Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][O:23][CH2:24][C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[C:19]3[CH:30]=[CH:31][CH:32]=[CH:33][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl>ClCCl>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[CH2:24][O:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:30]=[CH:31][CH:32]=[CH:33][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2CCOCc2ccco2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(c1nc2ccccc2n1CCOCc1ccco1)C1CCNCC1
Reaction time: 0.75 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-fur-2-ylmethoxy-ethyl)-1H-benzimidazole-2-carbonyl)piperidine (1.0 mmol) and dioxane (10 mL). Cool in an ice bath. Slowly add a solution of hydrochloric aicd in dioxane (0.25 mL, 4M, 1.0 mmol). After 45 minutes, dilute the reaction mixture with dichloromethane and extract with saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][Cl:35])=[CH:26][CH:25]=2)=[C:16]([Cl:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][Cl:35])=[CH:28][CH:29]=2)=[C:16]([Cl:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: ClCCCCOc1ccc(C(=C(Cl)c2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(C(=C(Cl)c2ccccc2)c2ccc(OCCCCCl)cc2)cc1
Reaction time: 1.5 h

Procedure:
Combine 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy)phenyl)-2-chloro-2-phenyl ethylene (0.1 g, 0.20 mmol), 5% palladium-on-carbon (30 mg), and ethyl acetate (1.5 mL). Treat with hydrogen at atmospheric pressure. After 1.5 hours, filter using a 0.45 micron membrane. Concentrate the filtrate in vacuo to give 1-(4-hydroxyphenyl)-1-(4-(4-chlorobutyloxy)phenyl)-2-chloro-2-phenyl ethylene.
Reaction SMILES: [ClH:1].[OH:2][CH2:3][CH2:4][NH:5][N:6]=[CH:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[C:18]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([CH2:31][CH2:32][C:33](=[O:35])[NH2:34])=[C:26](O)[CH:25]=[CH:24]2)(=[NH:20])[NH2:19].Cl.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:1].[ClH:1].[OH:2][CH2:3][CH2:4][NH:5][N:6]=[CH:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][C:26]2[CH:25]=[CH:24][C:23]3[C:28](=[CH:29][CH:30]=[C:21]([C:18](=[NH:19])[NH2:20])[CH:22]=3)[C:27]=2[CH2:31][CH2:32][C:33](=[O:35])[NH2:34])=[O:14])=[CH:11][CH:10]=1
Reactant: N=C(N)c1ccc2c(CCC(N)=O)c(O)ccc2c1
Reactant: O=C(O)c1ccc(NC=NNCCO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(CCC(N)=O)c(OC(=O)c3ccc(NC=NNCCO)cc3)ccc2c1
Reaction time: 2 h
Yield: 78.3 %

Procedure:
20 Milliliters of 20% hydrous pyridine was added to 1.45 g of 4-[(2-hydroxyethyl)aminoiminomethylamino]benzoic acid.hydrochloride, 1.5 g of 6-amidino-1-(2-carbamoylethyl)-2-naphthol.hydrochloric acid, 1.26 g of DCC and 62.3 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours at room temperature. Thereafter, the same procedure as in Example 1 was effected to obtain 1.17 g of the desired product.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)(=O)=O.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1>CN(C)P(N(C)C)(N(C)C)=O>[C:9]1([O:8][CH2:7][CH2:6][NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)OCCOc1cccc2ccccc12
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCOc2cccc3ccccc23)cc1

