Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([CH2:35][C@H:36]([OH:58])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([O:45]CC2C=CC=CC=2)=[C:41]([NH:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH:40]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:34]=[CH:33][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[OH:58][C@H:36]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([NH:53][S:54]([CH3:57])(=[O:55])=[O:56])[CH:40]=1)[CH2:35][NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:34]=[CH:33][C:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)NCCc4c[nH]c5ccccc45)cc3)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN[C@H]2CC[C@H](c3ccc(C(=O)NCCc4c[nH]c5ccccc45)cc3)CC2)ccc1O
Reaction time: 3 h

Procedure:
A suspension of 0.246 g (0.3 mmol) of trans-4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}-N-[2-(1H-indol-3-yl)ethyl]benzamide and of 0.332 g of palladium-on-charcoal (10% Pd, 50% in water) in a mixture of 5.4 ml of ethanol and 4 ml of tetrahydrofuran is placed under hydrogen atmosphere and is stirred for 3 h. The catalyst is subsequently filtered off and the solvents are evaporated under reduced pressure. The title compound is obtained in the form of a white solid (0.076 g, 40%) after purification on silica gel (eluent: dichloromethane/methanol/aqueous ammonia 99/1/0.1 to 85/15/1.5 gradient in 30 min).
Reaction SMILES: C([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:24]=[C:25]([C:30]4[S:34][C:33]([C:35]([OH:41])([CH3:40])[C:36]([F:39])([F:38])[F:37])=[N:32][CH:31]=4)[CH:26]=[C:27]([CH3:29])[CH:28]=3)[N:17]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1.Cl>CO>[CH3:29][C:27]1[CH:28]=[C:23]([NH:22][C:18]2[N:17]=[C:16]([O:15][CH:12]3[CH2:11][CH2:10][CH:9]([OH:8])[CH2:14][CH2:13]3)[CH:21]=[CH:20][N:19]=2)[CH:24]=[C:25]([C:30]2[S:34][C:33]([C:35]([OH:41])([CH3:40])[C:36]([F:38])([F:39])[F:37])=[N:32][CH:31]=2)[CH:26]=1
Reactant: Cc1cc(Nc2nccc(OC3CCC(OCc4ccccc4)CC3)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Agent: Cl
Solvent: CO
Product: Cc1cc(Nc2nccc(OC3CCC(O)CC3)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Reaction time: 4 h
Yield: 28.6 %

Procedure:
To 2-(5-{3-[(4-{[4-(benzyloxy)cyclohexyl]oxy}pyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-1,1,1-trifluoropropan-2-ol (Example 94B-3, 0.12 g, 0.21 mmol) was added methanol (0.70 mL) and concentrated hydrochloric acid (6.2 μL, 0.21 mmol). The solution was evacuated and then purged with argon 5 times. 10% Palladium on carbon (0.002 g) was added and the solution was evacuated and then purged with argon 3 times. A balloon filled with hydrogen was placed on top of the reaction and the reaction was evacuated and then backfilled with hydrogen 3 times. The reaction was stirred for four hours. The solution was then filtered carefully through celite. The filtrate was concentrated and purified by reverse phase HPLC (10-100% acetonitrile gradient with water over 12 minutes with a 0.05% trifluoroacetic acid buffer) to afford 4-{[2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}cyclohexanol (30 mg, 0.06 mmol, 30%) as a 60:40 mixture of diastereomers. MS ESI: [M+H]+ m/z 494.7. The following NMR data for the major isomer: 1H NMR (500 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.22-8.15 (m, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.68-7.60 (m, 2H), 7.11 (s, 1H), 6.31-6.13 (m, 1H), 5.08-4.93 (m, 1H), 4.65-4.53 (m, 1H), 3.54-3.42 (m, 1H), 2.33 (s, 3H), 2.09-1.98 (m, 1H), 1.91-1.72 (m, 5H), 1.59-1.37 (m, 2H), 1.32-1.19 (m, 2H), 1.12-1.03 (m, 1H). rhSYK activity=+++
Reaction SMILES: ClC1[N:3]=[N:4]C(C)=CC=1.[C:9]1([CH2:15][C:16]#[N:17])C=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2-].[Na+].C1(C(C2N=NC=CC=2)C#N)C=CC=CC=1>C1C=CC=CC=1>[CH3:13][C:12]1[N:4]=[N:3][C:9]([CH2:15][C:16]#[N:17])=[CH:10][CH:11]=1
Reactant: N#CCc1ccccc1
Reactant: Cc1ccc(Cl)nn1
Agent: N#CC(c1ccccc1)c1cccnn1
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(CC#N)nn1

Procedure:
To a solution of 6.5 g (0.05 mole) of 3-chloro-6-methylpyridazine and 7.0 g (0.06 mole) of phenylacetonitrile in 50 ml of dry benzene was gradually added 4.0 g of pulverized sodium amide. The mixture was then slowly heated to 80° to 90° C. and maintained at this temperature for one hour. The reaction mixture was thereafter treated in the same manner as in the preparation of 2-phenyl-2-(3-pyridazinyl)-acetonitrile (see Example 1). The resulting product was recrystallized from a mixture of ethanol and isopropyl ether, giving 6.0 g (58% yield) of 2-phenyl-2-(6-methyl-3-pyridazinyl acetonitrile as pale yellow crystals, m.p. 121°-122° C. (decomp.).
