Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[O:14]([CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(OC[C@@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
To a solution of (S)-(+)-N-Boc-2-phenoxymethylpyrrolidine (0.81 g, 2.9 mmol) in 5 mL of CH2Cl2 at 0° C. was added 5 mL of TFA dropwise over 1 hour. The solution was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was slowly poured into 30 mL of 10% NaOH and extracted thrice with 20 mL of CH2Cl2. The organic layer was then dried over Na2SO4, filtered and concentrated under reduced pressure to give a light yellow oil (0.41 g, 79%). ES (+) MS m/e=178 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([NH:6][C:7]([NH:28][C:25]1[CH:26]=[N:27][C:22]([S:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)=[CH:23][CH:24]=1)=[O:8])=[O:5]
Reactant: Cc1cccc(C)c1C(=O)N=C=O
Reactant: Nc1ccc(Sc2ccc(Cl)cc2)nc1
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1C(=O)NC(=O)Nc1ccc(Sc2ccc(Cl)cc2)nc1

Procedure:
2,6-Dimethylbenzoyl isocyanate (1.61 grams; 0.01 mole) and 6-(4-chlorophenylthio)-3-aminopyridine (2.36 grams; 0.01 mole) were mixed in 50 ml. of ethyl acetate and stirred at room temperature for 12 hours. Solvent was removed in vacuo. TLC showed four spots. The mixture was passed over a column of silica gel with a 1:1 mixture of toluene-ethyl acetate and the product (Rf ≅0.7) separated and crystallized from ethyl acetate-hexanes, yield 1.1 grams, m.p. 159°-160° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([S:18][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)S[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
In dichloromethane (5 ml) was dissolved (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (143 mg), followed by addition of triethylamine (0.076 ml) and isobutyryl chloride (58.6 mg) under ice-cooling. The mixture was stirred at room temperature for 15 minutes, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane-ethyl acetate=1:2). The desired fraction was concentrated to give (2R,3R)-2-(2,4-difluorophenyl)-3-isobutyrylthio-1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 62, 140 mg) as a colorless syrup. This product was treated with 4N hydrochloric acid (in ethyl acetate) to give the hydrochloride, which was then crystallized from ether to give compound 62 hydrochloride (156 mg) as a colorless powder. m.p. 129°-138° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1COCC1.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28].C([O-])(O)=O.[Na+]>CCOC(C)=O.C(N(CC)CC)C>[CH3:25][N:26]([CH3:30])[C:27]([N:15]1[CH:16]=[CH:17][C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)=[N:14]1)=[O:28]
Reactant: CN(C)C(=O)Cl
Reactant: Fc1ccc(Oc2ccc(-c3cc[nH]n3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)n1ccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Yield: 47.1 %

