Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][C:14]=2[F:22])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[NH2:23][O:24][CH2:25][CH2:26][OH:27].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CO>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][C:14]=2[F:22])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:23][O:24][CH2:25][CH2:26][OH:27])=[O:7]
Reactant: NOCCO
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(CCO)cc1F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(CCO)cc1F

Procedure:
3,4-Difluoro-2-[2-fluoro-4-(2-hydroxyethyl)anilino]benzoic acid was dissolved in MeOH and prepared from reaction with 2(aminooxy)ethanol and DMT-MM by the general procedure of Example 6, Step B, affording a crude yellow oil after workup which was purified by filtration through a plug of silica gel (100% EtOAc as eluant). 3,4-Difluoro-2-[2-fluoro-4-(2-hydroxyethyl)anilino]-N-(2-hydroxyethoxy)benzamide was isolated as a viscous, transparent oil (57%). 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (v br s, 1 H), 8.77 (br s, 1 H), 7.44-7.37 (m, 1 H), 7.15-7.05 (m, 1 H), 7.06 (dd, J=12.5, 1.7 Hz, 1 H), 6.90 (dd, J=8.2, 1.7 Hz, 1 H), 6.81 (ddd, J=8.8, 8.8, 4.5 Hz, 1 H), 4.75 (br s, 1 H), 4.63 (t, J=5.2 Hz, 1 H), 3.86 (t, J=5.0 Hz, 2 H), 3.61-3.52 (m, 4 H), 2.66 (t, J=6.9 Hz, 2 H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][C:11]([CH3:16])([CH3:15])/[C:10](=[N:17]/O)/[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[CH:10]([NH2:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)N(Cc2ccccc2)C(=O)/C1=N\O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCN(Cc2ccccc2)CC1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
To a solution of (Z)-1-benzyl-4,4-dimethylpiperidine-2,3,6-trione 3-oxime (490 mg, 1.88 mmol) in THF (5 mL) at 0° C. was slowly added LiAlH4 (1.0M in THF, 9.4 mL, 9.4 mmol). After the addition, the reaction mixture was warmed to room temperature and stirred for 2 h then heated at 60° C. overnight. The reaction mixture was cooled to 0° C. and carefully quenched by portionwise addition of solid Na2SO4.10H2O until gas evolution had ceased. The mixture was diluted with EtOAc and stirred vigorously at room temperature for 1 h then filtered, rinsing with EtOAc and MeOH. The filtrate was concentrated and the residue was purified by SiO2 chromatography (0% to 10% MeOH/CH2Cl2 (0.5% NH4OH)) to afford 210 mg (51%) of 1-benzyl-4,4-dimethylpiperidin-3-amine as a red oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[F:41][C:42]1[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:46]2[CH:45]=[CH:44][CH:43]=[C:42]([F:41])[C:47]=2[F:48])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: OB(O)c1cccc(F)c1F
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4cccc(F)c4F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3-difluorophenyl)boronic acid gave 219. 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.90-7.82 (m, 2H), 7.56-7.42 (m, 3H), 7.38-7.30 (m, 1H), 5.07 (t, J=5.7 Hz, 1H), 3.98-3.90 (m, 1H), 3.88-3.80 (m, 1H), 3.71 (s, 3H), 3.50-3.45 (m, 1H), 3.14 (d, J=1.5 Hz, 3H), 2.36-2.31 (m, 2H), 1.76-1.71 (m, 1H), 1.63-1.58 (m, 4H), 1.50-1.45 (m, 1H). LCMS (ES+) m/z 479 (M+1).
