Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[F:22])([CH3:14])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=3)[N:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1F
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccccc2F)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(2-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester by the procedure of Example 26. 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H, J=8.60 Hz), 7.12-6.96 (m, 4H), 6.79 (d, 2H, J=8.60 Hz), 4.15 (t, 2H, J=6.65 Hz), 3.26 (d, 1H, J=14.08 Hz), 3.19 (d, 1H, J=14.08 Hz), 2.98-2.80 (m, 2H), 2.32 (s, 3H), 2.02 (d, 2H, J=10.95 Hz), 1.81 (d, 2H, J=12.90 Hz), 1.70 (d, 1H, J=12.90 Hz), 1.85 (q, 2H, J=11.73 Hz), 1.40 (s, 3H), 1.39-1.23 (m, 3H). HRMS (ES+) m/z exact mass calcd for C28H33FNO5 482.2343, found 482.2349.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7](Cl)(=[O:9])=[O:8].[NH2:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>>[Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7]([NH:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cc(Cl)sc1Cl
Yield: 65.6 %

Procedure:
Prepared according to the procedure described for Example 127 using 2,5-dichlorothiophene-3-sulfonyl chloride (0.75 g, 3.0 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (0.73 g, 3.0 mmol) to afford the product (0.9 g); m.p. 189-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][N:4]=1.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:9][C:7]1[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1ccc(-c2cnc(OC)cc2C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2cnc(OC)cc2CBr)cc1
Reaction time: 48 h
Yield: 103.2 %

Procedure:
According to Scheme 31 Step 2: To a solution of 2-methoxy-5-(4-methoxyphenyl)-4-methylpyridine (2.20 mmol, 0.50 g, Example 48 Step 1) in CCl4 (10 mL) was added NBS (2 eq, 4.40 mmol, 0.78 g). The reaction was then heated to reflux and subjected to UV light for 48 hours. The reaction was allowed to cool, filtered and concentrated under reduced pressure to afford crude 4-(bromomethyl)-2-methoxy-5-(4-methoxyphenyl)pyridine (0.70 g) as a yellow oil which was used without any purification in the next step.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:14]=1[C:15]#[N:16]>>[Cl:12][C:13]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: N#Cc1cc(O)ccc1Cl
Product: N#Cc1cc(Oc2ccc(C=O)cc2C#N)ccc1Cl