Procedure:
A solution of 3-[4-(4-fluorophenoxy)phenyl]-1H-pyrazole (467 mg, 1.84 mmol) in 7 mL of THF containing 0.3 mL (2.13 mmol) of triethylamine was treated with 0.3 mL (3.2 mmol) dimethylcarbamyl chloride added via syringe. No reaction was observed at room temperature. An additional 0.3 mL of dimethylcarbamyl chloride was added and the reaction was heated at reflux overnight. The reaction was then added to a saturated aqueous NaHCO3 solution and EtOAc. The aqueous layer was washed with EtOAc and the pooled organic layers were dried (Na2SO4), filtered and concentrated to dryness. Column chromatography (7/3 hexane/EtOAc) afforded 282 mg of the title compound as a yellow oil that solidified on standing, mp 59-63° C. 1H NMR (CDCl3): δ 8.15 (d, 1H, J=2.7 Hz), 7.80 (d, 2H, J=8.4 Hz), 7.06-6.88 (m, 6H), 6.62 (d, 1H, J=2.7 Hz), 3.30 (br s, 6H).
Reaction SMILES: [CH2:1]([O:19][CH2:20][C:21]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:22]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:88]I>C1(C)C=CC=CC=1>[I:88][CH2:22][C:21]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)(COCCCCCCCCCCCCCCCCCC)COCCCCCCCCCCCCCCCCCC
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOCC(CI)(COCCCCCCCCCCCCCCCCCC)COCCCCCCCCCCCCCCCCCC
Temperature: 100 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
2,2,2-Tris(octadecyloxymethyl)ethanol (500 mg, 560 μmol) was dissolved in toluene (10 ml), triphenylphosphine (294 mg, 1.12 mmol), imidazole (76.2 mg, 1.12 mmol) and iodine (284 mg, 1.12 mmol) were added, and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, toluene (10 ml) was added, and the mixture was partitioned and washed three times with water (5 ml). The organic layer was evaporated under reduced pressure, and the residue was precipitated with acetonitrile (10 ml) to give 1-[3-iodo-2,2-bis(octadecyloxymethyl)propoxy]octadecane (555 mg, 553 μmol, yield 98%).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:21][NH:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-:22].[Mn+2:23].[Cl-:24]>CO>[Cl:22][C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:21][NH:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][N:8]1[Cl:24].[Mn+2:23]
Reactant: [Cl-]
Reactant: C1CCC(C2CNCCNCCNCCNCCN2)CC1
Agent: [Mn+2]
Solvent: CO
Product: ClN1CCNCCNCCNCCNCC1(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
2-Cyclohexyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 30E (0.50 g, 1.7 mmol) was added to a refluxing anhydrous MeOH solution (50 ml) containing anhydrous manganese(II) chloride (0.21 g, 1.7 mmol) under a dry nitrogen atmosphere. After refluxing for 2 h, the solution was stirred overnight at room temperature. The solution was filtered through celite and then taken to dryness. The solid was recrystallized from EtOH to give 0.44 g (62% yield) of a white solid after washing with ethyl ether and drying in vacuo: FAB mass spectrum (NBA+Li) m/z (relative intensity) 429 (M+ +Li, 5) , 387/389 [(M+ -Cl), 100/35]; Anal. calcd for C16H35N5MnCl2 : C, 45.40; H, 8.33; N, 16.54; Cl, 16.75. Found: C, 45.39; H, 8.04; N, 16.33; Cl, 16.37.
Reaction SMILES: C[O:2][C:3]1([C:19](F)([F:21])[F:20])[NH:7][C:6]2[CH:8]=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:5]=2[NH:4]1.[Na]>>[NH4+:4].[OH:2][C:3]1([C:19]([F:21])([F:20])[C:15]([F:18])([F:17])[F:16])[NH:7][C:6]2[CH:8]=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:5]=2[NH:4]1
Reactant: COC1(C(F)(F)F)Nc2cc(C(F)(F)F)cc([N+](=O)[O-])c2N1
Agent: [Na]
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc2c1NC(O)(C(F)(F)C(F)(F)F)N2
Product: [NH4+]

Procedure:
2-methoxy-2,6-bis(trifluoromethyl)-4-nitrobenzimidazoline, sodium salt
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[N:20][C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=2)=[C:22]([CH:26]=1)[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:18]1[CH:19]=[N:20][C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=2)=[C:22]([CH:26]=1)[C:23]([NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1)=[O:24]
Reactant: N[C@H]1CC[C@@H](CO)CC1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](CO)CC2)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
(cis-4-Amino-cyclohexyl)-methanol (73 mg, 0.56 mmol) and triethylamine (225 μl, 1.61 mmol) were dissolved in dimethylformamide (225 μl) and a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (150 mg, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg, 0.59 mmol) and 1-hydroxybenzotriazole (80 mg, 0.59 mmol) in dimethylformamide (5 ml) was added. The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between 0.5N HCl (10 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic phases were washed with brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (98.7:1.3:0.13, by volume). The product was triturated with ethyl acetate (3 ml) to give 5-fluoro-N-(cis-4-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (111 mg) as a white solid.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8](=[O:23])[CH2:9][CH2:10][C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1)=[O:12])([CH3:6])([CH3:5])[CH3:4].Cl.[NH2:25]O.S([O-])(O)(=O)=O.[Na+]>C(O)C.O>[C:3]([O:7][C:8](=[O:23])[CH2:9][CH2:10][C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[N:25][OH:1])[CH:16]=1)=[O:12])([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)CCC(=O)NCc1cccc(C=O)c1
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)CCC(=O)NCc1cccc(C=NO)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76 %