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.S(Cl)([Cl:14])=O>CN(C)C=O>[Cl:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1
Reactant: Cc1cnc(O)c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)c([N+](=O)[O-])c1

Procedure:
5 g of 2-hydroxy-5-methyl-3-nitropyridine are dissolved in 32 cm3 of thionyl chloride to which 2 cm3 of N,N-dimethylformamide have been added. The mixture is then brought to reflux for 2 hours. After removing the solvent under partial vacuum, the product is distributed between distilled water (30 cm3) and chloroform (3×100 cm3). The chloroform fractions are combined, dried over MgSO4, filtered and then concentrated under vacuum. The residue is recrystallized from ethanol/water. Yd.: 60-65%
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7].[BH4-].[Li+]>C1COCC1>[OH:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH:12]=[CH:11][N:10]=1)(=[O:7])=[O:8]
Reactant: COC(=O)CCS(=O)(=O)c1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NCc1ccnc(S(=O)(=O)CCCO)c1)c1cncc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a room temperature solution of 3-[4-({[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-methyl)-pyridine-2-sulfonyl]-propionic acid methyl ester (33 mg, 0.066 mmol) in THF (5 mL) was added lithium borohydride (8.6 mg, 0.40 mmol). The mixture was then warmed at reflux. After 1 hour, the reaction was cooled to room temperature, quenched with water (50 mL) and diluted with EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in CH2Cl2. The residue was further purified by reversed-phase HPLC. The desired fractions were combined and lyophilized to afford the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(Cl)(=O)C(Cl)=O.[C:20]1([C@@H:30]([NH2:32])[CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[C:20]1([C@@H:30]([NH:32][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:13][CH:12]=2)[CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: C=CCOc1ccc(C(=O)O)cc1
Reactant: C[C@H](N)c1cccc2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCOc1ccc(C(=O)N[C@@H](C)c2cccc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Allyloxybenzoic acid (2.0 g, 0.011 mole) was stirred in a mixture of 3 equivalents of oxalyl chloride, 25 mL of anhydrous methylene chloride and one drop of dimethylformamide (DMF) at room temperature for 2 hours. The solvent and excess oxalyl chloride were removed under vacuum. Benzene (10 mL) was added and the material was again subjected to vacuum distillation to remove the remaining traces of oxalyl chloride. The remaining light yellow oil was dissolved in 25 mL of anhydrous methylene chloride, and the resulting solution was added dropwise to an ice cold, stirring solution of 2 g (0.012 mole) of (S)-1-(1-naphthyl)ethylamine (Aldrich) and 1 equivalent of triethylamine in 50 mL of anhydrous methylene chloride. The mixture was stirred at 0° C. for 2 h and at room temperature for 1 h. The resulting methylene chloride solution was washed successively with 0.1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then with water. The phases were separated, and the aqueous phase was extracted twice with 50 mL portions of methylene chloride. The methylene chloride phases were combined, dried over anhydrous magnesium sulfate, and the solvent was removed to give (S)-N-1-(1-naphthyl)ethyl-4-allyloxybenzamide as a crude solid. The solid was recrystallized from absolute ethanol to give white crystals, 2.25 g (62%); mp 141°-143° C.; [α]D25 +58.18° (c=0.373, CHCl3); IR (KBr): 3220 and 1625 cm-1 ; NMR (δ): 1.80 (3H, d, J=7.5 Hz), 4.56 (2H, d, J=5 Hz), 5.24-5.56 (2H, m,), 5.86-6.20 (2H, m), 6,36 (1H, q, J=6 Hz), 6.80-7.00 (2H, m); 7.40-8.28 (9H, m). Anal. for C22H21NO2 : Calcd: C, 79.75; H, 6.34, N, 4.22. Found: C, 79.62; H, 6.40; N, 4.44.