Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15](OCC)[CH3:16]>C([Mg]Br)C>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([CH:11]([OH:12])[CH2:15][CH3:16])=[CH:13][CH:14]=1
Reactant: CCOCC
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: CC[Mg]Br
Product: CCC(O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-phenylbenzaldehyde (1.20 g) in diethyl ether (13.2 mL), ethylmagnesium bromide (about 3.0 mol/L, solution in diethyl ether, 3.29 mL) was added at 0° C. After stirring the mixture at room temperature for 3 hours, the precipitate was recovered by filtration. After dissolving the recovered precipitate in a liquid mixture of ethyl acetate and a saturated aqueous solution of ammonium chloride, three extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine. After passage through a phase separator, the washed organic layers were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-70:30) to give 1-(biphenyl-4-yl)propan-1-ol as a colorless solid (1.27 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.CN(C)[CH:16]=[O:17].Cl.C(=O)(O)[O-].[Na+]>C(OCC)C>[CH:16]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1)=[O:17]
Reactant: CN(C)C=O
Reactant: Brc1cccc(-c2ccccn2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=Cc1cccc(-c2ccccn2)n1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A solution of 7.05 g (30 mmol) of 6-bromo-2,2'-bipyridine in 50 ml of diethyl ether is added to a solution of 19.4 ml (31 mmol) of 1.6M butyllithium-in-hexane solution in 100 ml of diethyl ether at -80° C. under a nitrogen atmosphere. After the addition is complete, stirring is carried out for a further 30 minutes at this temperature, after which a solution of 4.39 g (60 mmol) of dimethylformamide in 30 ml of diethyl ether is added at from -80° to -90° C. After further stirring at this temperature for 1.5 hours, hydrolysis is carried out with 150 ml of quarter-concentrated hydrochloric acid at from -60° to -50° C. The reaction mixture is then neutralized at room temperature by adding solid sodium bicarbonate, the phases are separated and the aqueous phase is extracted once again with 50 ml of diethyl ether. The organic phases are combined and are dried over sodium sulfate and finally the solvent is distilled off under reduced pressure. The title compound is obtained as a reddish brown oil which crystallizes on standing.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[OH-].[Na+].[I:13]I>CO>[I:13][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:10])[C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: Cc1cc(C=O)ccc1O
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C=O)cc(I)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
At 5° C., to a stirred solution containing commercial 4-hydroxy-3-methylbenzaldehyde (4.65 g, 34.1 mmol) and sodium hydroxide (2.73 g, 68.25 mmol) in MeOH (171 mL) was added iodine (10.8 g, 42.7 mmol). The reaction was stirred for 16 h, eventually warming to ambient temperature. The reaction was quenched with 1N HCl (200 mL) and extracted with ether. The ethereal extracts were washed with 10% Na2S2O3 (3×), with brine (3×), dried (MgSO4) and concentrated. Purification on Biotage KP-Sil eluting with 70% CH2Cl2/pet. ether to give 7.28 g (81%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ2.30 (s, 3H), 7.65 (d, J=1.02 Hz, 1H), 8.09 (d, J=1.91 Hz, 1H), 9.74 (s, 1H), 10.25 (s, 1H).
Reaction SMILES: [Li+].[OH-].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH2:25][C@H:26]([NH:37][C:38](=[O:51])[C@@H:39]([NH:41][C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[CH3:40])[C:27]([O:29]CC2C=CC=CC=2)=[O:28])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O.CO>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH2:25][C@H:26]([NH:37][C:38](=[O:51])[C@@H:39]([NH:41][C:42](=[O:50])[CH2:43][N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)[CH3:40])[C:27]([OH:29])=[O:28])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O

Procedure:
A solution of LiOH (279 mg, 6.6 mmol) in water (6 mL) was added to a solution of (S)-benzyl 3-(3,4-bis(benzyloxy)phenyl)-2-((S)-2-(2-morpholinoacetamido) propanamido)propanoate (1.1 g, 1.66 mmol) in MeOH (30 mL) at 0° C. with stirring. The reaction mixture was stirred for 3 h and then acidified with 2 N aqueous HCl to pH=3. The resulting mixture was concentrated and the residue was carried forward without further purification.
