Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C1COCC1.O>[CH2:13]([O:20][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccnc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
2-Chloro-nicotinic acid (421) (3 g, 19.04 mmol) was dissolved in anhydrous THF (50 mL) and chilled to 0° C. on an ice bath. NaH (50 mmol, 60% suspension in mineral oil) was added portion wise to the solution over a period of 5 minutes. The resulting mixture was stirred at 0° C. for 30 minutes. Benzyl-alcohol (422) (2.27 g, 21 mmol) was added drop wise over a period of 10 minutes. The ice bath was removed and the mixture was warmed to room temperature over a period of 2 h. The mixture was refluxed for 16 h. LC-MS and TLC (Rf: 0.4–0.5 compared to Rf: 0.1 for compound 421 in 1:1 hexane/EtOAc, single spot) indicated complete reaction at this point. The mixture was diluted with water (300 mL) and the pH was adjusted to ˜6 by the addition of HCl (aqueous, 1M) and the product was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (100 mL) via extraction, dried over MgSO4 and concentrated under reduced pressure to give a yellow oil. Recrystallization from EtOAc/hexane gave the desired product (423) as a white powder (2.8 g, 12.2 mmol, 64% yield). LC-MS (ESI): (exact mass: 229.07) m/e=230.2 [M+1]+ (100%), 459.3 [2M+1]+ (90%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1C(OC(C)(C)C)=O.[F:16][C:17]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:18]=1[CH2:19][O:20][C:21]1[C:22]2[N:23]([C:28]([C:32](O)=[O:33])=[C:29]([CH3:31])[N:30]=2)[CH:24]=[C:25]([CH3:27])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.ClCCl>[F:16][C:17]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:18]=1[CH2:19][O:20][C:21]1[C:22]2[N:23]([C:28]([C:32]([NH:1][CH2:2][C@@H:3]3[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]3)=[O:33])=[C:29]([CH3:31])[N:30]=2)[CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NC[C@@H]3CCCCN3)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At RT, 53 mg (0.25 mmol, 1.1 equivalents) of tert-butyl (2S)-2-(aminomethyl)piperidin-1-carboxylate were added to 75 mg of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]-pyridine-3-carboxylic acid (Example 21A, 0.23 mmol, 1 equivalent), 90 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU, 0.24 mmol, 1.05 equivalents) and 88 mg of N,N-diisopropylethylamine (0.12 ml, 0.68 mmol, 3 equivalents) in 1.4 ml of DMF, and the mixture was stirred at RT overnight. After the reaction had ended, the mixture was purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product fractions obtained were dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate, filtered, concentrated and lyophilized. This gave 66 mg (64% of theory; purity 95%) of the title compound.
Reaction SMILES: [S:1](=[O:39])(=[O:38])([O:3][CH2:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][C@@H:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH2:22]4)[C:14]=3[CH:13]=[CH:12]2)[CH2:8][C@@H:7]1[O:30][Si](C(C)(C)C)(C)C)[NH2:2].N1C=CC=CC=1.O1CCCC1.F.N1C=CC=CC=1>>[S:1](=[O:39])(=[O:38])([O:3][CH2:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][C@@H:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH2:22]4)[C:14]=3[CH:13]=[CH:12]2)[CH2:8][C@@H:7]1[OH:30])[NH2:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1CCOS(N)(=O)=O
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: NS(=O)(=O)OCC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.9 %

Procedure:
2-((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethyl sulfamate (0.0442 g, 0.0773 mmol) was dissolved in pyridine (0.344 mL, 4.25 mmol) and tetrahydrofuran (0.345 mL, 4.25 mmol). The solution was cooled to 0° C. Pyridine hydrofluoride (0.500 mL, 5.55 mmol) was added dropwise. The solution was warmed to room temperature. After one hour, pyridine hydrofluoride (0.500 mL, 5.55 mmol) was added. After two hours, pyridine hydrofluoride (0.500 mL, 5.55 mmol) was added. The solution was stirred for 24 h. The reaction was quenched with dropwise addition of saturated sodium bicarbonate, and the mixture was extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 0 to 5% MeOH in EtOAc, to give the title compound (0.005 g, 0.01 mmol). 1H NMR (CD3OD, 400 MHz, δ): 8.17 (s, 1H), 7.28-7.12 (m, 5H) 6.67 (d, J=3.61 Hz 1H) 5.58 (t, J=7.44, 7.44 Hz 1H), 5.48-5.40 (m, 1H), 4.40-4.35 (m, 1H), 4.28-4.17 (m, 2H), 3.10-3.02 (m, 1H), 2.98-2.88 (m, 1H), 2.68-2.47 (m, 1H), 2.57-2.47 (m, 1H), 2.38-1.98 (m, 5H), 1.89-1.80 (m, 1H) ppm. LC/MS: Rt=1.25 min, ES+ 458 (FA standard).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:21]=[C:8]2[C:9]([C:13](=[O:20])[CH:14]([CH3:19])[C:15](OC)=O)=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH3:4].[C:22]([O:25]CCBr)(=[O:24])C.[Cl-].[NH4+]>CN(C)C=O>[CH2:3]([C:5]1[CH:21]=[C:8]2[C:9]([C:13](=[O:20])[CH:14]([CH3:19])[CH2:15][C:22]([OH:25])=[O:24])=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH3:4]
Reactant: CC(=O)OCCBr
Reactant: CCc1cc2c(C(=O)C(C)C(=O)OC)cccn2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCc1cc2c(C(=O)C(C)CC(=O)O)cccn2n1

Procedure:
60% sodium hydride (162 mg) was added to a solution of the compound of Example 183 (700 mg) in N,N-dimethylformamide (40 mL) in a stream of argon gas while the solution was stirred in an ice bath. The mixture was then stirred at room temperature for 15 min. Subsequently, bromoethyl acetate (597 μL) was added to the mixture under stirring in an ice bath. The mixture was further stirred at room temperature for 3 hours. Subsequently, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water (×2) and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification by silica gel column chromatography (hexane:ethyl acetate=2:1) gave the title compound as a mixture with o-alkylated form. This mixture was dissolved in 47% hydrobromic acid (20 mL) and the solution was stirred at 130° C. for 1 hour. After cooling, a 20% aqueous potassium hydroxide solution was added to make the mixture basic. The resulting crystals were separated by filtration and diluted hydrochloric acid was added to the filtrate to make it acidic. The filtrate was then extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent afforded the title compound as a yellow amorphous material (490 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][C@@H:9]1[C@@H:15]([OH:39])[C@@H:16]([N:24](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][C@@H:9]1[C@@H:15]([OH:39])[C@@H:16]([NH2:24])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)CCC1(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@@H](N)Cc2ccccc2)CCC1(C)C
Yield: 86.9 %

Procedure:
Dissolve 2-(R)-(2-(S)-dibenzylamino-1-(S)-hydroxy-3-phenylpropyl)-5,5-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (182 mg, 0.34 mmol) in methanol (4 mL) and add 10% palladium hydroxide on carbon (43 mg). Stir under 1 atmosphere of hydrogen gas overnight and filter through a filtering agent, wash with methanol and concentrate to give the title compound as a colorless oil (103 mg, 87% yield).
