Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[NH:13][C:14]([C:15]([O:17]C)=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[NH:13][C:14]([C:15]([OH:17])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1
Reactant: COC(=O)c1[nH]c(=O)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1[nH]c(=O)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
A mixture of 4.02 g (0.01 mole) of 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, methyl ester, 150 ml of methanol, 15 ml of water and 2 g (0.035 mole) of potassium hydroxide was heated to reflux for 5 hours under a nitrogen atmosphere. The solution was then concentrated down to 40 ml, acidified by addition of 4 ml of glacial acetic acid and crystallized by diluting with water. The precipitate was collected, dried and recrystallized from tetrahydrofuran/methanol/ethyl acetate to yield 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid which was decarboxylated as follows: A solution of 1 g of this acid in 5 ml of ethylene glycol was heated to reflux for 45 min and then partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic layer was washed with bicarbonate solution and water, dried and evaporated. Crystallization of the residue from ethyl acetate/ether gave end product which was further purified by chromatography over 20 g silica gel using methylene chloride/ethyl acetate 1:3. Crystallization from ethyl acetate/ether yielded the pure colorless product with mp 236°-238°. nmr (CDCl3) δ 4.25 ppm (broad d, 1) and 4.86 (broad d, 1) (AB-system, J=13 Hz, C4 --H) 6.25 (d, 1 , J=2 Hz, C3 --H) 6.98 (d, 1, J=2.5 Hz, C7 --H) 7.1-7.7 (m, 5, aromatic H) 8.0 (d, 1, J=8 Hz, C10 --H) 10.4 (broad s, 1, NH).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]([CH2:9][C@H:10]([CH2:21][NH:22][C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH3:12])[CH3:8])=[O:6])[CH:2]=[CH2:3].Cl>C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]([CH2:9][C@@H:10]([C@H:11]([OH:13])[CH3:12])[CH2:21][NH:22][C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH3:8])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NC[C@@H](CN(C)C(=O)OCC=C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)NC[C@@H](CN(C)C(=O)OCC=C)[C@@H](C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a stirred solution of (2S,3R)-1-(N-allyloxycarbonyl-N-methylamino)-2-allyloxycarbonylaminomethyl-3-t-butyldimethylsilyloxybutane (28.18 g) in ethyl acetate (500 ml) was added hydrochloric acid (6N, 17 ml), and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was washed in turn with cold water, aqueous sodium hydrogen carbonate, and brine, and dried over magnesium sulfate. Evaporation of the solvent gave a residue which was chromatographed on silica gel (500 ml) eluting with a mixture of n-hexane and ethyl acetate (9:1-6:4, V/V) to give (2S,3R)-2-(N-allyloxycarbonyl-N-methylaminomethyl)-1-allyloxycarbonylamino-3-hydroxybutane (20.11 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4]([CH:6]1[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:27]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:28]
Reactant: CCN(CC)C(=O)C1CN(Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)C(=O)C1CNCCNC1
Reaction time: 2 h

