noc(N2CCC([C@@H](C)O)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
A solution of 3-(1-methylethyl)-5-(trichloromethyl)-1,2,4-oxadiazole (25.8 g, 112 mmol) and (1R)-1-(4-piperidinyl)ethanol (13.4 g, 104 mmol) in MeOH (15 mL) was stirred at ambient temperature under a stream of nitrogen for 7 days. The reaction was diluted with MeOH (40 mL), cooled in an ice bath and 1N NaOH (25 mL) was added. The mixture was allowed to warm to ambient temperature and stir for 1 h. The reaction was partitioned in EtOAc (300 mL)/1N NaOH (75 mL) and the layers were separated. The aqueous layer was saturated with NaCl and extracted with EtOAc (200 mL). The combined EtOAc layers were dried over MgSO4, concentrated and placed under high vacuum for 18 h to afford (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethanol (16.75 g, 68%) as an orange oil. 1H NMR (400 MHz, CDCl3): δ 4.14 (m, 2H), 3.57 (quint, 1H, J=6.3 Hz), 2.98 (m, 2H), 2.83 (septet, 1H, J=7.0 Hz), 1.90 (m, 1H), 1.86 (br, 1H), 1.67 (m, 1H), 1.45 (m, 1H), 1.33 (m, 2H), 1.23 (d, 6H, J=7.0 Hz), 1.16 (d, 3H, J=6.3 Hz); LRMS (ESI), m/z 240 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=1)=[O:21].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][C:25]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)=[O:21]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(Cl)nc2)c1F
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(NCc3ccc(OC)cc3)nc2)c1F
Temperature: 50 °C

Procedure:
Step 7—To a solution of tert-butyl N-[(1R)-1-[4-chloro-3-(6-chloropyridine-3-carbonyl)-2-fluorophenyl]propyl]-carbamate (82.8 g, 194 mmol) from Step 6 in DMSO (5 vol) was added 4-methoxybenzylamine (53.1 g, 2 equi Vol). The mixture was heated to 50° C. (external temp) overnight then allowed to cool. The mixture was diluted with EtOAc (30 vol) and washed with 5% citric acid (5 vol), water (5 vol) and brine (5 vol) and concentrated to furnish tert-butyl N-[(1R)-1-[4-chloro-2-fluoro-3-(6-{[(4-methoxyphenyl)methyl]amino}pyridine-3-carbonyl)phenyl]propyl]carbamate as a brown oil, 109 g. m/z: 528.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[CH:4][CH:3]=1.C[Si](C)(C)[C:15]([F:18])([F:17])[F:16].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]([OH:10])[C:15]([F:18])([F:17])[F:16])=[CH:6][CH:7]=1
Reactant: CC(C)(C=O)c1ccc(Br)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(c1ccc(Br)cc1)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(4-bromophenyl)-2-methylpropanal (5.7 g, 25 mmol) and trimethyl(trifluoromethyl)silane (7.1 g, 50 mmol) in THF (60 mL) under nitrogen was added a solution of TBAF (0.66 g, 2.5 mmol) in THF (10 mL) dropwise at −30° C. The resulting solution was stirred at −30° C. for 1 hour and at ambient temperature for an additional 1 hour before the addition of 1 N aqueous HCl (20 mL). The mixture was vigorously stirred at ambient temperature for 10 minutes, and then extracted with EtOAc (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 2-4% EtOAc/hexane) to afford (S and R)-3-(4-bromophenyl)-1,1,1-trifluoro-3-methylbutan-2-ol as a light yellow oil. The racemic mixture was resolved by preparative chiral HPLC (Chiralpak IA, 2*25 cm; Mobile phase: 5% ethanol in hexane) to afford the two enantiopure title compounds.
Reaction SMILES: [I-].[Na+].[Br:3][C:4]1[C:5]([CH3:11])=[N:6][C:7](Br)=[CH:8][CH:9]=1.[I:12][Si](C)(C)C>C(#N)CC.C(OCC)(=O)C.O>[Br:3][C:4]1[C:5]([CH3:11])=[N:6][C:7]([I:12])=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)I
Reactant: Cc1nc(Br)ccc1Br
Agent: [I-]
Agent: [Na+]
Solvent: CCC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(I)ccc1Br
Temperature: 95 °C
Reaction time: 0.08 h
Yield: 95 %

Procedure:
Sodium iodide (2 equiv) and 3,6-dibromo-2-methylpyridine (1 equiv) were combined in propionitrile and the resulting slurry was stirred under nitrogen for 5 min. Iodotrimethylsilane (0.2 equiv) was added and the reaction was heated at 95° C., with stirring, under nitrogen for 24 h. The slurry was cooled to room temperature, diluted with a 1:1 mixture of ethyl acetate and water. The mixture was agitated for 15 min and the aqueous and organic phases were then separated. The organic layer was washed sequentially with equal volumes of saturated aqueous sodium bicarbonate solution, sodium thiosulfate (5% aqueous solution), and saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the desired product in 95% yield, as an oil, which crystallized to an off-white solid. MS (ESI) m/z 297.8 [M]+, 299.8 [M+2]+.
Reaction SMILES: [H-].[Na+].CCCCCC.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:12][CH:11]=1.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[CH2:20]([O:19][C:17]([CH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:15][CH:14]=1)=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)COc1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 2.1 g) was treated under argon with repeated washes of hexane. The oil-free residue was suspended in dry DMF (130 ml) and the product from step (i) (10 g) added in three portions to the cooled (4° C.) stirred mixture. Stirring was continued for a further 15 minutes when tertiary butyl bromoacetate (7.0 ml) was added dropwise over 15 minutes. After 1 hour at 4° C., the mixture was stirred for 6 hours at ambient temperature. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was re-extracted with further ethyl acetate and the combined organic phases washed with water and brine, then dried (MgSO4) and evaporated. The residue, after purification by flash chromatography on silica eluting with dichloromethane, gave tertiary butyl 4-(benzyloxycarbonylmethyl)phenoxyacetate, 7.5 g, as a colourless oil: NMR (CDCl3) d 7.31(5H, m), 7.20(2H, m), 6.85(2H, m), 5.12(2H, s), 4.49(2H, s), 3.60(2H, s), 1.48(9H, s); m/e 356 (M°)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
A mixture of 10 g. of ethyl p-[p-(benzyloxy)benzylamino]benzoate (prepared as described in Example 11) 10 g. of potassium hydroxide and 200 ml. of ethanol-water (9:1) are refluxed for 4.5 hours. While hot, the mixture is acidified with concentrated hydrochloric acid. Dilution with water and filtration gives tan crystals which are recrystallized from glacial acetic acid to give off-white crystals, m.p. 206°-208° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:21][CH2:22][Cl:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:23][CH2:22][CH2:21][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(Nc2cccc(O)c2)c2ccccc2n1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Nc2cccc(OCCCl)c2)c2ccccc2n1
Temperature: 70 °C
Yield: 44.5 %

Procedure:
To a heterogeneous mixture of 20 (2.16 g, 6.90 mmol) in acetone (22 mL) were sequentially added 1-bromo-2-chloroethane (7.2 mL, 86.50 mmol) and potassium carbonate (3.00 g, 21.71 mmol). The reaction was stirred and heated at 70° C. for 17 hours before it was allowed to cool to room temperature and was filtered. The solids were rinsed with a 3:1 mixture of dichloromethane/methanol (25 mL×3), and the filtrate was isolated and evaporated to give the crude product. Column chromatography on silica (dichloromethane to 20/1 to 15/1 to 5/1dichloromethane/methanol) gave 21 as a pale yellow solid (0.96 g, 35.5%).