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[S:8][C:9]([C:34]#[C:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][OH:39])=[CH:10][C:11]=1[N:12]([C:25]([CH:27]1[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]1)=[O:26])[CH:13]1[CH2:18][CH2:17][CH:16]([O:19][CH:20]2[CH2:24][CH2:23][O:22][CH2:21]2)[CH2:15][CH2:14]1)=[O:6]>CO.C1COCC1>[OH:39][CH2:38][CH2:37][C:36]([CH3:40])([CH3:41])[C:35]#[C:34][C:9]1[S:8][C:7]([C:5]([OH:6])=[O:4])=[C:11]([N:12]([C:25]([CH:27]2[CH2:28][CH2:29][CH:30]([CH3:33])[CH2:31][CH2:32]2)=[O:26])[CH:13]2[CH2:14][CH2:15][CH:16]([O:19][CH:20]3[CH2:24][CH2:23][O:22][CH2:21]3)[CH2:17][CH2:18]2)[CH:10]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)CCO)cc1N(C(=O)C1CCC(C)CC1)C1CCC(OC2CCOC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)CCO)sc2C(=O)O)C2CCC(OC3CCOC3)CC2)CC1
Yield: 34 %

Procedure:
NaOH (0.500 mL of a 1.0 N aqueous solution) was added dropwise to a solution of 5-(5-hydroxy-3,3-dimethyl-pent-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(tetrahydro-furan-3-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester (157 mg, 0.28 mmol) in methanol (1.5 mL) and THF (1.5 mL) at room temperature. The reaction was stirred until TLC indicated that all of the starting material was consumed. The reaction was evaporated to dryness to give a solid residue that was purified by column chromatography on reverse phase C18 silica gel (100% water to 5% acetonitrile/water). Fractions containing product were pooled and evaporated to provide 5-(5-hydroxy-3,3-dimethyl-pent-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(tetrahydro-furan-3-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid (Compound 314)(52 mg, 33%) as a solid. MS (m/z): 546.0 [M+H]+; HPLC retention time 3.75 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[C:13](=O)[N:12]2[N:15]=[C:16]([CH3:18])[CH:17]=[C:11]2[NH:10][C:9]=1[CH3:19].P(Cl)(Cl)([Cl:22])=O.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl>[Br:7][C:8]1[C:9]([CH3:19])=[N:10][C:11]2[N:12]([N:15]=[C:16]([CH3:18])[CH:17]=2)[C:13]=1[Cl:22]
Reactant: Cc1cc2[nH]c(C)c(Br)c(=O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2nc(C)c(Br)c(Cl)n2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
Pyridine (0.179 mL, 2.22 mmol) was added dropwise to a solution of 6-bromo-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7(4H)-one (0.179 g, 0.739 mmol) in phosphoryl chloride (1.85 mL, 19.8 mmol) and 1,2-dichloroethane (1.85 mL). The resultant reaction mixture was stirred at RT for 15 min, then warmed to 80° C. and stirred at that temperature for 15 h. The reaction mixture was concentrated in vacuo to yield a crude residue which was diluted with dichloromethane and the resultant solution was added dropwise to a saturated solution of sodium bicarbonate (40 mL) at 0° C. Additional dichloromethane (50 mL) was added, layers were separated and the organic layer was dried with sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. Purification by flash column chromatography (100% hexanes to 30% EtOAc/hexanes) gave the desired product (171 mg, 89%) as a white solid. LCMS calculated for C8H8BrClN3 (M+H)+: m/z=260.0, 262.0. found: 259.9, 261.9.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(CC)CC.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:21]=[C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[CH2:19][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[O:1]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Oc1nc2ccccc2s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Cn2c(=O)sc3ccccc32)cc1
Yield: 67 %

Procedure:
To a solution of 2-hydroxybenzothiazole (1.17 g, 7.58 mmol) in THF (10 mL) was added Et3N (1.1 mL, 7.89 mmol). A solution of 2-bromo-4′-methylacetophenone (1.67 g, 7.06 mmol) in THf (10 mL) was added dropwise. Another equivalent of Et3N was added after 24 hours. Purification by flash chromatography on silicagel (CH2Cl2) gave a white powder in 67% yield: mp 168-170° C.; 1H-NMR (DMSO-d6) 2.43 (s, 3H), 5.62 (s, 2H), 7.21 (t, 1H), 7.27 (d, 1H) 7.32 (t, 1H), 7.42 (d, 2H), 7.70 (d, 1H), 8.01 (d, 2H); Anal. (C16H13NO2S) C, H, N.