Procedure:
A solution of 29.1 g of 2-(1-naphthyloxy)ethanol O-methanesulfonate and 33 g of ethyl p-aminobenzoate in 100 ml of hexamethylphosphoramide is heated at 100° C. for 16 hours. The solution is worked up as described in Example 3 to give the product. Recrystallization gives crystals, mp 124°-127° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([NH:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:66])[C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][C:59]=2[Cl:65])[CH2:53][CH2:52]1)=[O:50].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[Cl:65][C:59]1[CH:60]=[C:61]([Cl:64])[CH:62]=[CH:63][C:58]=1[C:57]([N:54]1[CH2:53][CH2:52][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:21](=[O:23])[C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:25][CH:24]=2)[CH2:56][CH2:55]1)=[O:66]
Reactant: NCC(=O)N1CCN(C(=O)c2ccc(Cl)cc2Cl)CC1
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccc(Cl)cc2Cl)CC1)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
DIPEA (133 mg, 0.18 mL, 0.56 mmol) was added drop wise to 4-phenylamino-benzoic acid (preparation as described above) (75 mg, 0.35 mmol) in DMF (4 mL). EDCI (167 mg, 0.87 mmol) and HOBT (56 mg, 0.42 mmol) were added consecutively and, after 10 minutes, 2-amino-1-[4-(2,4-dichloro-benzoyl)-piperazin-1-yl]-ethanone in its TFA salt form (180 mg, 0.42 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added, filtered the solid precipitated. The solid was purified by column chromatography (using silica gel of 60-120 mesh and 70% EtOAc in Hexane as eluent) to afford 95 mg (53% yield) of N-{2-[4-(2,4-Dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LC-MS purity: 96.05%. 1H-NMR (DMSO-D6): δ 8.6 (s, 1H), 8.3 (t, 1H), 7.8 (d, 3H), 7.5 (m, 2H), 7.3 (t, 2H), 7.2 (d, 2H), 7.1 (d, 2H), 6.9 (t, 1H), 4.1 (dd, 2H), 3.6 (m, 4H), 3.5 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:1]1([CH2:9][CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: C1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of Azepane (2.3 mL), 2-(3-bromopropyl)isoindoline-1,3-dione (5.4 g) and potassium carbonate (5.5 g) in acetone (50 mL) was stirred at room temperature overnight. The solid was filtered and the filtrate was concentrated to provide 2-(3-(azepan-1-yl)propyl)isoindoline-1,3-dione, used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:25]([OH:27])=[O:26])[CH:21]=2)[N:16]=1.[CH3:28]O>Cl.O1CCOCC1>[CH3:28][O:26][C:25]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:3]1[CH:4]=[C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:9])[CH:6]=[CH:7][C:2]=1[OH:1])[CH:24]=[CH:23]2)=[O:27]
Reactant: O=C(O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3O)ccc2c1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3O)ccc2c1
Temperature: 60 °C

Procedure:
To the solution of 295 mg (0.81 mmol) of Compound 19 in 3 mL of methanol, 1 mL of 4M HCl/dioxane was added, and the mixture was heated at 60° C. overnight. The reaction mixture was then evaporated to dryness to give Compound 20 in quantitative yield. MS: 377.18 (M+H+).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:20]2[NH:21][N:22]=[N:23][CH:24]=2)=[O:19])[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[CH2:53][C:54]1[O:55][C:56](=[O:60])[O:57][C:58]=1[CH3:59].CN1CCOCC1>C(Cl)Cl.CC(O)=O>[CH3:59][C:58]1[O:57][C:56](=[O:60])[O:55][C:54]=1[CH2:53][O:12][C:11](=[O:13])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH:17][C:18]([C:20]1[NH:21][N:22]=[N:23][CH:24]=1)=[O:19])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:2][CH:3]=1
Reactant: Cc1oc(=O)oc1CO
Reactant: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Product: Cc1oc(=O)oc1COC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Reaction time: 0.17 h
Yield: 15.7 %

