Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[CH2:2].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH:1]([C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=[CH:7][CH:8]=1)=[CH2:2]
Reactant: Brc1ccccn1
Reactant: C=Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1cccc(-c2ccccn2)c1
Yield: 80 %

Procedure:
The reaction was performed with 3-vinyl-phenylboronic acid (10 g, 0.0676 mol), 2-bromopyridine (12.64 g, 0.08 mol), tetrahydrofuran (100 ml), 2M potassium carbonate aqueous solution (26 ml), and tetrakis(triphenylphosphine) palladium (Pd(Ph3)4, 0.06 g, 1 mol %) according to Example 1. The yield was 80%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([N:13]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:31][CH:30]=1)[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C2CCCCO2)=[CH:18][CH:17]=1)[CH3:15])(=[O:12])=[O:11].Cl>C(O)C.C(=O)(O)[O-].[Na+]>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([CH:14]([N:13]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:31][CH:30]=2)[S:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])(=[O:12])=[O:11])[CH3:15])=[CH:21][CH:20]=1
Reactant: Cc1cc(C)c(S(=O)(=O)N(c2ccc(OCCN3CCCC3)cc2)C(C)c2ccc(OC3CCCCO3)cc2)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(S(=O)(=O)N(c2ccc(OCCN3CCCC3)cc2)C(C)c2ccc(O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
To a solution of crude 2,4,6-trimethyl-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-N-{1-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-ethyl}-benzenesulfonamide (0.071 g, 0.12 mmol) in 4 mL absolute ethanol was added 0.8 mL of 1.2N HCl. The reaction mixture was stirred at room temperature overnight, was diluted with 10 mL saturated aqueous sodium bicarbonate, and the aqueous solution was washed with methylene chloride (3×10 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated. The residue was purified by preparative TLC (1.0 mm silica gel layer, elution with 15% methanol/methylene chloride) to afford 0.010 g of N-[1-(4-hydroxy-phenyl)-ethyl]-2,4,6-trimethyl-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzenesulfonamide. MS 509.0 (M+1)+
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][C:9]=1[OH:17].[Na].[BH4-]>C(O)C.O1CCCC1>[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[OH:16])=[CH:10][C:9]=1[OH:17]
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(O)c1ccc(OCCCCl)c(O)c1
Temperature: 10 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
To a flask charged with sodium borohydride (1.5 g, 39.4 mmol) under nitrogen and chilled to 10° C. was added, slowly, a solution of 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone (6.0 g, 26.2 mmol) dissolved in ethanol-tetrahydrofuran (120 ml, 2:1). After total addition, the ice bath was removed and the reaction was stirred at ambient temperature for 3 hours. An additional amount of sodium a borohydride (0.2 g, 5.3 mmol) was carefully added. After stirring at ambient temperature for one hour, the solvent was removed in vacuo. The resultant solid residue was diluted with water (100 ml) and left overnight. The product was isolated by vacuum filtration yielding 3.8 g. Two consecutive recrystallizations from toluene provided 3.3 g (55%) of 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzene methanol as a light brown solid, m.p.