Reaction SMILES: C(=N[OH:9])C1C=CC=CC=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:23](OCC)=[O:24])[CH2:22][CH2:21][CH2:20]2)=[C:15]([C:28]#[C:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:14]=1>CN(C=O)C.O1CCOCC1>[Cl:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[C:19]1([CH2:22][CH2:21][CH2:20]1)[C:23](=[O:24])[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]2[OH:9]
Reactant: ON=Cc1ccccc1
Reactant: CCOC(=O)C#Cc1cc(Cl)ccc1C1(C(=O)OCC)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
Benzaldehyde oxime (174 mg, 1434 μmol) in DMF (7 mL) was added to a stirred suspension of NaH (60% dispersion in mineral oil (57 mg, 1434 μmol)) in dioxane (7 mL) under a N2 atmosphere. The mixture was stirred for approximately 30 minutes before being cooled to 0° C. Ethyl 1-(4-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)cyclobutanecarboxylate (400 mg, 1195 μmol) in DMF (7 mL) was added via syringe, and the reaction was stirred at 0° C. for 1 hour. The reaction was quenched with water, and extracted with EtOAc. The aqueous layer was separated and brought to a pH of about 4 with 10% HCl and extracted again with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give an orange oil. The crude oil was purified by silica flash chromatography (0-20% EtOAc/hexane) to give the desired compound as a white solid (155 mg). MS (m/e)=307.1 (M+H)+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([CH:22]([CH2:26][CH3:27])[C:23]([OH:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[N:29]1[C:33](=[O:34])[CH2:32][CH2:31][C:30]1=[O:35]>O1CCOCC1>[C:16]1([CH:22]([CH2:26][CH3:27])[C:23]([O:25][CH:31]2[CH2:32][C:33](=[O:34])[NH:29][C:30]2=[O:35])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)N1O
Reactant: CCC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CCC(C(=O)OC1CC(=O)NC1=O)c1ccccc1
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of dicyclohexylcarbodiimide (6.91 g, 0.033 mol) in 33 mL of dry dioxane was added to a solution of 2-phenylbutyric acid (5.00 g, 0.030 mol) and N-hydroxysuccinimide (3.86 g, 0.034 mol) and the resulting mixture was allowed to stir overnight. The precipitated dicyclohexylurea by-product was filtered off and the filtrate concentrated under vacuum. The residue was dissolved in 5 mL of methylene chloride and filtered to remove a small amount of additional urea by-product. The solution was evaporated to give a white solid which was recrystallized from methanol to give 5.17 g (65%) of the product as white crystals; mp 96.5°-97.5° C.; 1H NMR (CDCl3) δ 0.99 (t, 3 H, J=7.4 Hz), 1.85-2.00 (m, 1 H), 2.13-2.28 (m, 1 H), 2.72 (br s, 4 H), 3.78 (t, 1 H, J=7.6 Hz), 7.35 (s, 5 H); 13C NMR (CDCl3) δ 11.49, 25.30, 26.89, 50.25, 127.95, 128.18, 128.92, 136.90, 169.24, 169.62; Anal. Calcd for C14H15NO4 : C, 64.36; H, 5.79; N, 5.36. Found: C, 64.63; H, 5.84; N, 5.34.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:20]>CN1CCCC1=O>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: CCOCCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Solvent: CN1CCCC1=O
Product: CCOCCn1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c21
Yield: 53.2 %

Procedure:
To a solution of 4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (160 mg) in 1-methyl-2-pyrrolidone (1.4 mL) was added 3-chloro-4-(pyridin-2-ylmethoxy)aniline (250 mg). The title compound (160 mg) was obtained as pale-yellow needle crystals by the reaction in the same manner as in Example 42 (ii).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH:5]([O:7][CH2:8][CH3:9])=[CH2:6].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:5]([O:7][CH:8]([O:4][CH2:1][C:2]#[CH:3])[CH3:9])[CH3:6]
Reactant: C=COCC
Reactant: C#CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C#CCOC(C)OCC
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A solution of 20 g (0.36 mol) of 2-propyn-1-ol in 637 ml (6.66 mol) of ethyl vinyl ether was treated at 0° under argon with 1.27 ml (16.7 mmol) of trifluoroacetic acid and the mixture was subsequently stirred at room temperature for 65 hours. 1.3 g of sodium carbonate were added, the reaction mixture was stirred at room temperature for a further 30 minutes and concentrated on a rotary evaporator. Distillation of the residue under reduced pressure yielded 1-(1-ethoxyethoxy)-2-propyne of boiling point 55°/30 mmHg.