Procedure:
(2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid (100 mg, 245 μmol, 1.0 eq.), EDCI (52 μL, 294 μmol, 1.2 eq.) and HOBt (39.7 mg, 294 μmol, 1.2 eq.) were dissolved in DCM (5 mL). After stirring for 10 minutes, 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one (127 mg, 979 μmol, 4.0 eq.) was added. The mixture was stirred for 1 hour and 4-methylmorpholine (40.4 μL, 1.5 eq.) was added. After 1 hour, the crude material was dissolved in AcOH and purified by preparative HPLC to yield the title compound (20 mg). MS m/z [M+H]+ calc'd for C27H28N4O7, 521.20. found 521.4.
Reaction SMILES: [N:1]1([C:6]2[CH:21]=[CH:20][C:9]([CH:10]=[C:11]([C:16](=[O:19])[CH2:17][CH3:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(OCC)(=O)C>[Pd].C(O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([C:16](=[O:19])[CH2:17][CH3:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:20][CH:21]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCC(=O)C(=Cc1ccc(-n2cccn2)cc1)C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)OC
Reaction time: 2 h

Procedure:
A mixture containing methyl 2-(4-(1H-pyrazol-1-yl)benzylidene)-3-oxopentanoate (mixture of alkene isomers, 3.5 g, 12 mmol, Intermediate 32: step a) and wet 10% palladium on carbon (2.6 g) in ethanol (123 mL) was stirred at 23° C. under an atmosphere of hydrogen gas (balloon pressure). After 2 hours, the reaction mixture was degassed by bubbling nitrogen gas through the solution. The degassed mixture was filtered through Celite®, rinsing with ethanol. The filtrate was concentrated to afford a colorless oil. Ethyl acetate (100 mL) was added. Celite® (8 g) was added to the solution and the solvent was removed by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a column of silica gel for purification. Elution with hexanes initially, grading to 40% ethyl acetate-hexanes provided the title compound as a clear, colorless oil.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@@H:15]2[CH2:16][CH2:17][C@@H:12]([C@@H:13]([OH:19])[C@H:14]2[OH:18])[N:11]1C(OC(C)(C)C)=O)=[O:9])#[N:2].[ClH:27]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:27].[OH:18][C@@H:14]1[C@H:13]([OH:19])[C@@H:12]2[CH2:17][CH2:16][C@H:15]1[C@@H:10]([C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[C:1]#[N:2])=[O:9])[NH:11]2
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)N2CCC[C@H]2C#N)[C@@H]2CC[C@H]1[C@@H](O)[C@H]2O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: N#C[C@@H]1CCCN1C(=O)[C@H]1N[C@H]2CC[C@@H]1[C@H](O)[C@@H]2O
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (1S,3S,4S,5S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-5,6-dihydroxy-2-azabicyclo[2.2.2]octane-2-carboxylate obtained in Example 1-4 (122 mg) in chloroform (1 mL), was added 4N HCl in dioxane (3 mL) at room temperature. The reaction mixture was stirred for 15 minutes and the organic solvent was removed in vacuo. The residue was triturated with ethyl acetate to give the target compound as a white powder (100 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[C:15]([OH:17])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[C:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: O=C(O)c1cnoc1-c1ccc([N+](=O)[O-])cc1
Product: O=C(c1cnoc1-c1ccc([N+](=O)[O-])cc1)N1CCCC1