=107°-109° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([C:22]2[CH:26]=[C:25]([C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[CH:30]=[CH:31][CH:32]=3)[O:24][N:23]=2)[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:61][CH2:62][CH2:63][S:64]([OH:67])(=[O:66])=[O:65]>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([C:22]2[CH:26]=[C:25]([C:27]3[CH:28]=[C:29]([C:33]4[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=4)[CH:30]=[CH:31][CH:32]=3)[O:24][N:23]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:61][CH2:62][CH2:63][S:64]([OH:67])(=[O:66])=[O:65])=[O:18])=[CH:20][CH:21]=2)=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc([C@H](Cc2ccc(C(=O)O)cc2)c2cc(-c3cccc(-c4ccc(Cl)cc4)c3)on2)cc1
Reactant: NCCS(=O)(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc([C@H](Cc2ccc(C(=O)NCCS(=O)(=O)O)cc2)c2cc(-c3cccc(-c4ccc(Cl)cc4)c3)on2)cc1
Reaction time: 14 h

Procedure:
To a mixture of (S)-4-{2-(4-tert-Butyl-phenyl)-2-[5-(4′-chloro-biphenyl-3-yl)-isoxazol-3-yl]-ethyl}-benzoic acid (0.25 g, 0.46 mmol), EDCI (133 mg, 0.69 mmol), HOBt (107 mg, 0.69 mmol), N,N-diispropylethylamine (0.25 mL, 1.95 mmol) in DMF (10 mL), and followed by taurine (116 mg, 0.093 mmol) was added. The resulting mixture was stirred for 14 h and monitored by LCMS after completion of the reaction the solvent was removed under reduced pressure. The resulting mixture was purified by column chromatography on C-18, eluting with H2O/Acetonitrile 40% to afford (4-{2-(4-tert-Butyl-phenyl)-2-[5-(4′-chloro-biphenyl-3-yl)-isoxazol-3-yl]-ethyl}-benzoylamino)ethane sulfonic acid (29) as a white solid. (125 mg, 42%): 1H NMR (300 MHz, MeOD): 8.01 (s, 1H), 7.78 (d, J=6.9 Hz, 2H), 7.70-7.47 (m, 6H), 7.35 (d, J=9.0 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 6.86 (s, 1H), 4.47 (t, J=6.9 Hz, 1H), 3.85-3.70 (m, 2H), 3.75 (dd, J=4.9, 13.2 Hz, 1H), 3.25-3.05 (m, 2H), 1.31 (s, 9H); LC-MS m/z=643 [C36H35ClN2O5S]+; HPLC conditions: Waters Atlantis C-18 OBD 4.6×150 mm; mobile phase=ACN/(H2O:0.1TFA) flow rate=1.0 mL/min; detection=UV @ 254 and 220 nm retention time in min: 21.20; Anal Calcd: (MF: C36H35ClN2O5S+1.5H2O+0.2 CH2Cl2) Calcd: C, 63.27; H, 5.63; N, 4.08. Found: C, 63.24; H, 5.75; N, 3.96. αD[25] MeOH (4.66 mg in 1.0 mL)=+13.487.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:32])[C:10](=[C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24]2)[C:11]([C:13]2[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:32])[C:10](=[C:23]2[NH:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[NH:27]2)[C:11]([C:13]2[CH:14]=[C:15]([S:19]([NH:22][C:33](=[O:35])[CH3:34])(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzenesulfonamide (hereinafter referred to as starting compound B, 500 mg), acetic anhydride (5 mL), pyridine (10 mL) and DMF (20 mL) was heated with stirring at 55° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed with aqueous saturated sodium hydrogencarbonate solution and water successively. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)acetamide (58 mg).
