Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](F)=[O:16])=[C:13]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:12]=1.C(O)(=O)C>CN(C)C=O>[NH2:8][C:7]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:13]2[C:14]([C:15](=[O:16])[C:6]=1[C:5]([NH:4][CH3:3])=[O:9])=[CH:18][CH:19]=[C:11]([Cl:10])[N:12]=2
Reactant: CNC(=O)CC#N
Reactant: O=C(F)c1ccc(Cl)nc1NCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(N)n(Cc2ccccn2)c2nc(Cl)ccc2c1=O
Reaction time: 1 h
Yield: 234.8 %

Procedure:
1.12 g (28.06 mmol) of sodium hydride at 60% in mineral oil are added, fractionwise, to a solution, cooled to 0-5° C., of 1.31 g (13.36 mmol) of N-methylcyanoacetamide (prepared according to 1.3) in 20 ml of anhydrous dimethylformamide. Stirring is continued at this temperature for ten minutes and then a solution of 3.55 g (4.93 mmol) of 6-chloro-2-[(pyridin-2-ylmethyl)amino]nicotinoyl fluoride in 20 ml of dimethylformamide is added. The medium is stirred overnight at ambient temperature and then 0.561 g (14.03 mmol) of sodium hydride at 60% is added fractionwise. Stirring is continued at this temperature for 1 hour minutes, and then the reaction mixture is poured onto ice and the subsequent mixture is acidified to pH 5-6 with an aqueous solution of acetic acid at 10%. The precipitate is isolated by filtration and, after drying in an oven, 3.98 g of the expected product are obtained in the form of a beige solid. MH+=344. Yield=87%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:3]=1.[Li+].CC([N-]C(C)C)C.[O:32]=[C:33]1[C:41]2[C:36](=[CH:37][C:38]([C:42]([O:44][CH3:45])=[O:43])=[CH:39][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[OH:32][C:33]1([C:11]2[S:12][C:8]([C:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([NH:13][C:14]4[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=4)[N:5]=3)=[CH:9][N:10]=2)[C:41]2[C:36](=[CH:37][C:38]([C:42]([O:44][CH3:45])=[O:43])=[CH:39][CH:40]=2)[CH2:35][CH2:34]1
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cncs2)c1
Reactant: COC(=O)c1ccc2c(c1)CCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCC2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
A solution of 4-methyl-6-(thiazol-5-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (1.5 g, 4.46 mmol) in THF (35.7 mL) was cooled to −78° C. LDA (2M, 6.69 mL, 13.38 mmol) solution was slowly added, and the resulting mixture was stirred as at −78° C. for 30 minutes. In a separate dry flask, methyl 1-oxo-2,3-dihydro-1H-indene-5-carboxylate (1.06 g, 5.57 mmol) was dissolved in THF (5 mL), then this solution was added to the reaction mixture, which was then allowed to warm to rt over a period of 3 hrs, then stirred at rt for an additional 13 h. The reaction was quenched by addition of 2 mL MeOH and then loaded directly onto a silica gel chromatography column and purified with a gradient solvent system of 0-100% EtOAc/hexanes. The product-containing fractions were evaporated to give methyl 1-hydroxy-1-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-2,3-dihydro-1H-indene-5-carboxylate 16C (912 mg, 39%) as a light yellow solid. MS ESI calcd for C26H21F3N4O3S [M+H]+ 527, found 527.
Reaction SMILES: [CH3:1][CH:2]([S:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)[CH3:3].Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1>>[CH3:1][CH:2]([S:4][C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: CC(C)Sc1ccc(B(O)O)cc1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(SC(C)C)cc3)cc2)CC1
Yield: 16.6 %