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:10][CH:9]=1.[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[CH:22]1([CH:14]([C:11]2[CH:10]=[CH:9][C:8]([CH3:7])=[CH:13][CH:12]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrC1CCCC1
Reactant: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
33.5 g (0.3 mol) of potassium tert-butylate are initially introduced into 100 ml of anhydrous DMF at 0° C., and 51.6 g (0.25 mol) of tert-butyl 4-methylphenyl-acetate in 250 ml of anhydrous DMF are added dropwise. The mixture is stirred at 0° C. for 30 minutes, 32.2 ml (0.3 mol) of cyclopentyl bromide in 150 ml of anhydrous DMF are added dropwise at 5-15° C. and the mixture is stirred at 25° C. for 20 hours. After concentration, the residue is partitioned between water and diethyl ether and the ether phase is dried over sodium sulphate and concentrated. The product crystallizes out.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([NH:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH:23]=[C:22]([C:24](O)=[O:25])[N:21]=[N:20]2)[CH2:15][CH2:14]1)=[O:11].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([NH:12][C@H:13]1[CH2:14][CH2:15][C@@H:16]([N:19]2[CH:23]=[C:22]([C:24]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:25])[N:21]=[N:20]2)[CH2:17][CH2:18]1)=[O:11]
Reactant: O=C(Cc1c(F)cccc1Cl)N[C@H]1CC[C@@H](n2cc(C(=O)O)nn2)CC1
Reactant: C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1c(F)cccc1Cl)N[C@H]1CC[C@@H](n2cc(C(=O)N3CCCCC3)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution under Ar of 1-{cis-4-[2-(2-chloro-6-fluoro-phenyl)-acetylamino]-cyclohexyl}-1H-[1,2,3]triazole-4-carboxylic acid (100 mg) in DMF (4 ml) were added piperidine (22 mg), TBTU (93 mg) and DIPEA (0.13 ml). The solution was stirred 1 h at RT before partitioning it between EtOAc (50 ml) and H2O (50 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated. Chromatography (silica, CH2Cl2 to CH2Cl2 5% MeOH) afforded the product (112 mg, 95%). Off-white solid. MS 448.1 (100, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:13]([C:12]2[C:8]([C:7]3[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:16])=[O:15])[CH2:29]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Reactant: Cc1onc(-c2cccnc2Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2cccnc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
Combine 3-(2-chloro-pyridin-3-yl)-5-methyl-isoxazole-4-carboxylic acid (0.50 g, 0.0021 mol) with (3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (0.63 g, 0.0021 mol), 1-[3-(dimethyl-amino)propyl]-3-ethylcarbodiimide hydrochloride (0.40, 0.0021 mol), 1-hydroxy-7-azabenzo-triazole (0.29 g, 0.0021 mol), and N,N-diisopropylethyl amine (1.10 mL, 0.0063 mol), in N,N-dimethylformamide (10 mL). Stir over a weekend at ambient temperature. Concentrate in vacuo and take up in water and extract with ethyl acetate. Wash the combined extracts with water, dry over sodium sulfate, and concentrate in vacuo. Elute over silica gel using ethanol/dichloromethane allowing for the isolation of 0.87 g (86%) of the desired amide as a white solid. MS(ES): (M+1)+ 483.1, 485.1 m/z.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:25]=[C:24]([NH:26][C:27]3[NH:28][N:29]=[C:30]([CH3:32])[CH:31]=3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[CH:11][CH:10]=1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:25]=[C:24]([NH:26][C:27]3[NH:28][N:29]=[C:30]([CH3:32])[CH:31]=3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[CH:11][CH:10]=1
Reactant: Cc1cc(Nc2nc(Nc3ccc(NC(=O)OC(C)(C)C)cc3)nc3ccccc23)[nH]n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nc(Nc3ccc(N)cc3)nc3ccccc23)[nH]n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of [2-(4-tert-Butoxycarbonylamino-phenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIc-60, 100 mg, 0.232 mmol) in a mixture of DCM/TFA (5/1, 12 mL) was stirred for 2 hours at room temperature. The solvents were removed in vacuo and the residue triturated in aqueous K2CO3. The resulting solid was collected by filtration and washed with diethyl ether to afford IIc-66 (69 mg, 90%) as an off-white solid, mp 164–167° C.; 1H NMR (DMSO) δ 2.24 (3H, s), 6.33 (1H, br s), 7.12 (2H, d), 7.48 (3H, m), 7.58 (1H, d), 7.86 (1H, t), 8.64 (1H, d), 10.86 (1H, br s), 11.46 (1H, s); IR (solid) 1681, 1512, 1496, 1433, 1415, 1187, 1129; MS 332.4 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[C:29]1([S:35](F)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[N:18]3[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc21
Reactant: O=S(=O)(F)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cn1c(S(=O)(=O)c2ccccc2)cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc21