Reaction SMILES: C(O[C:6](=O)[NH:7][CH:8]([C:10]1[N:14]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[C:13]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.ClC1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2C1CCCCO1.CCN(C(C)C)C(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(O)CCC.CO>[F:26][C:23]1[CH:24]=[CH:25][C:12]2[N:11]=[C:10]([CH:8]([NH:7][C:6]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][NH:33]4)[CH3:9])[N:14]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[C:13]=2[CH:22]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ncccc1F
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ncccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
A mixture of {1-[6-fluoro-1-(3-fluoropyridin-2-yl)-1H-benzoimidazol-2-yl]ethyl}-carbamic acid tert-butyl ester (84 mg, 0.22 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at RT for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford a dark orange oil. A mixture of this residue, 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (53 mg, 0.22 mmol) and DIPEA (110 μL, 0.63 mmol) in n-butanol (0.5 mL) was heated at 100° C. in a sealed vial for 16 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-60%, 0.1% NH4OH in acetonitrile/water) to afford 238 as a white solid (14 mg, 16%). LCMS (Method K): RT 3.09 min [M+H]+ 393.01. 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (1H, s), 8.07-7.81 (4H, m), 7.73 (1H, dd, J=8.86, 4.85 Hz), 7.56 (1H, s), 7.18-7.04 (2H, m), 5.68 (1H, s), 1.70 (3H, d, J=6.75 Hz)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[CH:17]=2)[N:12](COCC[Si](C)(C)C)[N:11]=1.C[CH2:36][O:37]CC>CO>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22](=[NH:23])[O:37][CH3:36])[CH:17]=2)[NH:12][N:11]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C#N)c3)cc12
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: COC(=N)c1cccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
HCl gas was bubbled through a suspension of 3-[3-(2-Methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzonitrile (40 mg, 0.088 mmol) in 2.5 ml of anhydrous MeOH for 3 minutes at 0° C. After stirring for 23 hours at room temperature, ether (10 mL) was added and precipitation occurred. The solid was collected after filtration and dried to afford methyl 3-(3-(2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzimidate as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([Cl:15])=[CH:7][C:8]([Cl:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].OS(O)(=O)=O.[N+:21]([O-])([OH:23])=[O:22]>>[C:1]([NH:4][C:5]1[C:13]([N+:21]([O-:23])=[O:22])=[C:9]([C:8]([Cl:14])=[CH:7][C:6]=1[Cl:15])[C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(C(=O)O)c(Cl)cc1Cl
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c(Cl)cc(Cl)c(C(=O)O)c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 81 %

Procedure:
5-Acetamido-2,4-dichlorobenzoic acid 1-4 (40.0 g, 0.161 mol) was added in portions to a cooled mixture of concentrated H2SO4 (400 mL) and concentrated nitric acid (400 mL) at 5° C. After stirring for 2 h concentrated H2SO4 (100 mL)/concentrated nitric acid (100 mL) was added. After another 90 min concentrated H2SO4 (400 mL)/concentrated nitric acid (200 mL) was added and stirring was continued for a further 2 h. The reaction mixture was cautiously poured onto ice resulting in the formation of a yellow precipitate. The product was collected by filtration then extracted into EtOAc. The combined organic layers were washed with H2O, brine, dried over Na2SO4, filtered and concentrated to provide the nitro compound 1-5 as a yellow/orange solid (38.1 g, 81% yield). 