Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([S@]([NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)[CH3:9])=O)(C)C.O1CCOCC1.CCOCC>Cl>[F:18][C:17]([F:19])([F:20])[O:16][C:13]1[CH:12]=[CH:11][C:10]([C@@H:8]([NH2:7])[CH3:9])=[CH:15][CH:14]=1
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@H](N)c1ccc(OC(F)(F)F)cc1
Reaction time: 1 h
Yield: 80.5 %

Procedure:
(R)-2-methyl-N—((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (5.08 g, 16.4 mmol) was dissolved by swirling in 4M HCl in dioxane (16.4 ml, 65.6 mmol), at room temperature. The solution was allowed to sit for 1 hr with occasional swirling. To the clear solution was added 45 ml ether and the resulting cloudy solution sonicated for 1 min, upon which time the white solid product precipitates out. The solid was filtered through a Buchner funnel, washed 5 times with ˜20 ml ether and allowed to air dry. Obtained (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (3.2 g, 13.2 mmol, 80% yield), 1H NMR (400 MHz, CD3OD) δ 1.64 (d, J=6.90 Hz, 3H) 4.52 (q, J=6.88 Hz, 1H) 7.38 (d, J=8.02 Hz, 2H) 7.57 (d, J=8.71 Hz, 2H). LCMS m/z 206.1 (M+H)+, Rt 0.52 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2cc(N3CCN(c4ccccc4)CC3)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 1-Phenylpiperazine (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture can then be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:26])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:26])([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2nccs2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester (4.36 g, 15.3 mmol) in CH2Cl2 (50 mL) at 0° C. was added DAST (2.4 mL, 1.2 eq.). The reaction mixture was stirred for 30 minutes before it was quenched by addition of saturated NaHCO3 solution (20 mL). The organic phase was separated and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (EtOAc:hexanes=1:4) to afford the desired product as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:6]1[S:13][C:12]2[CH:11]=[C:10]([C:14](Cl)=[O:15])[S:9][C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:17]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH2:20][CH3:21].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:6]1[S:13][C:12]2[CH:11]=[C:10]([C:14]([O:28][C:25]3[CH:24]=[CH:23][C:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:27][CH:26]=3)=[O:15])[S:9][C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(O)cc1
Reactant: CCCCCc1cc2sc(C(=O)Cl)cc2s1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCc1ccc(OC(=O)c2cc3sc(CCCCC)cc3s2)cc1

Procedure:
3.5 g of 5-n-pentyl-thieno[3,2-b]thiophene-2-carboxylic acid chloride [obtainable by reacting 5-n-pentylthieno[3,2-b]thiophene-5-carboxylic acid (m.p. 156°, c.p. 196°) with thionyl chloride] in 20 ml of toluene are added dropwise to a mixture of 2.25 g of 4-n-pentylphenol, 1.08 g of pyridine and 30 ml of toluene, the mixture is heated to the boil for 2 hours and allowed to cool, the pyridine hydrochloride is filtered off, and the mixture is worked up in the usual manner. 4-n-Pentylphenyl 5-n-pentyl-thieno[3,2-b]thiophene-2-carboxylate of melting point 58° and clear point 93° is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)=[CH:4][C:3]=1[OH:24].CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1.Cl.ClC1C=CN=CC=1>CN(C)C=O>[OH:24][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:2]=1[N:1]1[CH:27]=[CH:31][CH:30]=[CH:29]1)[CH2:6][NH:7]/[CH:8]=[C:9]1\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]2[C:18]\1=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2
Reactant: Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Reactant: COC1CCC(OC)O1
Agent: Cl
Agent: Clc1ccncc1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1ccc(-n2cccc2)c(O)c1
Reaction time: 2 h
Yield: 26.1 %