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a −75° C. solution of 4-(1-methyl-1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester compound 3-1 (330 mg, 1.05 mmol) in THF (25 mL) was slowly added t-BuLi (1.2 mL, 2.1 mmol). The reaction mixture was stirred for 30 minutes at −75° C. then warmed in an ice bath for 15 min. The reaction was re-cooled to −75° C. and benzenesulfonyl fluoride was added (0.2 mL, 1.6 mmol). The reaction was stirred cold for 1.5 h at which time the ice bath was removed and the reaction was allowed to warm to room temperature (45 min.). The reaction was quenched with a saturated solution of ammonium chloride (55 mL) and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with brine (25 mL), dried (MgSO4), filtered and concentrated to afford a yellow oil. The oil was chromatographed over silica eluting with hexanes/ethyl acetate (4:1) to afford 190 mg (40%) of 4-(2-benzenesulfonyl-1-methyl-1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (3-2).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.CCN(C(C)C)C(C)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:25][N:26]=[C:27]=[O:28].[N-]=C=O>CN1C(=O)CCC1.CN(C1C=CN=CC=1)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:25][NH:26][C:27](=[O:28])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1csc(N)n1
Agent: CN(C)c1ccncc1
Agent: [N-]=C=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Temperature: 160 °C

Procedure:
The commercial starting material ethyl 2-aminothiazole-4-carboxylate (2 mmol) was dissolved in NMP and DIEA (1 equivalent) was added followed by addition of the 3,4-dichloro-benzyl isocyanate (1 equivalent). Add 5% DMAP. Heat at 160° C. under microwave irradiation for 30 min Added additional isocyanate reagent (1.0 eq) and microwave for another 30 minutes at 160° C. to obtain ethyl 2-(3-(3,4-dichlorobenzyl)ureido)thiazole-4-carboxylate in >90% conversion.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]\[C:27]([CH2:38][CH3:39])([O:30][Si](CC)(CC)CC)[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([O:47][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]\[C:27]([CH2:38][CH3:39])([OH:30])[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:47])[CH2:10]1
Reactant: CCC(/C=C\CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(/C=C\CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)CC
Yield: 98 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{(Z)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)}pregna-5,7,16-triene (82.0 mg, 0.103 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate ethanol=20:80:1, developed once) to give the title compound as a white solid (46.1 mg, 98%).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:45])[N:29]([C@H:31]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:32][NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C>ClCCl>[CH3:30][N:29]([C@H:31]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:32][NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[C:28](=[O:45])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1
Reactant: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
At 0° C., trifluoroacetic acid (4 ml) was added to a solution of N-((1R)-1-(N-((1R)-1-benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester (997 mg, 1.8 mmol) in dichloromethane (4 ml). The solution was stirred for 15 min at 0° C. The solvent was removed in vacuo at 20° C. The residue was dissolved in dichloromethane and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (45 g), using dichloromethane/methanol/25% aqueous ammonia as eluent, to give 646 mg of N-((2R)-2-(N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-3-phenylpropyl)methanesulfonamide.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:26]([C:29]1[NH:30][CH:31]=[CH:32][N:33]=1)[CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:30]3[CH:31]=[CH:32][N:33]=[C:29]3[CH2:26][CH2:27][CH3:28])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: CCCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2OC)o1
Temperature: 125 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (500 mg), 2-propylimidazole (1.10 g), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 4 hours. The reaction mixture was poured into water (100 ml), the resulting solid precipitate was filtered, air-dried and recrystallized from acetone-hexane to give 4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(2-propyl-1-imidazolyl) oxazole as pale yellow prisms (233 mg, 39%). Melting point 89-90° C.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:37]([CH3:38])=[CH:36][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:23]=3)[S:21][C:17]=2[C:16]=1Br)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:37]([CH3:38])=[CH:36][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:23]=3)[S:21][C:17]=2[C:16]=1[C:44]1[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2nc(-c3cccc(OCc4ccccc4)c3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cccc(OCc4ccccc4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 120 °C