1H NMR (400 MHz, d6-DMSO) δ1.99 (s, 3H), 8.21 (s, 1H), 10.27 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2[F:20])[CH2:7][CH2:6]1)=[O:4]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[F:20])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)N1CCN(c2ccc(N)cc2F)CC1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of Example 119B (3.0 g, 10.59 mmol) in EtOAc (40 mL) was added 10% palladium on carbon (300 mg) and the solution was stirred under a balloon of H2 gas for 1.5 h. The solution was filtered through Celite, the catalyst washed with EtOAc, and the filtrate concentrated in vacuo to give the title compound (2.68 g, 10.59 mmol, 100%).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16](/[Cl:23])\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:4][CH3:5].CCN(CCOC1C=CC(/C(/C2C=CC=CC=2)=C(/Cl)\C2C=CC=CC=2)=CC=1)CC.C(C(O)(C(O)=O)CC(O)=O)C(O)=O>>[CH2:4]([N:3]([CH2:2][CH3:1])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16]([Cl:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH3:5]
Reactant: CCN(CC)CCOc1ccc(/C(=C(/Cl)c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CCN(CC)CCOc1ccc(C(=C(Cl)c2ccccc2)c2ccccc2)cc1

Procedure:
clomifene; chloramiphene; C26H28ClNO; mol. wt. 405.98, is as follows: ##STR1##
Reaction SMILES: C(NC1C(N)=CC(S(C(F)(F)F)(=O)=O)=CC=1)C.C(OC(=O)C(=O)C(OCC)=O)C.C([O:35][C:36]([C:38]1[N:42]([CH2:43][CH3:44])[C:41]2[CH:45]=[CH:46][C:47]([S:49]([C:52]([F:55])([F:54])[F:53])(=[O:51])=[O:50])=[CH:48][C:40]=2[N:39]=1)=[O:37])CCCC>C(O)CCCC.C(O)C.[OH-].[Na+]>[CH2:43]([N:42]1[C:41]2[CH:45]=[CH:46][C:47]([S:49]([C:52]([F:54])([F:53])[F:55])(=[O:50])=[O:51])=[CH:48][C:40]=2[N:39]=[C:38]1[C:36]([OH:37])=[O:35])[CH3:44]
Reactant: CCCCCOC(=O)c1nc2cc(S(=O)(=O)C(F)(F)F)ccc2n1CC
Agent: CCNc1ccc(S(=O)(=O)C(F)(F)F)cc1N
Agent: CCOC(=O)C(=O)C(=O)OCC
Agent: [Na+]
Solvent: CCCCCO
Solvent: CCO
Product: CCn1c(C(=O)O)nc2cc(S(=O)(=O)C(F)(F)F)ccc21
Temperature: 40 °C
Reaction time: 2 h

Procedure:
N1-Ethyl-4-trifluoromethanesulfonyl-benzene-1,2-diamine (134 mg, 0.50 mmol) and 2-oxo-malonic acid diethyl ester (91 μL, 1.2 equiv) were dissolved in 0.7 mL dry pentanol and heated to reflux for 24 h. The reaction mixture was then evaporated by blowing with a stream of nitrogen while heating, the oil was then placed under full vacuum for at least 20 h whereupon a low melting solid began to form. 1-Ethyl-5-trifluoromethanesulfonyl-1H-benzoimidazole-2-carboxylic acid pentyl ester 1HNMR (400 MHz, d6-DMSO) δ 8.52 (d, J=2.0 Hz, 1H), 8.30 (dd, J=9.2, 2.0 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H), 4.37 (t, J=6.6 H 4.31 (q, J=7.2 Hz, 2H), 1.71 (m, 2H), 1.37 (m, 4H), 1.27 (t, J=7.4 Hz, 3H), 0.89 (T, J=7.0 Hz, 3H); LCMS-APCI m/z 393 [M+1]+. This pentyl ester was used directly (85 mg, 0.217 mmol) and dissolved in warm ethanol (3 mL) with the addition of 1 M sodium hydroxide (1 mL). The reaction mixture was warmed to 40° C. and stirred for 2 h. The reaction mixture was then partially evaporated by blowing with a stream of nitrogen and transferred to a vial containing chloroform and water. The two phases were shaken together, the organic phase was removed, and the process repeated once with additional chloroform. To the aqueous phase was added ethyl acetate, the mixture was acidified with 3 M aqueous hydrochloric acid to pH 2.5, and the organic phase was separated, washed with saturated brine, dried (Na2SO4) and evaporated to yield the acid 42: 1HNMR (400 MHz, d6-DMSO) 8 14.3 (br s, 1H), 8.51 (d, J=2.35 Hz, 1H), 8.30 (dd, J=9.06, 2.28 Hz, 1H), 8.07 (d, J=9.09 Hz, 1H), 4.31 (q, J=7.14 Hz, 2H), 1.28 (t, J=7.10 Hz, 3H); LCMS-APCI m/z [M−1]− 321.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:16][CH2:17]2)[N:1]=[C:28]([CH3:35])[C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: COc1ccc(CN2CCC(COc3cccc(N)c3C#N)CC2)cc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCN(Cc4ccc(OC)cc4)CC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-((1-(4-methoxybenzyl)piperidin-4-yl)methoxy)benzonitrile (Example 125b) and ethyl 3-oxobutanoate as an off-white solid (30%). 