Procedure:
The title compound (7.1 mg, 17%) was prepared from {4-[(1-methylethyl)thio]phenyl}boronic acid (19.6 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 450 (M+Na).
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:32]=[CH:31][NH:30][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]([O:26]CC)=[O:25])[C:18](=[O:29])[CH2:17][CH2:16]4)[N:11]=2)[CH2:4][CH2:3][CH2:2]1>C1COCC1.O.[OH-].[Na+]>[CH:1]1([NH:5][C:6]2[C:7]3[CH:32]=[CH:31][NH:30][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:18](=[O:29])[CH2:17][CH2:16]4)[N:11]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)CN1C(=O)CCc2cc(Nc3nc(NC4CCC4)c4cc[nH]c4n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1C(=O)CCc2cc(Nc3nc(NC4CCC4)c4cc[nH]c4n3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(6-(4-(cyclobutyamino)-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (10 mg, 0.023 mmol) in THF (0.6 mL) and H2O (0.4 mL) was added NaOH (5N, 2 drops). After stirring for 3 h at room temperature, the reaction mixture was purified by preparative HPLC to yield 2-(6-(4-(cyclobutyamino)-7H-pyrrolo[2,3-d]pyrimidine-2-ylamino)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (MS calcd for C21H22N6O3 406.2. found [MH] 407.0; UV 207.5, 304.5 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[CH3:48][N:49]([CH3:51])[NH2:50]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:48][N:49]([CH3:51])[NH:50][C:18](=[O:19])[C:15]1[CH:14]=[CH:13][C:12]([CH:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[N:17][CH:16]=1
Reactant: CN(C)N
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)NC(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 68.4 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol) obtained in Example 50 were added triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and 1,1-dimethylhydrazine (21 μl, 0.23 mmol). The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the dichloromethane:methanol=50:1 eluate was concentrated under reduced pressure to give the title compound (60 mg, 0.13 mmol, 68%) as a colorless amorphous substance.
Reaction SMILES: [O:1]([CH:19]([CH3:24])[CH2:20][CH2:21][CH2:22][OH:23])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[S:31](Cl)([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>C(Cl)Cl>[O:1]([CH:19]([CH3:24])[CH2:20][CH2:21][CH2:22][O:23][S:31]([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[Si:2]([C:15]([CH3:16])([CH3:17])[CH3:18])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CCCO)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCC(C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Reaction time: 8 h
Yield: 85 %

Procedure:
4-(t-Butyldiphenylsiloxy)-pentanol (15 g, 0.04 mol) was dissolved in methylene chloride (100 mL) containing pyridine (7 g). Tosyl chloride (15.3 g, 0.08 mol) was added slowly and the mixture stirred overnight. The mixture was washed with saturated NaHCO3 (2×100 mL) and the aqueous then backwashed with methylene chloride (100 mL). The organic phases were combined and washed with 2M HCl (100 mL) and water. The solution was dried over Na2SO4, evaporated and purified by column chromatography (light petroleum: ethyl acetate, 3:1) to give the title compound as a thick oil (yield 85%). δC (CDCl3, 62.9 MHz): 19.2, 21.7, 21.8, 26.9, 28.6, 31.8, 63.5, 70.6, 127.7, 127.9, 129.6, 129.9, 133.2, 133.9, 135.6 and 144.7
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:27])=[CH:7][CH:6]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: Cc1sc2ncnc(N)c2c1-c1ccc(NC(=O)Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A 0° C. solution of Example 1E (80 mg, 0.3 mmol) in dichloromethane (4 mL) was treated with phenyl isocyanate (0.037 mL, 0.34 mmol), stirred overnight, and filtered. The filter cake was dried to provide 0.103 g (87%) of the desired product. MS (CI) m/e 376 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.89 (s, 1H); 8.75 (s, 1H); 8.26 (s, 1H); 7.63 (d, J=8.7 Hz, 2H); 7.47 (d, J=8.7 Hz, 2H); 7.33-7.26 (m, 4H); 6.99 (t, J=7.5 Hz, 1H); 2.30 (s, 3H); Anal. Calcd. for C20H17N5OS.0.1CH2Cl2: C, 62.88; H, 4.52; N, 18.24. Found: C, 62.85; H, 4.64; N, 18.15.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1>C1COCC1.C(Cl)(Cl)Cl.O=[Mn]=O>[O:12]=[C:9]1[NH:8][C:7]2[CH:13]=[C:3]([CH:2]=[O:1])[CH:4]=[CH:5][C:6]=2[S:11][CH2:10]1
Reactant: O=C1CSc2ccc(CO)cc2N1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)NC(=O)CS2
Temperature: 70 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
To a solution of 6-hydroxymethyl-4H-benzo[1,4]thiazin-3-one (360 mg, 1.8 mmol) in THF/CHCl3 (2:1, 18 mL) was added MnO2 (1.6 g, 18 mmol) and the resulting suspension was heated to 70° C. and stirred for 4 h. The suspension was filtered through diatomaceous earth and the filtrate was concentrated. The resulting solid was triturated with EtOAc/hexanes (1:1) and a minimal amount of CH3OH to provide 200 mg (56%) of the title compound as a tan solid. MS (ESI): exact mass calculated for C9H7NO2S, 193.02; m/z found, 194.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.94 (s, 1H), 8.78 (br s, 1H), 7.54-7.49 (m, 2H), 7.37 (d, J=1.5, 1H), 3.52 (s, 2H).
Reaction SMILES: [Cl-].[NH4+].ClCCl.[Br:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.Cl[C:15]([CH3:23])([CH2:17][CH2:18][C:19](Cl)([CH3:21])[CH3:20])[CH3:16]>O>[Br:6][C:7]1[CH:8]=[C:9]([OH:13])[C:10]2[C:15]([CH3:23])([CH3:16])[CH2:17][CH2:18][C:19]([CH3:21])([CH3:20])[C:11]=2[CH:12]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Oc1cccc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(C)(C)c2c(O)cc(Br)cc21
Temperature: 25 °C