Reaction SMILES: [CH:1](=[C:5]1/[C:6](=[O:11])[CH2:7][C:8](=[O:10])[NH:9]/1)\[CH:2]([CH3:4])[CH3:3].[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>ClCCl>[C:12]([O:11][C:6]1=[CH:7][C:8](=[O:10])[NH:9]/[C:5]/1=[CH:1]\[CH:2]([CH3:4])[CH3:3])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)Cl
Reactant: CC(C)/C=C1\NC(=O)CC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)OC1=CC(=O)N/C1=C\C(C)C
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
31.8 g of (Z)-5-isobutylidenepyrrolidine-2,4-dione was suspended in 318 ml of dichloromethane and cooled to -5° C. Then first 23.22 g of butyryl chloride was added and then 27.32 g of triethylamine was added. After the addition the mixture was stirred another 10 minutes at 0° C., then diluted with 100 ml of dichloromethane, and washed twice with 100 ml of 5 percent NaHCO3 solution each and twice with 100 ml of 0.4M hydrochloric acid each. The aqueous phases were extracted separately with dichloromethane and the combined organic phases were dried on magnesium sulfate. After the distilling off of the solvent, the crude product (46 g) was recrystallized from hexane. The yield of the title compound was 38.8 g (84 percent of theory). The title compound had a melting point of 111° to 112° C. Other data concerning the title compound was:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH3:31])=[C:21]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH3:30])[N:22]=2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH3:31])=[C:21]([CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[CH3:30])[N:22]=3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: Cc1oc(-c2ccc(-c3cccc(F)c3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 3-fluorobenzene boronic acid (201 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 70 mg (67%). MS (m/e) 365.2 (M+1)
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.C(=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccc1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(Cc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (31 mg, 0.090 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and benzaldehyde (13.6 μL, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 28.45 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-(1-Benzyl-piperidin-3-ylmethyl)-N-phenyl-propionamide 7 as a colorless oil (26.6 mg, 88%). LRMS 337.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].C(N1C=CN=C1)([N:13]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:13])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1[nH]c(C(=O)O)cc1I
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1[nH]c(C(N)=O)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of EXAMPLE 23B (7.7 g) in tetrahydrofuran (20 mL) at 0° C. was added carbonyldiimidazole (14.9 g). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C. and ammonium hydroxide (3 mL) was added. The mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate, washed with brine and concentrated to provide the title compound.