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:19](/[CH:20]=[CH:21]/[C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:17][CH2:16][C:15]1=[O:29]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH:19]1/[CH:20]=[CH:21]/[CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC(=O)/C=C/C1CCCC(=O)N1CCCCCCC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCCCC(O)/C=C/C1CCCC(=O)N1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
Sodium borohydride (42 mg, 1.10 mmol), followed by MeOH (0.38 mL), was added to a solution of 7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid methyl ester (40 mg, 0.11 mmol) in CH2Cl2 (1.13 mL) at 0° C. The mixture was allowed to warm to rt. After 3 h at rt, the reaction was quenched with aqueous HCl (1.0 M) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL) then dried (Na2SO4), filtered and concentrated in vacuo to afford 40 mg (99%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[S:27][C:28]([CH:31]=O)=[CH:29][N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:31][C:28]2[S:27][C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:30][CH:29]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cnc(-c2ccccc2)s1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cnc(-c2ccccc2)s1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 2-phenylthiazole-5-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 409.16 g/mol.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH:14]([C:21]1[CH:26]=[CH:25][C:24]([O:27]C2CCCCO2)=[CH:23][CH:22]=1)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)Cl>[OH:27][C:24]1[CH:25]=[CH:26][C:21]([CH:14]([C:10]2[N:9]([CH3:8])[CH:13]=[CH:12][N:11]=2)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CC(c1ccc(OC2CCCCO2)cc1)c1nccn1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(c1ccc(O)cc1)c1nccn1C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (21 mL) was added to a solution of protected ester 9.4 (21 g) in dry DCM (210 mL) with caution at 0° C. The mixture was brought to room temperature over 4 hours. The reaction mixture was concentrated under reduced pressure to provide a yellow oily residue, which was re-dissolved in DCM (200 mL) and washed with water, saturated NaHCO3, water and brine, and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure, and the product was crystallized in EtOAc-hexane. The mother liquid was concentrated and flash chromatographed (silica gel, 50% EtOAc in hexane as eluant). The product, (±)-ethyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate (9.5) was obtained as a colorless crystal (combined yield 11 g). LC-MS ESI (pos.) m/e: 275 (M+H). 1H NMR (500 MHz) (CDCl3) δ 9.28 (s, 1H); 6.98-7.00 (m, 3H); 6.65-6.77(m, 3H); 4.41 (dd, J=9.0, 3.0 Hz, 1H); 3.96 (q, J=7.0, 2H); 3.39 (s, 3H); 3.19 (dd, J=16.0, 7.0 Hz, 1H); 2.78 (dd, J=16.0, 6.5 Hz, 1H); 1.80 (t, J=7.0 Hz, 3H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([S:12]([C:15]2[CH:16]=[CH:17][C:18](=O)[NH:19][N:20]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:3][C:18]1[N:19]=[N:20][C:15]([S:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=c1ccc(S(=O)(=O)c2ccccc2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: O=S(=O)(c1ccccc1)c1ccc(Cl)nn1
Temperature: 0 °C

Procedure:
To stirring phosphorous oxychloride (87 ml) at 80° C. was added four 2.0 g portions of 6-phenylsulfonyl-3-oxo-2,3-dihydropyridazine every 30 minutes. After additional two 1.0 g portions were added with stirring, the reaction mixture was slowly poured into ice-water over 1 hour to form the precipitate, which was collected, washed well with water, and dried to give 6-chloro-3-ph-enylsulfonylpyridazine (8.4 g).