Procedure:
A mixture of (4Z)-4-{[(4-amino-3-hydroxybenzyl)amino]methylene}-6-iodoisoquinoline-1,3(2H,4H)-dion (300 mg, 0.67 mmol), 2,5-dimethoxytetrahydrofuran (182.2 mg 1.4 mmol), and 4-chloropyridine hydrochloride (101 mg, 0.67 mmol) were placed in a flask and N,N-dimethylformamide (5 mL) is added. The mixture is then placed in a pre-heated oil bath at 80° C. for 2 hours. After cooling, all the solvent is evaporated. The brown solid is stirred in water and washed with ether to give the product as a brown solid 85 mg (25% yield).; mp 230-231° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1C=[CH:15][CH2:14][CH2:13]1.C([Mg]Cl)(C)C.P(=O)(O)(O)O>ClCCl.CS(O)(=O)=O.O1CCCC1>[CH3:13][CH:14]([CH3:15])[C:9](=[O:11])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: C1=COCC1
Agent: CC(C)[Mg]Cl
Agent: CS(=O)(=O)O
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)CCc1ccccc1
Temperature: -60 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
A mixture of 3-phenylpropionic acid (13.0 g, 86.6 mmol), 2,3-dihydrofuran (6.67 g, 95.2 mmol) and dichloromethane (90 ml) was cooled to −60° C., followed by adding thereto a solution of methanesulfonic acid (0.012 g, 0.13 mmol) in dichloromethane (1 ml). The reaction mixture was heated to −5° C. and stirred at this temperature for 4 hours. The reaction mixture was re-cooled to −60° C., followed by adding dropwise thereto isopropylmagnesium chloride (a 2M tetrahydrofuran solution; 48 ml, 95.2 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a cooled aqueous phosphoric acid solution and extracted with chloroform. The extract solution was washed successively with water, a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography to obtain 5.97 g of 4-methyl-1-phenylpentan-3-one.
Reaction SMILES: N(OCCCC)=O.[C:8]([O:16][C@@H:17]1[C@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([C:31]([NH:33][CH2:34][CH3:35])=[O:32])[O:19][C@H:18]1[N:36]1[CH:44]=[N:43][C:42]2[C:37]1=[N:38][C:39](N)=[N:40][C:41]=2[Cl:45])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.II.[I:49]CI>C1COCC1.[Cu]I>[C:8]([O:16][C@@H:17]1[C@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([C:31]([NH:33][CH2:34][CH3:35])=[O:32])[O:19][C@H:18]1[N:36]1[CH:44]=[N:43][C:42]2[C:37]1=[N:38][C:39]([I:49])=[N:40][C:41]=2[Cl:45])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ICI
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: [Cu]I
Agent: CCCCON=O
Agent: II
Solvent: C1CCOC1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
n-Butyl nitrite (4.65 ml, 39.7 mmol) was added to a suspension of (2R,3R,4S,5S)-2-(2-amino-6-chloro-9H-purin-9-yl)-4-(benzoyloxy)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 18) (8.10 g, 14.7 mmol), iodine (3.73 g, 14.7 mmol), copper(I) iodide (6.16 g, 32.3 mmol) and diiodomethane (12.55 ml, 155.8 mmol) in THF (100 ml) and the mixture was heated at reflux for 2.5 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between aqueous sodium metabisulfite solution (5%, 100 ml) and dichloromethane (100 ml). The organic layer was separated, filtered through arbacel, dried (MgSO4) and solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1 by volume) to afford the title compound as a yellow foam (7.55 g, 78%).
Reaction SMILES: [CH2:1]([C:7]1[CH:18]=[CH:17][C:10]2[O:11][CH2:12][C:13](=[O:16])[CH2:14][O:15][C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5]C.[CH2:19](C1C=CC2OCC(=O)COC=2C=1)C=C.CC(C)CCC1C=CC2OCC(=O)COC=2C=1>>[CH3:19][CH:4]([CH3:5])[CH2:3][CH2:2][CH2:1][C:7]1[CH:18]=[CH:17][C:10]2[O:11][CH2:12][C:13](=[O:16])[CH2:14][O:15][C:9]=2[CH:8]=1
Reactant: C=CCc1ccc2c(c1)OCC(=O)CO2
Reactant: CCCCCCc1ccc2c(c1)OCC(=O)CO2
Agent: CC(C)CCc1ccc2c(c1)OCC(=O)CO2
Product: CC(C)CCCc1ccc2c(c1)OCC(=O)CO2