Procedure:
2.2 g (5.8 mmol) of 1,4-dibenzyl-[1,4]-diazepan-6-carboxylic acid diethylamide are dissolved in 50 ml of ethanol and hydrogenated over 2 h at room temperature and normal pressure in the presence of 0.5 g of 10% palladium on activated charcoal. Filtration over kieselguhr gives an almost colorless filtrate from which [1,4]-diazepan-6-carboxylic acid diethylamide is obtained in the form of a light yellow oil by concentration under vacuum.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(C2C=CC=CC=2)C=CC=CC=1.[CH3:17][C:18]1[CH:19]=[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=2)[CH:21]=[CH:22][C:23]=1[CH3:24].[C:33](Cl)(Cl)=[O:34]>C(=S)=S>[CH3:31][C:28]1[C:33](=[O:34])[C:30]2[C:25](=[CH:26][C:27]=1[CH3:32])[C:20]1[C:21](=[CH:22][C:23]([CH3:24])=[C:18]([CH3:17])[CH:19]=1)[CH:29]=2
Reactant: Cc1ccc(-c2ccc(C)c(C)c2)cc1C
Reactant: O=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC1=C(C)C(=O)C2=Cc3cc(C)c(C)cc3C2=C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
35.6 g of anhydrous aluminium chloride are added in portions to a solution of 20 g of biphenyl according to (a) and 14 g of phosgene in 130 ml of carbon disulfide at -10° C. to 0° C. in the course of 2 hours. After stirring at room temperature for 15 hours, the mixture is refluxed for 2 hours, poured onto ice-water and extracted with 1.5 l of chloroform. The residue from the organic phase (22.9 g) is separated by column chromatography on silica gel. Elution with methylene chloride/toluene=13:7 gives 9.8 g of 1,2,6,7-tetramethyl-fluorenone (Rf value 0.62) and 10.04 g of 2,3,6,7-tetramethyl-fluorenone (Rf value 0.41).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](N)=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].C(ON=O)CC(C)C.C(OCC)(=O)C.O>O1CCCC1.CN(C)C=O>[C:1]([C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N)nc1C
Agent: CC(C)CCON=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1scnc1C
Yield: 54.6 %

Procedure:
To a solution of 5-acetyl-2-amino-4-methylthiazole (15.6 g) in a mixture of tetrahydrofuran (200 ml) and dimethylformamide (50 ml) was dropwise added isoamylnitrite (14.6 g) at 50° C. to 55° C. with stirring and the mixture was stirred at 55° C. to 60° C. for 4 hours. The reaction mixture was poured into a mixture of ethyl acetate and water with stirring. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was subjected to column chromatography on silica gel and eluted with a mixture of diisopropyl ether and ethyl acetate (1:1). The fractions containing the desired compound were combined and evaporated in vacuo to give 5-acetyl-4-methylthiazole (7.7 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[O:17][C:16]([C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=2[F:27])[C:21](O)=[O:22])=[CH:15][CH:14]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:61][N:62]1[CH2:68][CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[O:17][C:16]([C:18]2[CH:19]=[C:20]([C:21]([N:65]3[CH2:66][CH2:67][CH2:68][N:62]([CH3:61])[CH2:63][CH2:64]3)=[O:22])[CH:24]=[CH:25][C:26]=2[F:27])=[CH:15][CH:14]=1
Reactant: CN1CCCNCC1
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2cc(C(=O)O)ccc2F)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCCN(C(=O)c2ccc(F)c(-c3ccc(C=C4C(=O)Nc5ccc(Cl)cc54)o3)c2)CC1
Temperature: 25 °C