Reaction SMILES: N[C@H](C(O)=[O:14])CC1C2C(=CC=CC=2)NC=1.[NH2:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH2:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:14])=[CH:21][CH:20]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
Trp, Phe
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:12]1[CH:17]=[C:16]([C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>CCCCCC.CN(C)C=O>[CH2:9]([S:10][C:12]1[CH:17]=[C:16]([C:18]2[S:22][C:21]([C:23]3[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=3)=[N:20][C:19]=2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[CH:15]=[CH:14][N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(F)c2)c1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(SCc3ccccc3)c2)c1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
After sodium hydride (60% paraffin dispersion, 0.13 g, 3.2 mmol) was washed with hexane twice, it was suspended in N,N-dimethylformamide (15 mL). Phenylmethanethiol (0.35 mL, 3.0 mmol) was added to this suspension and stirred for 10 minutes. A solution of 5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole (0.49 g, 1.2 mmol) in N,N-dimethylformamide (5 mL) was added to this mixture and stirred for 1 hour. An 8N aqueous solution of sodium hydroxide was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and the extract was washed with water. This extract was dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 2:1) to obtain 0.48 g (yield 79%).
Reaction SMILES: [CH2:1]([C:3]([C:8]1[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[CH2:1]([C:3]([C:8]1[C:9]([CH3:14])=[N+:10]([O-:20])[CH:11]=[CH:12][CH:13]=1)([O:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(OC)c1cccnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCC(CC)(OC)c1ccc[n+]([O-])c1C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a solution of 3-(1-ethyl-1-methoxy-propyl)-2-methyl-pyridine (0.176 g, 0.911 mmol) in CH2Cl2 (10 mL) was added 3-chloroperoxybenzoic acid (0.473 g, 2.75 mmol). The mixture was stirred for 16 h and concentrated by evaporation under vacuum. The residue was purified by flash chromatography on a silica gel column (6:1 EtOAc/MeOH), affording 3-(1-ethyl-1-methoxy-propyl)-2-methyl-pyridine I-oxide as a white solid (0.188 g, 98%). 1H NMR (CDCl3) δ 0.74 (t, 6H, J=7.5 Hz), 1.94 (q, 4H, J=7.5 Hz), 2.80 (s, 3H), 3.01 (s, 3H), 7.07-7.10 (m, 1H), 7.21 (d, 1H, J=8.1 Hz), 8.27 (d, 1H, J=6.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A solution of 9.0 g of 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole in 25 ml of dimethylformamide is added with stirring to a suspension of 1.93 g of sodium hydride (50% suspension in oil) in 25 ml dimethylformamide. To the mixture is added 5.5 ml of ethyl 2-bromo-2-methylpropionate. The reaction mixture is stirred 24 hr at 80° C., poured onto ice/water and extracted with ether. The ether extracts are combined and washed with dil sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent is removed in vacuo to give a yellow oil which crystallizes on standing. Recrystallization from ether affords ethyl 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}-2-methylpropionate, mp 70° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][CH2:12][C:13]1[N:18]=[C:17](Cl)[C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][CH2:12][C:13]1[N:18]=[C:17]([O:30][CH3:29])[C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: COC(=O)c1ccc(CCc2cc(Br)ccc2OCc2ccccc2)nc1Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CCc2cc(Br)ccc2OCc2ccccc2)nc1OC
Temperature: 140 °C
Yield: 88.9 %

Procedure:
A mixture of methyl 6-[2-benzyloxy-5-bromophenethyl]-2-chloro-3-pyridinecarboxylate (7.0 g) and sodium methoxide (2.5 mole equivalents) in methanol was heated at 140° C. for 5 hours in a Carius Tube. The solvent was evaporated and the residue extracted with ethyl acetate and washed with saturated aqueous NH4Cl, water and brine. The organic solution was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on 7734 silica gel, eluting with 1% MeOH/CH2Cl2, to give methyl 6-[2-benzyloxy-5-bromophenethyl]-2-methoxy-3-pyridinecarboxylate (6.16 g).