1H NMR (400 MHz, DMSO-d6) δ 1.29-1.33 (m, 5H), 1.74 (m, 2H), 1.92 (m, 3H), 2.54 (s, 3H), 2.83 (m, 2H), 3.38 (s, 2H), 3.71 (s, 3H), 4.04 (d, J=8.0 Hz, 2H), 4.31 (q, J=8.0 Hz, 2H), 6.86 (d, J=8.0 Hz, 2H), 6.90 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 8.04 (brs, 2H). MS 464 (MH+).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]([OH:44])[CH3:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]([OH:44])[CH3:43])[C:38]2=[N:45][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:49][CH2:50]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(C)O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1C(C)O)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 66.4 %

Procedure:
Prepared in 66.4% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-5-(1-hydroxyethyl)-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.95 (s, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.23 (dd, J=9.4, 2.6 Hz, 1H), 7.19-7.14 (m, 2H), 6.44 (d, J=9.8 Hz, 1H), 5.57 (s, 1H), 5.29-5.15 (m, 1H), 4.70-4.58 (m, 1H), 3.84 (br. s., 2H), 3.56-3.42 (m, 3H), 2.68-2.58 (m, 1H), 2.33 (s, 3H), 1.99-1.53 (m, 10H), 1.50 (d, J=6.5 Hz, 3H), 1.20 (s, 3H), 1.12 (s, 9H), 1.09 (d, J=6.0 Hz, 3H); LCMS (ESI, M+1): 688.3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1
Reactant: C1=COCCC1
Reactant: COC(=O)c1cnc(CCO)cn1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cnc(CCOC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(2-hydroxyethyl)pyrazine-2-carboxylate (1.07 g) in dichloromethane (20 mL) were added 3,4-dihydro-2H-pyrane (1.6 mL) and pyridinium p-toluenesulfonate (295 mg) at room temperature, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:2) to obtain methyl 5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyrazine-2-carboxylate (1.25 g) as a pale yellow oily substance.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CN(C=O)C>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(F)c(F)cc(C(=O)O)c1F
Solvent: CN(C)C=O
Product: Cc1c(F)c(F)cc(C(=O)Cl)c1F

Procedure:
A mixture of 2,4,5-trifluoro-3-methylbenzoic acid (6.0 g), thionyl chloride (26 ml) and DMF (0.01 ml) was refluxed for 4 hours. Then excess thionyl chloride was removed under reduced pressure, the resulting residue was distilled under reduced pressure to give the title compound (4.51 g) as pale yellow liquid, bp 90°-92° C./40 mmHg.
Reaction SMILES: [CH3:1][P@@:2]([NH:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[O:13])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].C[O:20]C(=O)[C@@H](CC(C)C)N[P@](C)(C1C=CC=CC=1)=O.NO[K].Cl>>[OH:20][NH:14][C:12](=[O:13])[C@H:11]([NH:10][P@:2]([CH3:1])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3])[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CC(N[P@@](C)(=O)c1ccccc1)C(N)=O
Reactant: COC(=O)[C@@H](CC(C)C)N[P@@](C)(=O)c1ccccc1
Agent: Cl
Agent: NO[K]
Product: CC(C)C[C@@H](N[P@@](C)(=O)c1ccccc1)C(=O)NO
Reaction time: 6 h

Procedure:
N-Hydroxy-2)-[[(S)-methylphenylphosphinyl]amino]-4-methylpentanamide: N-((S)-Methylphenylphosphinyl)-D-leucine methyl ester (55 mg, 0.19 mmol) is treated with a solution of NH2OK (0.57 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478. The reaction is stirred for 6 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The residue is purified by silica gel flash chromatography (80:20 ethyl acetate:ethanol) followed by crystallization from ethyl acetate/hexane to give N-hydroxy-2(R)-[[(S)-methylphenylphosphinyl]amino]-4-methylpentanamide as a colorless solid: MS-IS m/z 285 [M+H]+.(R1 =H, R2 =isobutyl, R3 =methyl, R4 =phenyl).