Reaction SMILES: C([O:8][C@:9]12[C@@H:16]([CH2:17][O:18]CC3C=CC=CC=3)[O:15][C@@H:14]([N:26]3[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]3=[O:28])[C@@:13]1([O:35][CH3:36])[O:12][CH2:11][CH2:10]2)C1C=CC=CC=1.C>CO.[OH-].[Pd+2].[OH-]>[OH:8][C@:9]12[C@@H:16]([CH2:17][OH:18])[O:15][C@@H:14]([N:26]3[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]3=[O:28])[C@@:13]1([O:35][CH3:36])[O:12][CH2:11][CH2:10]2
Reactant: CO[C@]12OCC[C@@]1(OCc1ccccc1)[C@@H](COCc1ccccc1)O[C@H]2n1cc(C)c(=O)[nH]c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CO[C@]12OCC[C@@]1(O)[C@@H](CO)O[C@H]2n1cc(C)c(=O)[nH]c1=O
Reaction time: 12 h
Yield: 79.9 %

Procedure:
To a solution of nucleoside 16 (1.20 g, 2.43 mmol) in methanol (10 cm3) was added 20% palladium hydroxide over charcoal (250 mg) and the mixture was carefully degassed under reduced pressure. An atmosphere of hydrogen was applied and stirring was continued for 12 h. The catalyst was removed by filtration of the reaction mixture through a glass column (1×8 cm) packed with silica gel in methanol. The column was additionally washed with methanol (20 cm3). All fractions were collected, evaporated to dryness and co-evaporated with petroleum ether to yield a glass-like solid. This residue was purified by silica gel chromatography eluting with a gradient of 5-10% methanol in dichloromethane (v/v). The fractions containing the product were collected, combined and evaporated to dryness. The residue was dissolved in anhydrous methanol (5 cm3) and anhydrous benzene (100 cm3) was added. Lyophilisation yielded nucleoside 17 (0.61 g, 79%) as a white solid material. δH (CD3OD) 7.45 (1H, S, 6-H), 5.93 (1H, s, 1′-H), 4.15-3.81 (5H, m, 5-Ha, 5-Hb, 2″-Ha, 2″-Hb, 4′-H), 3.43 (3H, s, CH3—O), 2.47-2.40 (1H, m, 1″-Ha), 2.03-1.93 (1H, m, 1″-Hb), 1.92 (3H, s, CH3). δC (CD3OD) 164.1 (C-4), 150.1 (C-2), 138.3 (C-6), 109.6 (C-5), 108.3 (C-2′), 84.4, 84.1, 82.4 (C-1′, C-3′, C-4′), 68.0, 59.5 (C-5′, C-2″), 49.6 (CH3—O), 34.0 (C-1″), 10.5 (CH3). FAB-MS m/z 315.13 [M+H]+, 337.09 [M+Na]+ (Found: C, 49.9; H, 5.7; N, 8.2; C13H18O7N2 requires C, 49.7; H, 5.8; N, 8.9%).
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13])C.Cl.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][NH2:40])=[CH:35][CH:34]=1)#[N:32].O>CN(C)C=O>[CH3:25][N:9]1[C:8](=[O:26])[C:7]([C:6]2[N:39]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[N:40]=[CH:4][CH:5]=2)=[C:12]([CH3:13])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:10]1=[O:24]
Reactant: CCOC(C#Cc1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1=O)OCC
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 5-(3,3-diethoxyprop-1-ynyl)-3,6-dimethyl-1-(3-trifluoromethylphenyl)-pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 61) and 4-cyanophenylhydrazine hydrochloride (27.9 mg) in N,N-dimethy formamide (2.0 ml) was stirred at 130° C. for seven hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with water (10 ml×2) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (17.9 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Sn](CCCC)(CCCC)CCCC)[N:3]=1.I[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]3[O:35][C:34]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)=[N:33][N:32]=3)[CH:29]=2)[N:24]([S:46]([C:49]2[CH:55]=[CH:54][C:52]([CH3:53])=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH:23]=1.CN(C=O)C>C(Cl)Cl.[Cu]I.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>[Cl:1][C:2]1[N:3]=[C:4]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]4[O:35][C:34]([NH:36][CH2:37][C:38]5[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=5)=[N:33][N:32]=4)[CH:29]=3)[N:24]([S:46]([C:49]3[CH:50]=[CH:51][C:52]([CH3:53])=[CH:54][CH:55]=3)(=[O:48])=[O:47])[CH:23]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 100 °C
Yield: 49.1 %

Procedure:
In a 20 mL glass microwave tube, 2-chloro-6-(tributylstannyl)pyrazine (0.807 g, 1.999 mmol), 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (1.00 g, 1.665 mmol), CuI (0.381 g, 1.999 mmol), Pd(PPh3)4 (0.096 g, 0.083 mmol) was purged with argon and treated with DMF (15 mL). The tube was heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 1 h. The crude mixture was then diluted with DCM and washed with water. The organic layer was dried, filtered and concentrated and the residue was purified with flash chromatography to give 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (0.48 g, 0.818 mmol, 49%) as a light yellow amorphous solid. MS (ESI, pos. ion) m/z: 586.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.44 (1H, s), 9.02 (1H, s), 8.85 (1H, s), 8.71 (1H, s), 8.28-8.36 (1H, m), 8.18 (1H, d, J=8.8 Hz), 8.03 (1H, m, J=8.4 Hz), 7.95 (1H, s), 7.88-7.95 (1H, m), 7.45 (1H, m, J=8.2 Hz), 7.33 (2H, m, J=8.6 Hz), 6.90 (2H, m, J=8.6 Hz), 4.37 (2H, d, J=6.1 Hz), 3.72 (3H, s), 2.33 (3H, s).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:10]([OH:17])(=[O:16])[CH2:11][CH2:12][C:13]([CH3:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C1(C)C=CC=CC=1>[C:10]([O:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:16])[CH2:11][CH2:12][C:13]([CH3:15])=[O:14]
Reactant: CC(=O)CCC(=O)O
Reactant: CCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)CCC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Bromooctane (332 g, 1.72 mol) was added to a stirring mixture of levulinic acid (200 g, 1.72 mol), tetrabutylammonium bromide (55.1 g, 0.17 mol), and K2CO3 (357 g, 2.58 mol) in DMF (500 mL) drop-wise and stirred at room temperature for overnight. The resulting mixture was diluted in toluene and the organic layer was washed with HCl (10%), brine, and water. The solvent was concentrated in vacuo and the oil was purified by vacuum distillation to afford the product octyl levulinate as a clear oil.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:38][CH:39]=[N:40][N:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[S:38][CH:39]=[N:40][N:41]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1nncs1
Product: C[C@@H](c1ccc(-c2nncs2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 2-bromo-[1,3,4]thiadiazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI+): m/z=438 [M+H]+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)[CH:4]=1.C1([O:29][C:30](=O)[NH:31][C:32]2[N:33]=[N:34][CH:35]=[CH:36][CH:37]=2)C=CC=CC=1.NC1N=NC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:31][C:32]3[N:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:19][CH2:18]2)[CH:4]=1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: Cc1ccnc(Oc2cccc(C=C3CCNCC3)c2)c1
Agent: Cl
Agent: Nc1cccnn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccnc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnn4)CC3)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Methyl-2-(3-piperidin-4-ylidenemethyl-phenoxy)-pyridine hydrochloride (530 mg, 1.5 mmol, from Example 72, Step 5), pyridazin-3-yl-carbamic acid phenyl ester (404 mg, 1.88 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-aminopyridazine) and triethylamine (0.79 mL, 5.66 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 hours, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (60-100% EtOAc/DCM) to afford the desired product (289 mg) as a white foam. MS (APCI 10V) AP+ 402.0, 281.1 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.34 (s, 3H) 2.45 (td, J=5.72, 1.18 Hz, 2H) 2.57 (td, J=5.68, 1.17 Hz, 2H) 3.53-3.61 (m, 2H) 3.62-3.74 (m, 2H) 6.44 (s, 1H) 6.76 (dt, J=1.40, 0.76 Hz, 1H) 6.87-6.95 (m, 2H) 6.96 (ddd, J=5.28, 1.40, 0.63 Hz, 1H) 7.07 (d, J=7.55 Hz, 1H) 7.36 (dd, J=8.78, 7.71 Hz, 1H) 7.58 (dd, J=9.05, 4.67 Hz, 1H) 7.97 (d, J=5.51 Hz, 1H) 8.11 (d, J=8.77 Hz, 1H) 8.78 (d, J=4.73 Hz, 1H)
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34](=[O:36])[NH2:35])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:11][CH2:10]1)C)(C)(C)C>Cl.O1CCOCC1.CO>[F:22][C:20]1[CH:19]=[CH:18][C:17]([NH:23][C:24]2[C:25]3[C:32]([CH3:33])=[C:31]([C:34]([NH2:35])=[O:36])[S:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[C:16]([O:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([NH:7][CH3:6])[CH2:10][CH2:11]2)[CH:21]=1