Procedure:
Odor: Marine, floral-aldehyde odor.—IR (film): ν=1502/1418/1466/1580 cm−1 (ν C═C, Ar), 1265/1304/1201 cm−1 (ν ring), 1050 cm−1 (ν C—O—C), 1741 cm−1 (ν C═O).—1H-NMR (CDCl3): δ=0.88 (2d, J=6.4 Hz, 6H, 4′-Me2), 1.18–1.24 (m, 2H, 3′-H2), 1.53–1.61 (m, 4H, 2′-H2, 4′-H), 2.50 (t, J=7.8 Hz, 2H, 1′-H2), 4.69 (d, J=8.0 Hz, 4H, 2-, 4-H2), 6.78 (dd, J=8.0, 4.0 Hz, 1H, 8-H), 6.82 (d, J=4.0 Hz, 1H, 6-H), 6.90 (d, J=8.0 Hz, 1H, 9-H).—13C-NMR (CDCl3): δ=22.44 (2q, 4′-Me2), 27.74 (d, C-4′), 29.07 (t, C-2′), 35.14 (t, C-1′), 38.39 (t, C-3′), 75.35/75.63 (2t, C-2,-4), 120.30/120.48 (2d, C-6,-9), 123.50 (d, C-8), 138.86 (s, C-7), 146.03/147.83 (2s, C-5a,-9a), 204.76 (s, C-3).—MS (EI): m/z (%)=77 (13) [C6H5+], 91 (8) [C7H7+], 135 (7) [M+-C5H11—C2H2O], 149 (16) [M+-C5H11—CO], 177 (100) [M+-C5H11], 191 (1) [M+-C4H9], 205 (3) [M+-C3H7], 248 (38) [M+].
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1([C:9]2[N:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH2:17][OH:18])[C:10]=2[CH2:19][OH:20])[CH2:8][CH2:7]1.[OH-].[Na+].[CH3:23][C:24]([CH3:26])=O>>[CH:6]1([C:9]2[C:10]([CH2:19][OH:20])=[C:11]3[CH2:17][O:18][C:24]([CH3:26])([CH3:23])[O:16][C:12]3=[C:13]([CH3:15])[N:14]=2)[CH2:7][CH2:8]1
Reactant: CC(C)=O
Reactant: Cc1nc(C2CC2)c(CO)c(CO)c1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(C2CC2)c(CO)c2c1OC(C)(C)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Sulfuric acid (18.71 g, 0.1908 mole, 10 ml) was added to a solution of 6-cyclopropyl-4,5-bis-hydroxymethyl-2-methyl-pyridin-3-ol (166) (10.0 g, 47.7 mmol) in anhydrous acetone (60 mL) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred overnight, poured into a cold solution of aqueous sodium hydroxide (excess) and the crude product was extracted with chloroform and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified on a silica gel column using a mixture of ethyl acetate hexane (2:8) as eluant to give (6-cyclopropyl-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)-methanol (167) (5.2 g, 44% yield) as a brown liquid.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl.[NH2:26][C:27]1[CH:28]=[C:29]([C:33]2[N:38]=[C:37]([NH:39][C:40]3[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH3:49])=[C:42]([O:50][CH3:51])[CH:41]=3)[C:36]3=[C:52]([CH3:56])[N:53]=[C:54]([CH3:55])[N:35]3[N:34]=2)[CH:30]=[CH:31][CH:32]=1>>[CH3:56][C:52]1[N:53]=[C:54]([CH3:55])[N:35]2[C:36]=1[C:37]([NH:39][C:40]1[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([O:46][CH3:47])[CH:45]=1)=[N:38][C:33]([C:29]1[CH:28]=[C:27]([NH:26][C:1](=[O:4])[CH3:2])[CH:32]=[CH:31][CH:30]=1)=[N:34]2
Reactant: COc1cc(Nc2nc(-c3cccc(N)c3)nn3c(C)nc(C)c23)cc(OC)c1OC
Reactant: CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COc1cc(Nc2nc(-c3cccc(NC(C)=O)c3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
14 mg (0.21 mmol) of acetic acid, 31 mg (0.23 mmol) of HOBt, 63 mg (0.62 mmol) of 4-methylmorpholine, 44 mg (0.23 mmol) of EDC and 87 mg (0.21 mmol) of 3-[5,7-dimethyl-4-(3,4,5-trimethoxyphenoxy)imidazo[5,1-f][1,2,4]triazin-2-yl]-aniline from example 7 are reacted analogously to example 2.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:21]([CH3:22])=[CH:20][C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)=[CH:7][C:6]=1[CH3:23].C1CCC(N=C=NC2CCCCC2)CC1.[C:39]1([SH:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:23])=[CH:7][C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](=[O:16])[S:45][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:20][C:21]=1[CH3:22]
Reactant: COCOc1c(C)cc(/C=C/c2cccc(C(=O)O)c2)cc1C
Reactant: Sc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCOc1c(C)cc(/C=C/c2cccc(C(=O)Sc3ccccc3)c2)cc1C
Reaction time: 18 h