Yield: 97.8 %

Procedure:
The mixture of (S)-2-(2-(3-(benzyloxy)phenyl)-7-bromo-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (100 mg, 0.164 mmol), 4-chlorophenylboronic acid (38 mg, 0.246 mmol), 2N K2CO3 (400 μL), Pd(PPh3)4 (18 mg, 0.016 mmol) in dioxane in sealed tube was heated at 120° C. After the reaction is finished, the reaction mixture was washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column (0-50% EtOAc in Hexanes) to give the product (103 mg, 97%). LCMS-ESI+: calc'd for C38H40ClNO4S: 642.2 (M+H+); Found: 642.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[K+].[K+].CI>O1CCCC1>[CH3:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:14])[CH3:15])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)n1nc(Br)c2ccc(O)cc2c1=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Yield: 76.9 %

Procedure:
To a stirred solution of 7-Hydroxy-2-Isopropyl-4-bromo-2H-phthalazin-1-one (0.4 g, 1.4 mmol) in tetrahydrofuran (THF) (5 ml) were added successively, K2CO3 (0.59 g, 4.3 mmol) and methyl iodide (0.22 g, 1.55 mmol) and the mixture was heated to reflux for 24 hours. After this time, LC-MS indicated complete consumption of starting material, and the reaction mixture was concentrated under vacuum. The residue was re-dissolved in ethyl acetate (50 ml) and washed with water (2×30 ml), the organic layer was dried (MgSO4), filtered and concentrated under vacuum to give the title compound (0.32 g, 76% yield) as an orange powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][C:11]([NH:19]C(=O)OC(C)(C)C)([CH2:12]3)[CH2:10]1)[CH2:16]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][C:11]([NH2:19])([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: CC(C)(C)OC(=O)NC12CC3CC(CC(C#Cc4cnccn4)(C3)C1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC12CC3CC(C1)CC(C#Cc1cnccn1)(C3)C2
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a stirred solution of tert-butyl 3-(pyrazin-2-ylethynyl)-1-adamantylcarbamate (108 mg, 0.31 mol) in DCM (3 mL) was added TFA (0.5 mL). After stirring at room temperature for an hour, the reaction was concentrated under reduced pressure. The resulting residue was diluted with DCM (25 mL), washed with Sat. NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure to yield 60 mg (78%) of the title compound, 3-(pyrazin-2-ylethynyl)-1-adamantylamine, as a white solid. ESI-MS m/z: 254 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1)=[O:5]
Reactant: CON(C)C(=O)[C@@H]1CCC[C@H]1c1c[nH]c2ccc(C#N)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]cc([C@@H]3CCC[C@H]3C=O)c2c1
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 70.5 %

Procedure:
Trans-2-(5-cyano-1H-indol-3-yl)-cyclopentanecarboxylic acid methoxy-methyl-amide (460 mg, 1.5 mMol) was dissolved in THF and cooled to −40° C. Lithium aluminum hydride (117 mg, 3.1 mMol) was added and the temperature was maintained between −40 and −30° C. for 1 h. The reaction was quenched with ethyl acetate (10 mL) and warmed to 0° C. The reaction was treated dropwise with water (0.12 mL) and stirred 5 min. Then sodium hydroxide (1N, 0.36 mL) was added and the reaction was stirred 5 min. Then a further addition of water (0.12 mL) was made and the reaction was stirred for 20 min. The reaction was filtered through celite and sand, and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel with ethyl acetate/hexanes (50%) to give the product as a clear oil (252 mg, 68%). 1H NMR (400 MHz, CDCl3) δ 9.67 (1H, d, J=2.8 Hz), 8.37 (1H, brs), 7.96 (1H, s), 7.36–7.44 (2H, m), 7.14 (1H, d, J=2.3 Hz), 3.60 (1H, q, J=8.5 Hz), 2.98 (1H, q of d, J=7.5, 2.7 Hz), 2.30 (1H, m), 1.71–2.20 (5H, m); MS m/e 239.2 (M+H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7](CC#N)=[CH:6][CH:5]=1.[C:13]([OH:16])(=[O:15])[CH3:14]>Br>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:14][C:13]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(CCBr)cc1
Reactant: CC(=O)O
Agent: Br
Product: O=C(O)Cc1ccc(CCBr)cc1

Procedure:
A solution of [4-(2-bromoethyl)phenyl]acetonitrile (56.0 g., 0.25 mole) in 48% hydrobromic acid (200 ml.) and acetic acid (600 ml.) is boiled under reflux for 4 hours. The solution is reduced to one-third volume by distillation at reduced pressure. The residue is diluted with 400 ml. of water to force out the oily product which is taken up in ether, washed with water, and dried over sodium sulfate. Evaporation of the solvent leaves the title compound as a residual oil.