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](N(C)C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.684 g tert-butyl-trans-4-(−2-(6-carbamoyl-5-methylthieno[2,3-d]pyrimidin-4-ylamino)-5-fluorophenoxy)cyclohexyl(methyl)carbamate in 5 ml 4 M HCl/dioxane and 5 ml MeOH was stirred at rt for 1.5 h. The reaction mixture was concentrated in vacuo. The crude was purified by chromatography to give the desired product.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:12](=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:8][N:7]1[C:33](=[O:50])[C:34]1[CH:39]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:37]([O:44][CH3:45])=[C:36]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:35]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:16][CH2:15][CH2:14][CH2:13][C:12]([NH:11][C@@H:9]2[CH2:8][N:7]([C:33](=[O:50])[C:34]3[CH:39]=[C:38]([C:40]([CH3:41])([CH3:42])[CH3:43])[C:37]([O:44][CH3:45])=[C:36]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:35]=3)[C@H:6]([C:4]([OH:5])=[O:3])[CH2:10]2)=[O:32])=[CH:19][CH:20]=1
Reactant: CCOC(=O)[C@@H]1C[C@H](NC(=O)CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CN1C(=O)c1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C(C)(C)C)cc(C(=O)N2C[C@@H](NC(=O)CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C[C@H]2C(=O)O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To the solution of (2S,4S)-4-[6,6-Bis-(4-fluoro-phenyl)-hexanoylamino]-1-(3,5-di-tert-butyl-4-methoxy-benzoyl)-pyrrolidine-2-carboxylic acid ethyl ester (33) (0.32 g, 0.52 mmol) in THF (15 ml), MeOH (5 ml) and water (5 ml) was added LiOH (0.1 g, 2.45 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was neutralized with 2N HCl to pH˜2 and dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2: MeOH (10:1) to give 0.26 g of desired product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[CH2:14][CH2:15]Br>>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13]([CH2:14][CH2:15][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])[CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cccc(CCBr)c1
Reactant: CCc1ccncc1
Product: CC(CCc1cccc(C(F)(F)F)c1)c1ccncc1
Yield: 15.3 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 2.37 g (9.35 mmol) of 3-trifluoromethylphenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 0.40 g of the desired compound (yield: 15.3%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[N:8]([CH3:19])[CH:7]=1)=[O:5])C>Cl>[F:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[F:18])[N:8]([CH3:19])[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16]
Reactant: CCOC(=O)c1cn(C)c2cc(F)c(F)cc2c1=O
Agent: Cl
Product: Cn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Yield: 89 %

Procedure:
6,7-Difluoro-1,4-dihydro-1-methyl-4-oxo-quinoline-3-carboxylic acid ethyl ester (7.24 g, 27.1 mmol) was mixed with 1N hydrochloric acid (300 ml) and heated to reflux for 2 hours. The reaction mixture was filtered, and the precipitate washed with water and dried under vacuum to provide the title product as a white solid, m.p. 284°-287° (5.78 g, 24.2 mmol, 89% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[F:9]
Reactant: Fc1ccc(Cl)c(F)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Temperature: 28 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1chloro-2,4-difluorobenzene (0.829 g, 5.58 mmol, Aldrich, used as received) in conc. H2SO4 (8.0 mL) at 0° C., KNO3 (0.565 g, 5.59 mmol) was added in one lot. The resulting solution was allowed to warm to 28° C. and stirred overnight at 28° C. It was then poured into ice (80 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil was dried further under vacuum to afford 1.007 g (93%) of the pure (1H NMR) title compound as a light red oil; 1H NMR (CDCl3): δ 7.168 (dd, 1H, J1 =9.9 Hz, J2 =8.4 Hz), 8.238 (t, 1H, J=7.5 Hz).