Procedure:
To a solution of (E)-3-[4-(methoxymethoxy)-3,5-dimethylstyryl]benzoic acid (0.1 g, 0.320 mmol) in DCM (5 mL) were added DCC (72.6 mg, 0.352 mmol), DMAP (7.9 mg, 0.064 mmol), and benzenethiol (65.7 μL, 0.640 mmol) at room temperature. The reaction mixture was stirred overnight (about 18 hours) and filtered through Celite. The filtrate was washed with 10% citric acid, brine, and dried with Na2SO4. The solution was filtered and concentrated. The compound was purified by column chromatography (9:1 Hexane:EtOAc) to afford (E)-S-phenyl 3-(4-(methoxymethoxy)-3,5-dimethylstyryl)benzothioate in quantitative yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[NH:11][C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:13]=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C>[CH3:8][O:9][C:10]1[N:11]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:13]=2
Reactant: BrCC1CCOCC1
Reactant: COCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
8-(Methoxy)-2-{[2-(methoxy)ethyl]oxy}-9H-purin-6-amine trifluoroacetate salt (0.30 g) was heated with anhydrous potassium carbonate (0.4698 g) in anhydrous DMF (5 mL) at 60° C. for 1 hour. The reaction mixture was cooled to room temperature before 4-(bromomethyl) tetrahydro-2H-pyran (0.1669 g) was added in anhydrous DMF (1 mL). The reaction mixture was then stirred overnight at 50° C. The reaction mixture was quenched into water (20 mL) and extracted into ethyl acetate (20 mL, 3 times).
Reaction SMILES: C1C2C(OC([NH:17][C@@H:18]([CH3:49])[C:19]([NH:21][C:22]3[CH:48]=[CH:47][C:25]([CH2:26][C@@H:27]4[CH2:31][CH2:30][C@H:29]([C@H:32]([OH:39])[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:28]4[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[CH:24][CH:23]=3)=[O:20])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C1COCC1>[NH2:17][C@@H:18]([CH3:49])[C:19]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][C@@H:27]2[CH2:31][CH2:30][C@H:29]([C@H:32]([OH:39])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:28]2[C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])=[CH:47][CH:48]=1)=[O:20]
Reactant: C[C@H](NC(=O)OC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: C[C@H](N)C(=O)Nc1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 35 °C

Procedure:
To a stirred solution of 3.15 g (4.65 mmol) of tert-butyl (2S,5R)-2-{4-[((2S)-2-{[(9H-fluoren-9-yloxy)carbonyl]amino}propanoyl)amino]benzyl}-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate from step A above in 3 mL of anhydrous THF was added 0.396 g (4.65 mmol) of piperidine. The resulting mixture was heated to 35° C. underan atmosphere of nitrogen for 2 h then all volatiles were removed in vacuo to afford the crude title compound which was used without further purification. LC-MS: m/z (ES) 454 (MH)+.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:27]([OH:28])=[CH:26][C:20]4[O:21][CH2:22][CH2:23][CH2:24][O:25][C:19]=4[CH:18]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4=[CH:18][C:19]5[O:25][CH2:24][CH2:23][CH2:22][O:21][C:20]=5[CH:26]=[C:27]4[O:28][CH2:36]3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1C(c2cc3c(cc2O)OCCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(8-hydroxy-3,4-dihydro-2H-1,5-benzo-dioxepin-7-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1H)-one was obtained (75%) as a pale pink solid: mp 165-168° C. (ethyl acetate/methanol); 1H NMR (300 MHz, CDCl3) δ 7.42-7.28 (m, 10H), 7.15 (dd, J=7.2, 1.4 Hz, 1H), 7.06 (s, 1H), 7.04-6.94 (m, 2H), 6.61 (s, 1H), 6.50 (d, J=7.5 Hz, 1H), 6.35 (s, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 4.29-4.22 (m, 1H), 4.16-4.03 (m, 2H), 4.01-3.93 (m, 1H), 2.24-2.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.7, 156.9, 153.1, 146.4, 141.8, 137.7, 137.6, 132.5, 128.9, 128.8, 128.6, 128.44, 128.41, 128.0, 124.0, 123.4, 123.2, 116.1, 112.3, 103.6, 80.7, 70.92, 70.88, 58.8, 57.8, 32.3; MS (ES+) m/z 476.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.N1C=CC=CC=1.Cl[S:19]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[CH:24][C:23]=1[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:21])=[O:20]>C(Cl)Cl>[OH:10][B:7]1[C:6]2[CH:11]=[C:2]([NH:1][S:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:34])[C:30]([F:31])([F:32])[F:33])=[CH:24][C:23]=3[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:20])=[O:21])[CH:3]=[CH:4][C:5]=2[CH2:9][O:8]1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: CCOC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.9 %