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-chloro-5-hydroxybenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11]([CH3:14])(=[O:13])=[O:12].[BH4-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[S:11]([CH3:14])(=[O:12])=[O:13]
Reactant: CC(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A round bottom flask was charged with 1-(4-chloro-3-(methylsulfonyl)phenyl)ethanone (12.0 g, 50.0 mmol) and tetrahydrofuran (100 mL) at 0° C. Sodium borohydride (3.7 g, 100 mmol) was added in portions and the reaction was stirred for 12 h at room temperature. The reaction was quenched with ice and extracted with MTBE. The organic solvents were removed under reduced pressure and the residue was purified by flash chromatography to get the title compound.
Reaction SMILES: [Cl-].[Li+].C([Li])CCC.P(=O)([O-])OC(CC)(CC)Cl.[C:18]([O:21][CH:22]1[CH:31]2[O:32][C:33]([CH3:36])([CH3:35])[O:34][C:30]32[CH:25]([CH:26]([C:38](=O)[CH3:39])[CH2:27][CH2:28][CH:29]3[CH3:37])[CH:24]=[C:23]1[CH3:41])(=[O:20])[CH3:19].[C:42]([Cl:46])(Cl)(Cl)[Cl:43]>O1CCCC1>[C:18]([O:21][C@H:22]1[C@@H:31]2[O:32][C:33]([CH3:36])([CH3:35])[O:34][C@@:30]32[C@@H:25]([C@H:26]([C:38]([CH3:39])=[C:42]([Cl:46])[Cl:43])[CH2:27][CH2:28][C@H:29]3[CH3:37])[CH:24]=[C:23]1[CH3:41])(=[O:20])[CH3:19]
Reactant: CC(=O)OC1C(C)=CC2C(C(C)=O)CCC(C)C23OC(C)(C)OC13
Reactant: ClC(Cl)(Cl)Cl
Agent: CCC(Cl)(CC)O[PH](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)=C(Cl)Cl)CC[C@@H](C)[C@@]23OC(C)(C)O[C@@H]13
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To dry lithium chloride (1.0 g) in tetrahydrofuran (45 ml) was added n-butyllithium (4.75 ml) at 0° C. under a nitrogen atmosphere. The mixture was stirred for 10 min and then cooled to −78° C. before adding diethylchloromethyl phosphonate (1.85 ml) in tetrahydrofuran (13 ml). After stirring for 10 min, carbon tetrachloride (1.15 ml) in tetrahydrofuran (13 ml) was added. After stirring for a further 10 min, a solution of 3aS,4R,6aS,7R,10S,10aS)-7-acetyl-2,2,5,10-tetramethyl-4,6a,7,8,9,10-hexahydro-3aH-naphtho[1,8a-d][1,3]dioxol-4-yl acetate (Preparation 148, 2 g) in tetrahydrofuran (13 ml) was added and the solution was stirred for 2 h at −78° C. After this time the mixture was quenched into water (50 ml) and extracted with diethyl ether (3×50 ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give an orange oil. The oil was purified by flash, chromatography using a Biotage® cartridge (90 g) to give the title compound as a transparent oil (1.05 g, 45%).
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[CH2:9]([O:16][N:17]1[C:23](=[O:24])[N:22]2[CH2:25][CH:18]1[CH2:19][CH2:20][CH:21]2/[CH:26]=[N:27]/[OH:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:29]([Si:31]([CH3:34])([CH3:33])[CH3:32])#[CH:30].CCN(C(C)C)C(C)C>N1C=CC=CC=1.C(Cl)Cl>[CH2:9]([O:16][N:17]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:18]1[CH2:19][CH2:20][C@H:21]2[C:26]1[CH:30]=[C:29]([Si:31]([CH3:34])([CH3:33])[CH3:32])[O:28][N:27]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1N2CC(CCC2/C=N/O)N1OCc1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)c1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 39.6 %

Procedure:
NCS (290 mg, 2.17 mmol) and pyridine (2 drops) were added to a solution of (E)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbaldehyde oxime (560 mg, 2.04 mmol) in dry DCM (15 mL). The reaction mixture was stirred at rt for about 3-4 hrs. Ethynyltrimethylsilane (240 mg, 2.44 mmol) was added, then a solution of DIPEA (290 mg, 2.24 mmol) in dry DCM (5 mL) was added slowly over a 0.5 h period. After addition, the reaction mixture was stirred at rt overnight. The reaction mixture was then washed with 10% citric acid, water, saturated sodium chloride (10 mL), dried and concentrated. The residue was purified by silica gel column chromatography (10:1 petroleum ether/EtOAc) to afford (2S,5R)-6-(benzyloxy)-2-(5-(trimethylsilyl)isoxazol-3-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (300 mg, 41%) as a colorless oil. ESI-MS (EI+, m/z): 372 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[CH:16]=[C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:9]([C:10]([O:12]CC)=O)=[CH:8][N:7]=1)[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C[Al](C)C>C1COCC1>[CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[CH:16]=[C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:9]([C:10]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:12])=[CH:8][N:7]=1)[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCNC(=O)Nc1cc(Nc2cccnc2)c(C(=O)OCC)cn1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(Nc2cccnc2)c(C(=O)Nc2ccccc2)cn1
Temperature: 125 °C
Yield: 40.9 %