Procedure:
A 3.2 M aqueous solution of sodium hydroxide (0.5 ml, 1.60 mmol) was added to a solution of N-(3-formylbenzyl)succinamic acid tert-butyl ester (312 mg, 1.07 mmol) and hydroxylamine hydrochloride (89 mg, 1.29 mmol) in ethanol (2.5 ml) and water (0.5 ml). The reaction mixture was stirred at room temperature for 3 days. A 10% aqueous solution of sodium hydrogensulphate (20 ml) and water (50 ml) were added. The mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo to give 249 mg of crude N-[3-((hydroxyimino)methyl)benzyl]succinamic acid tert-butyl ester, which was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][C:14]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16][C:15]=3[CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].[CH3:32][Zn+]>O1CCCC1.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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[C:12]([CH3:32])=[CH:13][C:14]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16][C:15]=3[CH:22]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C[Zn+]
Reactant: CN1CCc2cc(OS(=O)(=O)C(F)(F)F)c(S(=O)(=O)c3ccc(F)cc3)cc2CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1S(=O)(=O)c1ccc(F)cc1)CCN(C)CC2
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of D7 (100 mg, 0.21 mmol) in dry tetrahydrofuran (2 mL) was degassed with argon for 10 minutes. To the solution Pd(PPh3)4 (30 mg) was added followed by methylzinc chloride (0.22 mL, 0.43 mmol) then heated at reflux for 30 minutes. The mixture was cooled to room temperature and quenched with water. Extraction with dichloromethane followed by purification by SCX and chromatography on silica gave the title compound D8 as a gum (56 mg). MH+ 334. 1H NMR δ (CDCl3) 2.36 (3H, s), 2.38 (3H, s), 2.47-2.66 (4H, m), 2.90-3.05 (4H, m), 6.96 (1H, s), 7.10-7.20 (2H, t), 7.83-7.92 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][CH3:8])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:21]1[S:22][C:23]([CH:27]=[O:28])=[C:24]([Cl:26])[N:25]=1>O1CCCC1>[Cl:26][C:24]1[N:25]=[C:21]([N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:8])[S:22][C:23]=1[CH:27]=[O:28]
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: CNCc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(Cl)cc1)c1nc(Cl)c(C=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119525.2 %

Procedure:
To a solution of (4-chloro-benzyl)-methyl-amine (550, 2 g, 0.01 mol) and N,N-diisopropylethylamine (4 mL, 0.03 mol) in tetrahydrofuran (50 mL) was added 2,4-dichloro-thiazole-5-carbaldehyde (93, 3 g, 0.01 mmol) in tetrahydrofuran (20 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was collected by filtration and washed with hexanes to provide the desired compound as a light-yellow solid (551, 3.6 g, 90%).
Reaction SMILES: O[C:2]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10].C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1(C)C=CC=CC=1>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:2]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10])=[CH:16][CH:15]=1
Reactant: OC(CCCCCCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(C(=CCCCCCCBr)c2ccc(F)cc2)cc1

Procedure:
31.9 g (80 mmol) 8-hydroxy-8,8-bis-(4-fluorophenyl)-octyl bromide dissolved in toluene are added to 0.3 g toluene sulfonic acid and the mixture is subsequently heated for an hour with water separator under reflux. After withdraw of the solvent, the residue is chromatographically purified over silica gel with petroleum ether/acetic acid ethyl ester (90/1): Yield 28.6 g (94%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:16]3[O:15][CH2:14]2)[C:6]1=[O:25].C(N(CC)CC)C.[Cl:33][C:34]1[CH:38]=[CH:37][S:36][C:35]=1[C:39](Cl)=[O:40]>ClCCl>[Cl:33][C:34]1[CH:38]=[CH:37][S:36][C:35]=1[C:39]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:16]3[O:15][CH2:14]2)[C:6]1=[O:25])=[O:40]
Reactant: O=C(Cl)c1sccc1Cl
Reactant: NCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)c1sccc1Cl
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of 1′-(3-aminopropyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.05 g, 0.13 mmol) in dichloromethane (4.00 mL) was added triethylamine (0.03 g, 0.26 mmol) and 3-chlorothiophene-2-carbonyl chloride (0.02 g, 0.12 mmol) at 0° C. The mixture was stirred for 2 h, washed with 15% HCl solution and water. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was dissolved in ethyl acetate, and the product was precipitated with the addition of hexane. The white solid was collected by filtration and dried in vacuo to yield the title compound (0.04 g) in 67% yield: 1H NMR (300 MHz, CDCl3) δ 7.60 (t, 1H), 7.41 (d, 1H), 7.33-7.27-(m, 1H), 7.17 (d, 1H), 7.08-7.03-(m, 1H), 6.93 (t, 1H), 6.49 (s, 1H), 6.11 (s, 1H), 5.95 (m, 2H), 4.90 (d, 1H), 4.65 (d, 1H), 3.96-3.79-(m, 2H), 3.53-3.36-(m, 2H), 2.04-1.93-(m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.3, 160.6, 156.0, 149.0, 142.4, 141.8, 132.5, 129.4, 129.2, 129.1, 124.2, 123.7, 123.6, 119.2, 108.5, 102.9, 101.6, 93.7, 80.5, 58.3, 37.4, 36.5, 27.3; MS (ES+) m/z 483 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl.[CH3:32][N:33]([CH2:35][CH2:36]Cl)[CH3:34]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:36][CH2:35][N:33]([CH3:34])[CH3:32])[C:9]=2[CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)cccc2-c2ccc(Cl)cc2)CC1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCOc1cccc(-c2ccc(Cl)cc2)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of EXAMPLE 199A (1.5 g) in N,N-dimethylformamide (20 ml) was added 60% sodium hydride (0.596 g). The mixture was stirred at room temperature for 30 minutes and dimethylaminoethyl chloride hydrochloride salt (1.073 g) was added. After the resulting mixture was stirred overnight, additional 60% sodium hydride (0.596 g) and dimethylaminoethyl chloride hydrochloride salt (1.073 g) were added. The reaction mixture was further stirred overnight, diluted with ethyl acetate and washed with water, saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:20])[C:6]=1[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:63]([O:67][C:68]([NH:70][C:71]1[S:75][C:74]([C:76]2[C:81]([F:82])=[CH:80][CH:79]=[CH:78][C:77]=2[F:83])=[N:73][C:72]=1[C:84](O)=[O:85])=[O:69])([CH3:66])([CH3:65])[CH3:64]>C(Cl)Cl>[F:83][C:77]1[CH:78]=[CH:79][CH:80]=[C:81]([F:82])[C:76]=1[C:74]1[S:75][C:71]([NH:70][C:68](=[O:69])[O:67][C:63]([CH3:65])([CH3:64])[CH3:66])=[C:72]([C:84](=[O:85])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:20])[C:6]=2[C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9][CH:8]=2)[N:73]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.2 %