Procedure:
13.40 g (100.0 mmol) of ammonium chloride and 100 ml of dichloromethane are introduced into a three-necked flask under an argon atmosphere. A solution composed of 34.60 g (199.0 mmol) of 3-bromophenol, 89.00 g (486.0 mmol) of 2,5-dichloro-2,5-dimethylhexane and 300 ml of dichloromethane is added dropwise. The reaction mixture is stirred for sixteen hours at room temperature. The reaction mixture is poured into water and extracted with dichloromethane, the extract is washed with water and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture composed of 80% heptane and 20% dichloromethane. After evaporating the solvents, 30.00 g (53%) of the expected compound are collected in the form of white crystals with a melting point of 93° C.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:15][CH2:16][C:11]=2[C:10]([NH2:25])=[N:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([CH2:41][N:42]3[CH2:47][CH2:46][N:45]([C:48](=O)[CH2:49]CCl)[CH2:44][CH2:43]3)=[CH:40][C:35]=2[O:34][CH2:33]1>>[NH2:25][C:10]1[C:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:13](=[O:24])[C:12]=2[N:8]([C:6](=[O:5])[CH2:49][CH2:48][N:45]2[CH2:46][CH2:47][N:42]([CH2:41][C:39]3[CH:38]=[CH:37][C:36]4[O:32][CH2:33][O:34][C:35]=4[CH:40]=3)[CH2:43][CH2:44]2)[N:9]=1
Reactant: O=C(CCCl)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Reactant: Cc1ccc(N2CCc3c(N)nn(C(=O)OC(C)(C)C)c3C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(Cc5ccc6c(c5)OCO6)CC4)c3C2=O)cc1

Procedure:
A target compound (101.7 mg, 0.196 mmol, 51.9%) was yielded as white solid in the same manner as Example 1 by reacting 1-N-t-butoxycarbonyl-3-amino-4,5,6,7-tetrahydro-6-N-(p-tolyl)pyrazolo[3,4-c]pyridin-7-one (130 mg, 0.379 mmol) with potassium carbonate (57.6 mg, 0.417 mmol) and 1-[4-{(benzo[d][1,3]dioxol-5-yl)methyl}piperazin-1-yl]-3-chloropropan-1-one (123.7 mg, 0.398 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:21])[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc(NCC2CCOCC2)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(N(C)CC2CCOCC2)c1C
Temperature: 80 °C
Yield: 82.8 %

Procedure:
To a stirred solution of methyl 5-chloro-2-methyl-3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzoate (0.80 g, 2.71 mmol) in acetonitrile (20 mL), cesium carbonate (1.75 g, 5.42 mmol) and methyl iodide (1.93 g, 13.6 mmol) were added. The resulting reaction mass was heated at 80° C. for 8 h. On completion, the mixture was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to give crude material which was purified by column chromatography to give the title compound (0.70 g, 84%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][C@H:13]([C:18]([N:20]1[CH2:25][C@@H:24]2[CH2:26][C@H:21]1[CH2:22][N:23]2C(OC(C)(C)C)=O)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:21]12[CH2:26][C@H:24]([NH:23][CH2:22]1)[CH2:25][N:20]2[C:18]([C@@H:13]([NH:12][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:19]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@H](NC(=O)c1cc2ccccc2[nH]1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1-dimethylethyl (1S,4S)-5-[N-(1H-indol-2-ylcarbonyl)-3-methyl-L-valyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (40.5 g, 89.2 mmol) in CH2Cl2 (300 mL) was added TFA (75 mL) at 0° C. The mixture was stirred at room temperature for 18 h. The reaction was quenched with 1N NaOH while adjusting the pH of the solution to 8-9. The reaction was then extracted with CH2Cl2 (3×500 mL), dried over Na2SO4, filtered, and concentrated to yield the crude product. LCMS (m/z): 355.3 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[N:16][CH:15]=1.C(=O)([O-])O.[Na+].[N+:33]([O-])([OH:35])=[O:34]>>[O:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[N:16][CH:15]=1)[N+:33]([O-:35])=[O:34]
Reactant: CN1CCN(c2ccc(C(=O)NCCCCCCCCCCO)cn2)CC1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1CCN(c2ccc(C(=O)NCCCCCCCCCCO[N+](=O)[O-])cn2)CC1
Reaction time: 4 h
Yield: 42 %