Procedure:
A solution of ethyl 6-(3-ethylureido)-4-(pyridin-3-ylamino)nicotinate (0.60 g, 1.82 mmol) and aniline (250 μL, 2.73 mmol) in THF (10 mL) was purged with nitrogen for 15 minutes. To this solution was added trimethylaluminium (2M in toluene, 5.40 mL, 10.80 mmol) dropwise over 10-15 min. The reaction mixture was heated at 125° C. for 30 min in a microwave reactor. The reaction mass was then quenched with water and extracted with EtOAc (3×1000 mL). The organics were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue thus obtained was purified by preparative HPLC to afford Compound 13 (0.28 g, 41%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.89 (s, 1H), 9.15 (s, 1H), 8.59 (s, 1H), 8.54 (s, 1H), 8.35 (d, J=4.8 Hz, 1H), 7.93 (br s, 1H), 7.73 (t, J=8.0 Hz, 3H), 7.45-7.41 (m, 1H), 7.37 (t, J=7.6 Hz, 2H), 7.23 (s, 1H), 7.13 (t, J=7.6 Hz, 1H), 3.16-3.13 (m, 2H), 1.08 (t, J=7.2 Hz, 3H). [M+H]+ m/z=377.22.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.[CH3:26][C:27]([S:30](Cl)=[O:31])([CH3:29])[CH3:28]>C(Cl)Cl>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:30]([C:27]([CH3:29])([CH3:28])[CH3:26])=[O:31])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: CC(C)(C)S(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)S(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 43.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.450 g, 1.22 mmol), 2-methylpropane-2-sulfinic chloride (0.205 g, 1.46 mmol), TEA (2.0 mL), DCM (10 mL) to afford 0.250 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.23 (s, 9H), 4.24 (m, 2H), 7.63-7.87 (m, 4H), 7.86 (d, J=8.7 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H); MS (m/z): 472.095 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][CH2:11][C:12]([NH:14][N:15]1[C:19]([C:20]([NH2:22])=[O:21])=[CH:18][N:17]=[CH:16]1)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.CCO>[CH2:3]([O:10][CH2:11][C:12]1[NH:22][C:20](=[O:21])[C:19]2=[CH:18][N:17]=[CH:16][N:15]2[N:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)c1cncn1NC(=O)COCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c(COCc2ccccc2)nn2cncc12
Temperature: 110 °C
Yield: 71.9 %

Procedure:
A solution of KOH (4.4 g, 78.5 mmol) in water (50 mL) was added dropwise to a solution of compound 3 (7.3 g, 26.6 mmol) in EtOH (60 mL) at room temperature. The resulting solution was heated to 110° C. for 3 hours. After removal of the organic solvent, the mixture was poured into ice water and the pH was adjusted to 7.0 with 1M aqueous HCl solution. The suspension was filtered and the filtrate was dried to afford compound 4 (4.9 g, 71% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.05 (s, 1H), 8.45 (s, 1H), 7.74 (s, 1H), 7.39˜7.29 (m, 5H), 4.59 (s, 2H), 4.36 (s, 2H). LC-MS: m/z 257.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[N:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cn(C)c(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(C(=O)O)nc1-c1ccccc1
Yield: 94.9 %