Procedure:
To 3-(5-((5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-4-fluorobenzoic acid (39 mg, 0.102 mmol) in DMF was added HBTU (58 mg, 0.153 mmol) and DIEA (53 μL, 0.306 mmol). The mixture was stirred at room temperature then was added 1-methylhomopiperazine (16 μL, 0.122 mmol) and allowed to stir at room temperature. The solid formed was isolated by filtration and purified by HPLC to yield 5-chloro-3-((5-(2-fluoro-5-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=480).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@@H:11]([CH2:13]I)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=3[NH:23][C:22]2=[O:31])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][C@@H:11]([CH2:13][N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[C:25]5[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=5[NH:23][C:22]4=[O:31])[CH2:19][CH2:20]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([C@H]2C[C@@H](CI)CO2)cc1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(C[C@H]2CO[C@@H](c3ccc(F)cc3)C2)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 1.74 g of cis-2-(4-fluorophenyl)-4-(iodomethyl)tetrahydrofuran, 1.5 g of 1-(4-piperidyl)-5-chloro-benzimidazolin-2-one and 0.8 g of potassium carbonate in 20 ml of dimethylformamide is heated with stirring at 70° C. for 16 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The crystalline residue is recrystallized from ethanol to give 1-[1-(cis-2-(4-fluorophenyl)-tetrahydro-4-furylmethyl)-4-piperidyl]-5-chloro-benzimidazolin-2-one as colorless prisms, melting at 207.5°-208.5° C. The corresponding maleate melts at 207° C. with decomposition.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[C:50]([F:56])=[C:51]([CH:53]=[CH:54][CH:55]=2)[NH2:52])[CH:38]=[CH:37][N:36]=1.[N:57]1[CH:62]=[CH:61][CH:60]=[C:59]([S:63](Cl)(=[O:65])=[O:64])[CH:58]=1>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[C:50]([F:56])=[C:51]([NH:52][S:63]([C:59]3[CH:58]=[N:57][CH:62]=[CH:61][CH:60]=3)(=[O:65])=[O:64])[CH:53]=[CH:54][CH:55]=2)[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2F)c(-c2ccnc(Cl)n2)s1
Yield: 75.3 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline (3 g, 8.6 mmol) and pyridine-3-sulfonyl chloride (1.68 g, 9.5 mmol) the title compound of Step A was obtained (2.1 g, 75.3% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.97-9.01 (br, 1H), 8.76-8.79 (m, 1H), 8.35 (d, J=5.3 Hz, 1H), 8.08-8.12 (m, 1H), 7.68-7.74 (m, 1H), 7.40-7.44 (m, 1H), 7.22-7.34 (m, 3H), 6.69 (d, J=5.3 Hz, 1H), 3.29-3.38 (m, 1H), 1.44 (d, J=6.8 Hz, 6H). MS (ES+): 490 [M+H]+.
Reaction SMILES: Cl.Cl.[C:3]1([CH2:9][O:10][NH:11][CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][NH:14][CH2:13]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[O:29]=[C:30](Cl)OC(Cl)(Cl)Cl.CN(C1C=CC=CN=1)C>C(#N)C>[C:3]1([CH2:9][O:10][N:11]2[CH:12]3[CH2:13][N:14]([NH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=43)[C:30]2=[O:29])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(CONC2CNNc3ccccc32)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1N2CC(c3ccccc3N2)N1OCc1ccccc1
Reaction time: 1 h
Yield: 135.7 %

Procedure:
3.13 g of the compound obtained in stage C are dissolved in 1.9 l of acetonitrile. 4.81 g (6.6 ml) of triethylamine are added dropwise over 10 minutes. 0.943 g (575 μl) of diphosgene is subsequently added slowly at 0° C., followed by 1.27 g of dimethylaminopyridine. The temperature is subsequently allowed to return to ambient temperature. After one hour, the acetonitrile is evaporated and the residue is treated with NaH2PO4 (1M aqueous solution). Extraction is carried out with a heptane/AcOEt 1:2 mixture and washing is carried out with water. The organic phase is dried over MgSO4 and evaporated to dryness. This residue is crystallized from ether at 0° C. 1.82 g of the expected compound (68%) are obtained.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:6]1OS(C(F)(F)F)(=O)=O)(=[O:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.C(Cl)Cl>[N:32]([C@@H:6]1[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:26][C@H:5]1[O:4][C:1](=[O:3])[CH3:2])=[N+:33]=[N-:34]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@@H](OS(=O)(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 40 °C
Yield: 80.6 %

Procedure:
To a solution of mannose triflate 56 (1.28 g, 2.66 mmol) in 14 mL of DMF is added sodium azide (0.69 g, 10.5 mmol). The reaction mixture is heated at 40° C. for 1.75 h, cooled to room temperature, diluted with 100 mL of CH2Cl2, washed with H2O (100 mL), saturated NaCl (100 mL), dried over MgSO4, filtered, and concentrated to afford a yellow oil. The product is purified by flash chromatography (33% EtOAc/hexane) to afford 0.80 g (81%) of 2-azido-2-deoxy-1,3,4,6-tetra-O-acetyl-β-D-glucopyranose 57: Rf 0.31 (33% EtOAc/hexane) δ 5.55 (d, J=8.6 Hz, 1H, H-1), 5.015.15 (m, 2H, H-3, H-4), 4.31 (dd, J=12.7, 4.5 Hz, 1H, H-6), 4.08 (d, J=12.5 Hz, 1H, H-6), 3.77-3.84 (m, 1H, H-5), 3.69 (app t, J=9.1 Hz, 1H, H-2), 2.10 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C)C=O>[CH2:25]([O:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:9]2[N:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[CH:15][CH:16]=1)[CH:24]=[CH2:23]
Reactant: Oc1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Reaction time: 0.75 h