Reaction SMILES: CNC.[Br:4][C:5]1[C:6]([CH3:17])=[N:7][N:8]([CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=O)[C:9]=1[CH3:10].BrC1[C:23](Br)=[C:22](C)[N:21]([CH:26](C)[C:27](O)=O)N=1>>[Br:4][C:5]1[C:6]([CH3:17])=[N:7][N:8]([CH:11]([CH2:15][CH3:16])[C:12]([N:21]([CH2:26][CH3:27])[CH2:22][CH3:23])=[O:14])[C:9]=1[CH3:10]
Reactant: CCC(C(=O)O)n1nc(C)c(Br)c1C
Reactant: Cc1c(Br)c(Br)nn1C(C)C(=O)O
Agent: CNC
Product: CCC(C(=O)N(CC)CC)n1nc(C)c(Br)c1C

Procedure:
Following the procedure of Example 1, Part C, but substituting diethylamine for dimethylamine and further substituting the 4-bromo-α-ethyl-3,5-dimethylpyrazole-1-acetic acid prepared in Example 60, Part B, above, for the 3,4-dibromo-α,5-dimethylpyrazole-1-acetic acid, there was prepared the corresponding 4-bromo-N,Nα-triethyl-3,5-dimethylpyrazole-1-acetamide having a melting point at 42° to 44° C.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[CH:23]=4)=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=[C:7]([F:30])[C:3]=1[C:4]([NH2:6])=[O:5].B(Br)(Br)Br.O>C(Cl)Cl>[F:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=4)=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=[C:7]([F:30])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1cccc(-c2ccc3sc(COc4ccc(F)c(C(N)=O)c4F)nc3c2)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1c(F)ccc(OCc2nc3cc(-c4cccc(O)c4)ccc3s2)c1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
To a suspension of 2,6-difluoro-3-[5-(3-methoxy-phenyl)-benzothiazol-2-ylmethoxy]-benzamide (0.14 g, 0.3 mmol) in 15 ml of anhydrous DCM was added drop wise boron tribromide (0.493 g, 1.9 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 3 h under nitrogen atmosphere. To the reaction mixture 5 ml of water was added at 0° C. The compound was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400μ) using ethyl acetate (40:60) as the eluent to provide the title compound as yellow solid (0.020 g, 14%). 1H NMR (DMSO-d6, 400 MHz): δ 5.71 (s, 2H), 6.80 (dd, 1H, J=9.6 Hz (o-coupling), 7.11 (dt, 1H, J=8.0 Hz (o-coupling), 7.17 (dt, 1H, J=8.0 Hz (o-coupling), 7.29 (t, 1H, J=8.0 Hz (o-coupling), 7.39-7.43 (m, 1H), 7.71 (dd, 1H, J=9.6 Hz) 7.89 (broad s, 1H), 8.18-8.22 (m, 2H). MS ES+ (413.01), HPLC (method 5) Rt=14.95 min
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C@@H:7]([NH:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][N:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[C:42]([NH:50][NH2:51])(=[O:49])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>C(Cl)Cl.CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+]>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([C:25]([NH:24][C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]=[CH:19][C:18]([C:21]([NH:51][NH:50][C:42](=[O:49])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:23])=[CH:17][N:16]=3)=[CH:11][CH:10]=2)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:34])([CH3:33])[CH3:35]
Reactant: CCCCCCC(=O)NN
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(C(=O)O)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCCC(=O)NNC(=O)c1cnc(-c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC(C)(C)C)cc2)nc1
Reaction time: 18 h
Yield: 60.3 %

Procedure:
Prepared using General Procedure 7. Into a stirring solution of (S)-2-(4-(3-(tert-butoxy)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl)pyrimidine-5-carboxylic acid (50 mg, 0.10 mmol) in DCM (2 mL) were added EDC (34 mg, 0.20 mmol), DMAP (3 mg, 0.02 mmol) and heptanehydrazide (16 mg, 0.11 mmol). After 18 h, the reaction mixture was diluted with NaHCO3 and extracted with DCM (2×). The organic layers were combined, dried (Na2SO4), concentrated and purified by chromatography (EA/Hexane) to provide 38 mg (61%) of tert-butyl (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(2-heptanoylhydrazine-1-carbonyl)pyrimidin-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for C36H47BN5O5: 629.8; no m/z observed, tR=3.84 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 9.17 (s, 2H), 8.42 (d, J=8.2 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 6.70 (d, J=7.3 Hz, 1H), 5.01 (dd, J=12.6, 5.8 Hz, 1H), 3.41-3.20 (m, 2H), 2.35 (t, J=7.5 Hz, 2H), 1.81-1.61 (m, 2H), 1.59 (d, J=14.0 Hz, 2H), 1.45 (s, 4H), 1.42-1.22 (m, 18H), 0.88 (t, J=6.8 Hz, 3H).