Reaction SMILES: C([NH:4][C:5]1[N:9]([CH2:10][C:11](OCC)=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:6]=1[C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)C.[BH4-].[Na+].[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[N:9]([CH2:10][CH2:11][OH:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:6]=1[C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)Cn1nc(-c2cccc(F)c2)c(C#Cc2ccccc2)c1NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(C#Cc2ccccc2)c(-c2cccc(F)c2)nn1CCO
Temperature: 25 °C
Reaction time: 36 h
Yield: 85.4 %

Procedure:
To a solution of ethyl 2-(5-acetamido-3-(3-fluorophenyl)-4-(phenylethynyl)-1H-pyrazol-1-yl)acetate (3.25 g, 8.02 mmol) in ethanol (90 mL) was added sodium borohydride (610 mg, 16.04 mmol) and the reaction stirred at room temperature for 36 h. Additional sodium borohydride was added (305 mg, 8.02 mmol) and the reaction stirred at room temperature for 36 h. 25% NaOH (0.9 mL) was added and the reaction mixture was stirred at 80° C. for 3.5 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate twice and the organic phases combined, dried over MgSO4, filtered and evaporated. The crude material was suspended in diethylether (30 mL) and the product was filtered and dried in vacuo to give 2-(5-amino-3-(3-fluorophenyl)-4-(phenylethynyl)-1H-pyrazol-1-yl)ethanol as a white solid (2.2 g), which was used as such in the subsequent step.
Reaction SMILES: [NH2:1][C@H:2]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:3][C:4]([N:6]1[CH2:29][CH2:28][CH2:27][C@H:7]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[C:16](Cl)[CH:15]=[CH:14][C:13]=1[O:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22])=[O:9])=[O:5].[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C@H:2]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:3][C:4]([N:6]1[CH2:29][CH2:28][CH2:27][C@H:7]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22])=[O:9])=[O:5]
Reactant: [H][H]
Reactant: N[C@@H](CC(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1OCC(=O)NC1CC1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N[C@@H](CC(=O)N1CCC[C@H]1C(=O)NCc1ccccc1OCC(=O)NC1CC1)Cc1ccccc1
Yield: 71.5 %

Procedure:
Palladium hydroxide on activated charcoal (˜50 mg) was added to a solution of 15 mg of 1-[(3R)-3-amino-4-phenylbutanoyl]-N-{5-chloro-2-[2-(cyclopropylamino)-2-oxoethoxy]benzyl }-L-prolinamide in 1 mL methanol and the mixture was stirred under a balloon of hydrogen for 6 h. The reaction was diluted with methanol, filtered through a pad of Celite, and concentrated in vacuo. Purification using preparative TLC (silica gel, 13.5:1.5:85 methanol:concentrated ammonium hydroxide:methylene chloride) afforded 10 mg of the title compound. 1H NMR (400 MHz, CD3OD) δ 7.33–7.10 (m, 7H), 7.01–6.83 (d, 2H), 4.58–4.22 (m, 5H), 3.61–3.35 (m, 3H), 2.84–2.48 (m, 4H), 2.38–2.08 (m, 2H), 2.05–1.80 (m, 3H), 0.78–0.60 (m, 4H).
Reaction SMILES: BrC1C=C2C(C(CC([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=3)=O)=CN2)=CC=1.[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36]([C:41](=O)[NH:42]C(C)(C)C)=[C:35]2[CH2:48][C:49]([OH:51])=O>>[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36]([C:41]#[N:42])=[C:35]2[CH2:48][C:49]([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]1[CH:19]=[C:20]([Cl:29])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:22]([Cl:24])[CH:23]=1)=[O:51]
Reactant: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3cc(Br)ccc23)cc1Cl
Reactant: CC(C)(C)NC(=O)c1[nH]c2ccc(Br)cc2c1CC(=O)O
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c(C#N)[nH]c3ccc(Br)cc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 1, but using 2-(5-bromo-2-(tert-butylcarbamoyl)-1H-indol-3-yl)acetic acid (preparation J) in step 25 (A), the title compound was prepared. 1H-NMR (500 MHz, CD3OD) δ ppm 2.19 (d, J=12.82 Hz, 3 H) 3.79 (s, 2 H) 4.31 (s, 2 H) 7.00 (s, 1 H) 7.26 (s, 1 H) 7.35 (d, J=8.24 Hz, 1 H) 7.85 (s, 1 H).