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.7 g, 4.7 mmol), pyridine (1 mL, 12.4 mmol) in DCM (10 mL) was added ethyl 2-(2-(chlorosulfonyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate (1.5 g, 4 mmol). The reaction was stirred at r.t. for 2 hr and monitored by LC/MS. Purification: The solvent was removed and worked up with EtOAc and 1N HCl, brine, dried over Na2SO4. A portion of the crude material was purified by the preparative HPLC give the title product ethyl 2-(2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-5-(2,2,2-trifluoroacetamido)phenyl)acetate 18 mg as white powder 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.54 (s, 1H), 10.36 (s, 1H), 9.21 (bs, 1H), 7.85 (d, J=8 Hz, 1H), 7.71 (m, 2H), 7.44 (d, J=2 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.12 (dd, J=8, 2 Hz, 1H), 4.87 (s, 2H), 4.06 (m, 4H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z=485.1 (M−H, negative).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.COC(C1C=CC2SCC(=O)NC=2C=1)=O.[Li+].[OH-]>C1COCC1.O>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Agent: COC(=O)c1ccc2c(c1)NC(=O)CS2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid. To a solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl ester (1.5 g, 6.7 mmol) in a THF/H2O mixture (1:1, 63 mL) was added 4 N LiOH (8.0 mL, 32 mmol) and the resulting solution was stirred at RT for 24 h. The solution was partially concentrated and diluted with H2O (50 mL). The solution was acidified using concentrated HCl and a solid precipitated. The solid was collected via filtration, washed with H2O and dried in vacuo to provide 0.79 g (60%) of the title compound as a white solid. MS (ESI): exact mass calculated for C9H7NO3S, 209.01; m/z found, 210.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.65-7.61 (m, 2H), 7.40 (d, J=8.1, 1H), 3.48 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([CH3:9])[O:4][N:3]=1.[O:10]=[S:11]1(=[O:34])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([NH:20][C@@H:21]([CH2:26][C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)[C:22]([O:24][CH3:25])=[O:23])=[N:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[O:10]=[S:11]1(=[O:34])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([NH:20][C@@H:21]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:8][CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:9])=[CH:29][CH:28]=2)[C:22]([O:24][CH3:25])=[O:23])=[N:12]1
Reactant: Cc1noc(C)c1CO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC1=NS(=O)(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCc2c(C)noc2C)cc1)NC1=NS(=O)(=O)c2ccccc21
Temperature: 5 °C

Procedure:
(3,5-Dimethylisoxazol-4-yl)methanol (0.28 g, 1.5 mmol), methyl (2S)-2-[(1,1-dioxo-1,2-benzoisothiazol-3-yl)amino]-3-(4-hydroxyphenyl)propionate (0.36 g, 1 mmol) and triphenylphosphine (0.79 g, 3 mmol) were dissolved in tetrahydrofuran (2 ml). After cooling to 5° C., DEAD (0.52 g, 3 mmol) was added to the reaction mixture. The reaction was then stirred at room temperature for 18–24 h. THF was evaporated to obtain crude title product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:9]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([NH:27][CH3:28])=[O:26].FC(F)(F)C(O)=O>CC(O)C>[F:20][C:5]1[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:9]2)=[N:7][C:2]([NH:21][C:22]2[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=2)[C:25]([NH:27][CH3:28])=[O:26])=[N:3][CH:4]=1
Reactant: Fc1ccc(OC2CN(c3nc(Cl)ncc3F)C2)cc1
Reactant: CNC(=O)c1cccc(N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2ncc(F)c(N3CC(Oc4ccc(F)cc4)C3)n2)c1
Temperature: 84 °C
Reaction time: 0.17 h
Yield: 100.4 %

Procedure:
To 2-chloro-5-fluoro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidine (90.0 mg, 0.302 mmol) and 3-amino-N-methylbenzamide (49.9 mg, 0.333 mmol) in a disposable sealed tube in 2-propanol (2.50 mL) was added trifluoroacetic acid (0.070 mL, 0.907 mmol). The resulting reaction mixture was heated at 84° C. for 3 d, cooled to RT and concentrated. The residue was stirred in EtOAc and saturated aqueous NaHCO3 for 10 min and transferred to a reparatory funnel. The organic layer was washed with brine, dried and concentrated giving 3-(5-fluoro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidin-2-ylamino)-N-methylbenzamide (124.8 mg).