Procedure:
To a solution of tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (85 mg, 0.31 mmol) in DCM (20 mL) was added DIPEA (0.5 mL, 2.87 mmol), PyBOP (0.238 g, 0.46 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (0.114 g, 0.32 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-75% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a white solid (54 mg, 29%).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][N:30]([C:33](OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.Cl[CH2:41][Cl:42]>FC(F)(F)C(O)=O>[Cl:42][C:41]1[CH:19]=[CH:20][C:15]([CH2:33][N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:18]4[CH:17]=[CH:16][C:15]([O:14][CH2:13][C@:2]5([CH3:1])[O:6][C:5]6=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]6[CH2:3]5)=[CH:20][CH:19]=4)=[CH:26][CH:25]=3)[CH2:28][CH2:29]2)=[CH:16][CH:17]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(OC[C@@]4(C)Cn5cc([N+](=O)[O-])nc5O4)cc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(COc2ccc(-c3ccc(N4CCN(Cc5ccc(Cl)cc5)CC4)cc3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
850 mg of (R)-2-methyl-2-(4′-(4-tert-butoxycarbonylpiperazin-1-yl)biphenyl-4-yloxymethyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole was dissolved in 10 ml of trifluoroacetic acid and 5 ml of dichloromethane, followed by stirring at room temperature overnight. Thereafter, the reaction solution was concentrated under a reduced pressure, and then, 6 ml of dichloromethane and 6 ml of triethylamine were added thereto. The mixture was stirred at room temperature for 5 minutes, and it was then concentrated under a reduced pressure. The residue was dissolved in 10 ml of DMF, and then, 444.2 mg of 4-chlorobenzaldehyde and 672 mg of triacetoxy sodium borohydride were added thereto while cooled by ice, followed by stirring at room temperature overnight. Thereafter, an aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, the mixture was stirred, and the insoluble precipitate was removed by filtration. The filtrate was washed with water and ethyl acetate, and was then dried to obtain 730 mg (yield: 51.8%) of light yellow powders, (R)-2-(4′-(4-(4-chlorobenzyl)piperazin-1-yl)biphenyl-4-yloxymethyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:7]=1.CCN(C(C)C)C(C)C.C1N=CN([C:39]([N:41]2[CH:45]=N[CH:43]=[CH:42]2)=[O:40])C=1.N1CC[C@H:48]([OH:51])C1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:39]([N:41]4[CH2:42][CH2:43][C@H:48]([OH:51])[CH2:45]4)=[O:40])=[C:15]3[N:14]=2)[CH:7]=1
Reactant: O[C@H]1CCNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(N)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(NC(=O)N3CC[C@H](O)C3)c2n1
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a DCM (5 mL) solution of (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (25 mg, 0.076 mmol) and DIEA (0.04 mL, 0.23 mmol) was added CDI (25 mg, 0.15 mmol) at ambient temperature in one portion. After stirring for one hour, (S)-pyrrolidin-3-ol (20 mg, 0.23 mmol) was added in one portion. The reaction was stirred overnight before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a yellowish solid (28 mg, 83% yield). MS (apci) m/z=441.2 (M+H).