Procedure:
A 2.73 g portion of dry 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenol was dissolved in 50 ml of dry dimethylformamide. A 528 mg portion of sodium hydride (50% in oil) was added, the reaction was sealed and stirred for 45 minutes. A solution of 1.33 g of allyl bromide in 10 ml of dimethylformamide was added, the sealed mixture was stirred overnight and then evaporated at 80° C. The residue was partitioned between water and chloroform. The organic phase was separated, dried and filtered. The filtrate was evaporated and the residue crystallized from chloroform-hexane, giving 1.7 g of the desired product as yellow crystals, mp 105°-108° C.
Reaction SMILES: [C:1]([C:9]1[C:18]([CH2:19][S:20][CH3:21])=[N+:17]([O-:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[C:1]([C:9]1[C:18]([CH2:19][S:20]([CH3:21])=[O:32])=[N+:17]([O-:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:23])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSCc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)Cc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]

Procedure:
A solution of 3.26 g. (0.01 mol) of 2-benzoyl-3-methylthiomethylquinoxaline 1,4-dioxide and 2.20 g. (0.01 mol.) of 85% pure 3-chloroperbenzoic acid in 150 ml. of chloroform is stirred at room temperature overnight. The reaction mixture is washed with 5% sodium bicarbonate solution, dried, and evaporated in vacuo to afford crude 2-benzoyl-3-methylsulfinylmethylquinoxaline 1,4-dioxide.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][CH:14]([CH:19]1[CH2:21][CH2:20]1)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[CH3:10])=O)(C)(C)C.[ClH:22]>O1CCOCC1>[ClH:22].[NH2:8][C@H:9]([C:11]([NH:13][CH:14]([CH:19]1[CH2:21][CH2:20]1)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[CH3:10]
Reactant: COC(=O)C(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(NC(=O)[C@H](C)N)C1CC1
Yield: 100 %

Procedure:
A solution of methyl {[N-(tert-butoxycarbonyl)-L-alanyl]amino}(cyclopropyl)-acetate (72 mg, 0.24 mmol) in 4 N HCl in dioxane (1 mL) was stirred at rt for 45 min. Concentrate to afford 57 mg (100%) of methyl (L-alanylamino)(cyclopropyl)acetate hydrochloride as a solid: 1H NMR (DMSO-d6) δ 0.42-0.60, 1.21-1.26, 1.68, 3.65-3.91, 4.60, 8.17; MS (ESI+) for C8H12N2O2 m/z 201 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[N:3]=1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[N:3]=1
Reactant: O=C1CCc2c(cc(Br)nc2-c2ccc(F)cc2F)N1c1c(Cl)cccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1ccc2c(-c3ccc(F)cc3F)nc(Br)cc2n1-c1c(Cl)cccc1Cl

Procedure:
To a refluxing solution of 7-bromo-1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-1,6-naphthyridin-2(1H)-one (0.747 g) and AIBN (0.03 g) in 30 mL of CCl4 was added recrystallized N-bromosuccinimide (0.302 g). The reaction was stirred at reflux for 1 h, then removed from the heat. DBU (0.23 mL) was added and the mixture was stirred at rt for 15 min. The reaction mixture was washed with 100 mL of saturated sodium bicarbonate and back extracted with 50 mL of dichloromethane. The combined organics were washed with 100 mL of brine, dried with sodium sulfate, and concentrated to give the desired product. Mass spectrum m/z (ESI) 481.3 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1([N:13]([C:15](=[O:26])[CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=2[CH3:25])[OH:14])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=O.CC(C)([O-])C.[K+].O.Cl>CN(C)C=O>[Cl:24][C:20]1[CH:19]=[C:18]([CH3:25])[C:17]([C:16]2[C:15](=[O:26])[N:13]([OH:14])[C:5]3([CH2:6][CH2:7][N:8]([O:11][CH3:12])[CH2:9][CH2:10]3)[C:3]=2[OH:2])=[C:22]([CH3:23])[CH:21]=1
Reactant: COC(=O)C1(N(O)C(=O)Cc2c(C)cc(Cl)cc2C)CCN(OC)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(Cl)cc1C)C(=O)N2O
Reaction time: 8 h