Procedure:
6.00 g of N-(10-hydroxy-1-decanyl)-6-(4-methyl-1-piperazinyl)nicotinamide were added under ice-cooling to 20 ml of fuming nitric acid and the mixture was stirred below -5° C. for 4 hrs. This mixture was poured into an aqueous sodium hydrogencarbonate solution, extracted with methylene chloride, washed with eater and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (chloroform:methanol=20:1) and recrystallized from acetone-hexane to give 2.80 g (42%) of the title compound. m.p.62°-64° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([C:46]([F:49])([F:48])[F:47])[CH2:13][C:14]([NH:16][C@@:17]([C:32]1[CH:37]=[C:36]([O:38][C:39]([F:44])([F:43])[CH:40]([F:42])[F:41])[CH:35]=[C:34]([F:45])[CH:33]=1)([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15].NN>CO>[NH2:3][CH:12]([C:46]([F:49])([F:48])[F:47])[CH2:13][C:14]([NH:16][C@@:17]([C:32]1[CH:37]=[C:36]([O:38][C:39]([F:44])([F:43])[CH:40]([F:42])[F:41])[CH:35]=[C:34]([F:45])[CH:33]=1)([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15]
Reactant: O=C(CC(N1C(=O)c2ccccc2C1=O)C(F)(F)F)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: NN
Solvent: CO
Product: NC(CC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)C(F)(F)F
Temperature: 50 °C
Yield: 31 %

Procedure:
To a solution of 3-(1,3-dioxoisoindolin-2-yl)-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 325, 30 mg, 0.04 mmol) in MeOH (1 mL) was added hydrazine (0.03 mL, 1 mmol) and the reaction mixture was heated at 50° C. for 4 h. The reaction mixture was purified by preparative HPLC (Axia luna column, 30×75 mm, 10-100% ACN/H2O with 0.1% TFA over 10 min, flow rate 40 mL/min, monitoring at 220 nm) to yield 3-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 326) as white solid (7 mg, 24% yield). LCMS: RT=3.62 min [M+H] 565.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.34 (1H, d, J=17.94 Hz), 7.13-7.24 (3H, m), 6.96-7.11 (4H, m), 6.82-6.92 (3H, m), 6.62 (2H, d, J=7.83 Hz), 5.86 (1H, t, J=1.77 Hz), 3.88 (1H, t, J=12.63 Hz), 3.75-3.84 (1H, m), 3.70 (1H, d, J=13.14 Hz), 2.82-2.93 (1H, m), 2.77 (1H, m).
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([N:12]([CH3:24])[C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)[CH3:3].N1C=CC=CC=1.[C:31](Cl)(=[O:42])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH2:41]>C(Cl)Cl>[CH3:24][N:12]1[C:13](=[O:23])[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@H:11]1[CH2:10][CH2:9][C@@H:8]1[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@H:7]1[CH2:6][CH2:5][C@@H:4]2[CH:2]([O:1][C:31](=[O:42])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH2:41])[CH3:3]
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C=CCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCCCCCCCCC(=O)OC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 20-hydroxy-4-methyl-5α-4-azapregnan-3-one (0.167 g, 0.5 mM) and pyridine (0.1 mL) in anhydrous methylene chloride (4.5 mL) at ice-bath temperatures was added 10-undecenoyl chloride (0.13 mL, 0.6 mM) dropwise. After 10 minutes, the reaction mixture was allowed to warm to room temperature and stir overnight. After diluting further with methylene chloride the mixture was washed with dilute hydrochloric acid, water, and brine, and dried (Na2SO4). The residue obtained from concentration of the filtered solution was flash chromatographed on silica gel using ethyl acetate as eluant to give the title compound as a glaze. MS M+ calculated for C32H53NO3, mw=499.78; observed m/e 499.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:22](O)(=[O:25])[CH2:23][CH3:24]>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:22](=[O:25])[CH2:23][CH3:24])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: CCC(=O)O
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc(C)c(-c2ccc(C(=O)NCC3CC3)cc2)c1
Reaction time: 72 h

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (30 mg, 0.11 mmol) and propionic acid (18.5 mg, 0.25 mmol) were mixed in THF (3 ml). Carbodiimde resin (295 mg, 0.31 mmol) was added and shaking continued for 72 h. The reaction was filtered, the resin washed with THF and methanol and the combined filtrate and washings filtered through an SPE (SCX), to give, after evaporation of the solvent under vacuum, N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)propionamide. NMR; δH [2H6]—DMSO 9.84,(1H, s), 8.60,(1H, t), 7.91,(2H, d), 7.50-7.47,(2H, m), 7.40,(2H, d), 7.21,(1H, d), 3.16,(2H, t), 2.29,(2H, q), 2.15,(3H, s), 1.08-1.02,(4H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.00 min, MH+337.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[O:15])[O:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)oc1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (53 mg, 0.24 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (93 mg, 0.24 mmol)[prepared according to Preparation 6] and N,N-diisopropylethylamine (0.21 ml, 1.20 mmol) in dichloromethane (2.4 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (124 mg, 0.26 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (113 mg, 0.21 mmol, 85% yield) as a white foam: LCMS (ES) m/e 551 (M+H)+.