Procedure:
0.6 g of ethyl 1-methyl-2-phenyl-1H-4-imidazolecarboxylate was dissolved in 10 ml ethanol and 1 ml of 5N sodium hydroxide was added, followed by heating under reflux for 1 hour. The reaction solution was ice-cooled and neutralized with 2N hydrochloric acid, followed by extracting with ethyl acetate and tetrahydrofuran. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give 0.5 g of 1-methyl-2-phenyl-1H-4-imidazolecarboxylic acid.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:23])([CH2:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:6]1=[O:24])[CH2:2]CC.[Cl:25]C1C=C2C(=CC=1)N(CC)C(=O)C2=O.C(C1C=CC=CN=1)(=O)C>>[Cl:25][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:1][CH3:2])[C:6](=[O:24])[C:7]2([OH:23])[CH2:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CCN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Agent: CC(=O)c1ccccn1
Product: CCN1C(=O)C(O)(CC(=O)c2ccccn2)c2cc(Cl)ccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 5-chloro-1-ethylindoline-2,3-dione and 2-acetyl pyridine (purchased from Fisher Scientific). 1H-NMR δ 8.70 (ddd, 1H), 8.11 (dd, 1H), 7.93 (ddd, 1H), 7.57 (ddd, 1H), 7.31-7.27 (m, 2H), 6.79 (d, 1H), 5.5 (bs, OH), 3.77 (d, 1H), 3.74 (m, 2H), 3.53 (d, 1H), 1.27 (t, 3H). calculated mass for C17H15ClN2O3, 330.08, observed, 331.0 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]=[C:23]3[CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]#[N:13])[CH:8]=[CH:7]2.C([Li])CCC.[CH:34](=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37]>C1COCC1>[OH:39][CH:34]([C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]=[C:23]3[CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]#[N:13])[CH:8]=[CH:7]2)[CH2:35][CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)C1=NCCc2ccc(C=Cc3cc(I)c4cc(C#N)ccc4c3)cc21
Reactant: CC(C)CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CC(O)c1cc(C=Cc2ccc3c(c2)C(C(C)C)=NCC3)cc2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of Example 8E (250 mg, 0.52 mmol) in THF (5 mL) at −90° C. was treated with 2.5M n-butyllithium in hexanes (0.210 mL, 0.525 mmol), stirred for 2 minutes, treated with isovaleraldehyde (0.056 mL, 0.63 mmol), and stirred for 30 minutes. The reaction was warmed to room temperature, quenched with water, and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 25% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [F:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[C:14]([C:29]([F:32])([F:31])[F:30])[CH:13]=2)[CH2:8][O:7]C(C)=[N:5]1.[ClH:33]>C(O)C>[ClH:33].[NH2:5][C:4]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)=[C:14]([C:29]([F:30])([F:31])[F:32])[CH:13]=1)([CH2:3][CH2:2][F:1])[CH2:8][OH:7]
Reactant: CC1=NC(CCF)(CCc2ccc(OCCCc3cccc(C)c3)c(C(F)(F)F)c2)CO1
Agent: Cl
Solvent: CCO
Product: Cc1cccc(CCCOc2ccc(CCC(N)(CO)CCF)cc2C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Compound 107-1 (230 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diisopropyl ether to give the object product (230 mg) as a white powder.
Reaction SMILES: C(O)(C(F)(F)F)=O.[BH4-].[Na+].[Cl:10][C:11]1[C:12]([OH:45])=[C:13]([S:18]([N:21]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29](O)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)(=[O:20])=[O:19])[CH:14]=[C:15]([Cl:17])[CH:16]=1>C(Cl)Cl>[CH2:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:21]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)[S:18]([C:13]2[CH:14]=[C:15]([Cl:17])[CH:16]=[C:11]([Cl:10])[C:12]=2[OH:45])(=[O:19])=[O:20])=[CH:28][CH:27]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1ccc(C(O)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1ccc(Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of TFA (1 mL) at 0° C. was added sodium borohydride (14 mg, 0.037 mmol), followed by 3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxy-N-(4-(hydroxy(phenyl)methyl)benzyl)benzenesulfonamide (10 mg, 0.018 mmol) in DCM (0.5 mL). The resulting mixture was stirred at 0° C. for 0.5 h. The solvent was removed and the residue was carefully quenched by the addition of MeOH. The mixture was purified by preparative HPLC to give the title compound (6 mg) as a white solid. MS (ESI): 530.1 (M+H)+.
Reaction SMILES: ON1C(=O)CCC1=O.[NH:9]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@@H:10]([C:38](O)=[O:39])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:37])[N:16]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[NH2:51][CH2:52][C:53]([OH:55])=[O:54]>>[NH:9]([C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[C@@H:10]([C:38]([NH:51][CH2:52][C:53]([OH:55])=[O:54])=[O:39])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:37])[N:16]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: NCC(=O)O
Reactant: N=C(NCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: O=C1CCC(=O)N1O
Product: N=C(NCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)O)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Yield: 87 %

Procedure:
Cbz-D-Arg(Cbz)2-Gly-OH is prepared according to Example 1 by coupling the N-hydroxysuccinimide active ester of Cbz-D-Arg(Cbz)2-OH to glycine in a yield of 87%.
Reaction SMILES: [Na].C1(C[O:9][C:10](=[O:29])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][S:18]([NH:21]CC2C=CC=CC=2)(=[O:20])=[O:19])C=CC=CC=1.Cl.C>CO.[Pd].C1COCC1>[NH2:21][S:18]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([OH:29])=[O:9])(=[O:20])=[O:19]
Reactant: O=C(OCc1ccccc1)c1ccccc1OS(=O)(=O)NCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)Oc1ccccc1C(=O)O
Reaction time: 4 h
Yield: 39.4 %