Procedure:
To a suspension of 4-{[2-(4-chloro-2,6-dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (0.40 g, 1.04 mmol) in dimethylformamide (3 ml) at 0° C. was added potassium tert-butoxide (0.35 g, 3.12 mmol) in portions. After completion of the addition, stirring was continued at 0° C. for 30 minutes and at room temperature overnight. The reaction mixture was poured into cold water (0° C.), the pH adjusted to ca 5.5 by adding 1 N HCl and then thoroughly extracted with ethyl acetate (three times). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. The resulting crude material was purified by column chromatography on silica gel (gradient ethyl acetate/cyclohexane 1:1→ethyl acetate). Yield: 0.14 g of 3-(4-chloro-2,6-dimethyl-phenyl)-1,4-dihydroxy-8-methoxy-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2ii.103) as a white solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([F:23])=[CH:25][CH:26]=2)=[O:35])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1ccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol (355 mg, 1.17 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (223 mg, 1.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (336 mg, 1.76 mmol) and 1-hydroxybenzotriazole hydrate (179 mg, 1.17 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively-with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (333 mg, 61%).
Reaction SMILES: C(Cl)(=O)C.[CH3:5][NH:6][CH3:7].[C:8]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([N+:21]([O-:23])=[O:22])([CH2:14]3)[CH2:12]1)[CH2:18]2)(O)=[O:9]>CN(C=O)C>[CH3:5][N:6]([CH3:7])[C:8]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([N+:21]([O-:23])=[O:22])([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:9]
Reactant: O=C(O)C12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Reactant: CNC
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: CN(C)C(=O)C12CC3CC(C1)CC([N+](=O)[O-])(C3)C2
Reaction time: 2 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1-carboxy-3-nitroadamantane obtained by the method of Example 43 was dissolved in 10 ml of DMF. To the mixture, 15 mmole of acetyl chloride was added dropwise over 30 minutes. The mixture was heated to begin to reflux around the conclusion of the addition. After refluxing for 2 hours, the mixture was cooled,and 25 mmole of dimethylamine was added dropwise over 30 minutes while retaining the temperature of the mixture at 10° C. or less followed by stirring for more 2 hours. As a result, the conversion of 1-carboxy-3-nitroadamantane was 99%, and 1-(N,N-dimethylcarbamoyl)-3-nitroadamantane (yield 95%) was formed.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:25][C:24]([F:30])([C:26]([O:28]C)=[O:27])[CH2:23]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[Li+].[OH-]>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:25][C:24]([F:30])([C:26]([OH:28])=[O:27])[CH2:23]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:32])[F:31])[CH:8]=1
Reactant: COC(=O)C1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CC(F)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
(Z)-Methyl 1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-fluoroazetidine-3-carboxylate (0.01 g, 1.0 eq.) was dissolved in methanol:water (0.2 mL, 1:1), and LiOH (1.0 mg, 1.0 eq) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 10 mL of water and acidified with dilute HCl to pH 2-3. The aqueous layer was extracted with ethyl acetate (10 mL×3). The combined organic layers were then washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 0.002 g of (Z)-1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-fluoroazetidine-3-carboxylic acid. Yield (20.83%). 1H NMR (400 MHz, CDCL3) δ 8.92 (S, 1H), 8.54 (s, 2H), 8.29 (s, 1H), 7.45-7.42 (d, J=10.4, 1H), 6.00-5.98 (d, J=10.4 Hz, 1H), 3.73 (m, 4H).