Procedure:
To a suspension of 2-[[(phenylmethyl)aminosulfonyl]oxy]benzoic acid (phenylmethyl)ester sodium salt (35.3 g, 0.076 mole) in methanol (500 ml) was added 6.2 ml of concentrated hydrochloric acid and 2 g of 5% palladium on carbon catalyst wetted with methanol (50 ml). The mixture was hydrogenated for 4 hr and filtered. The filtrate was concentrated to an oil and resuspended in THF. The solids were removed by filtration and the filtrate concentrated. The residue was triturated with 1,1,1-trichloroethane, giving 8.82 g of light purple solid. The solid was dissolved in THF, treated with activated charcoal, filtered, and concentrated again. The residue was recrystallized from 1,1,1-trichloroethane to give 6.5 g of white solid, mp 139°-140° C.
Reaction SMILES: [P:1]([CH2:14][CH2:15][CH2:16][PH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([P:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:25]=[CH2:26].CC(N=NC(C#N)(C)C)(C#N)C>>[P:1]([CH2:14][CH2:15][CH2:16][P:17]([CH2:26][CH2:25][CH2:24][P:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(PCCCP(c2ccccc2)c2ccccc2)cc1
Reactant: C=CCP(CC)CC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCP(CC)CCCP(CCCP(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 210 °C
Reaction time: 20 h

Procedure:
Ph2P(CH2)3P(H)Ph (3.68 g, 10.9 mmol), allyldiethylphosphine (1.71 g, 13.1 mmol) and AIBN (0.011 g) were mixed in a Schlenk flask and radiated with a 365 nm UV lamp for 20 hours. After confirming that the reaction was complete by 31P NMR analysis, it was distilled under vacuum (<0.5 mm Hg) at a final heating mantle temperature of 210° C. for an hour to remove impurities. The ligand remained in the pot. Yield: 3.36 g (66%). 31P NMR (122 MHz, CDCl3, δ, ppm): −16.74 (s), −23.09 (s) and −25.98 (s). There are peaks near the three major peaks, which have not been determined if are part of the ligand or due to impurities. 1H NMR (500 MHz, CDCl3, δ, ppm): 1.001 (d of q, JH-P&H=7.0 Hz 4H's methylenes of ethyl groups), 1.3 to 2.2 (m, H's on methyls and propylenes) (d of t, JH-P&H=211 & 6.6 Hz, H on the P), and 7.30 to 7.47 (m, 15H's on phenyl rings).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([F:14])=[C:12]([NH2:15])[CH:11]=[CH:10][N:9]=1.[Cl-].[NH4+]>>[F:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][C:12]=1[NH2:15]
Reactant: Nc1ccnc(Cl)c1F
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1ccnc(N2CCOCC2)c1F

Procedure:
Morpholine (3 ml) was added to 2-chloro-3-fluoropyridin-4-amine (133 mg) obtained in the 2nd step, followed by microwave irradiation (Initiator™, 180° C., 20 minutes, 2.45 GHz, 0-240 W). A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with a saturated ammonium chloride aqueous solution and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. A light brown solid of 3-fluoro-2-morpholinopyridin-4-amine (153 mg) was thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]2[C:16]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:17][CH:18]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:20]=2)[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[C:16]([N:24]3[CH2:25][CH2:26][N:27]([C:4]([C:3]4[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:2]=4[F:1])=[O:6])[CH2:28][CH2:29]3)=[N:17][CH:18]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:20]=2)[CH2:13][CH2:14]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: O=C(O)c1ccc(I)cc1F
Product: O=C(c1ccc(I)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 92.9 %

Procedure:
Using 2-fluoro-4-iodobenzoic acid (2.027 g) and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (1.85 g) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (3.47 g) was obtained.