Procedure:
The title compound was prepared from 5-(4-nitrophenyl)isoxazole-4-carboxylic acid (11.7 mg, 0.050 mmol) and pyrrolidine (4.3 mg, 0.060 mmol) as described in synthetic method A and thereafter purified, first by preparative HPLC method A and then by method B, to give a solid (13.4 mg). MS (pos) m/z 288.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.[CH3:33][C:34]1[N:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](O)=[O:37].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][C:36]([C:35]2[C:34]([CH3:33])=[N:42][CH:41]=[CH:40][CH:39]=2)=[O:37])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]2[CH3:20]
Reactant: Cc1ncccc1C(=O)O
Reactant: COc1ccccc1NCc1c(-c2ccc(O)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccccc1NCc1c(-c2ccc(OC(=O)c3cccnc3C)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 6-(4-hydroxy-2-methoxyphenyl)-5-(2-methoxyphenylaminomethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-1, 25.0 mg, mmol), 2-methylnicotinoic acid (8.0 mg, 0.058 mmol), N,N-diisopropylethylamine (20.2 μL, 0.116 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (24.3 mg, mmol) was dissolved in anhydrous N,N-dimethylformamide (0.5 mL), and then the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (70 mL). The mixture was washed with water (70 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (20.7 mg) as a colorless solid. (Yield 65%)
Reaction SMILES: [Si]([O:8][CH:9]([C:14]1[S:18][C:17]([C:19](=[O:21])[CH3:20])=[N:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[F:12][C:10]([F:11])([F:13])[CH:9]([C:14]1[S:18][C:17]([C:19](=[O:21])[CH3:20])=[N:16][CH:15]=1)[OH:8]
Reactant: CC(=O)c1ncc(C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)c1ncc(C(O)C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (3 mL) was dissolved 1-(5-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl) thiazol-2-yl)ethanone (356 mg, 1.05 mmol) obtained in Step 3. To the solution were added acetic acid (0.072 mL, 1.26 mmol) and tetrabutylammonium fluoride (1.0 mol/L solution in THF, 1.26 mL, 1.26 mmol) and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium carbonate solution was added to the reaction mixture. Extraction with ethyl acetate, washing with a saturated aqueous ammonium chloride solution and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give Compound A46 (214 mg, 91%).
Reaction SMILES: [CH3:1][C:2](=[CH2:19])[CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]2=[CH:15][S:16][CH:17]=[C:6]2[C:5]1=O.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH3:19][C:2](=[CH2:1])[CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]2=[CH:15][S:16][CH:17]=[C:6]2[CH2:5]1
Reactant: C=C(C)CN1C(=O)c2cscc2Nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)CN1Cc2cscc2Nc2ccccc21

Procedure:
A 4.9 g. portion of 4,9-dihydro-9-(2-methylallyl)-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of dried tetrahydrofuran is added with stirring and ice bath cooling, under nitrogen, to 2.9 g. of lithium aluminum hydride in 100 ml. of dried tetrahydrofuran. The mixture is refluxed overnight and then decomposed with stirring and cooling under nitrogen by the successive addition of 3 ml. of water, 3 ml. of 15% sodium hydroxide and 9 ml. of water. The complex is filtered and washed with ether. The combined filtrate and washing is dried over sodium sulfate, filtered and evaporated to a residue on a steam bath. The residue is recrystallized from hexane giving the desired product, mp. 83°-84° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:38])[CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](C3N(C)C=CN=3)[S:17][C:10]=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C([C:56]3[N:60]([CH3:61])[CH:59]=[N:58][CH:57]=3)SC=12>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:38])[CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:56]3[N:60]([CH3:61])[CH:59]=[N:58][CH:57]=3)[S:17][C:10]=12
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Reactant: Cn1cncc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cncn4C)sc23)c(F)c1
Yield: 24 %

Procedure:
Following the procedure described above for the compound 28a (example 8, step 2) but replacing amine 9 for amine 18, title compound 28c was obtained in 24% yield. 1H NMR (DMSO-d6) δ (ppm): 10.58 (s, 1H), 9.62 (s, 1H), 8.49 (d, 1H), 8.05 (dd, 1H), 7.85 (m, 2H), 7.77 (s, 1H), 7.48 (t, 1H), 7.41 (m, 2H), 7.05 (m, 2H), 6.90 (m, 2H) 6.63 (dd, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.63 (s, 2H). MS (m/z): 531.8 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>C(#N)C>[O:14]1[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][CH2:3][CH2:2][NH:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[C:27]([F:26])([F:36])[F:37])=[N:13]1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1ccccc1CNCCCOc1cccc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2-(trifluoromethyl)benzylamine, and acetonitrile essentially as described above in example 56. Purity by LC/MS (APCI)=98%, [M+H]+=433.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([OH:20])([CH3:19])[CH2:11][P:12]([CH2:15][CH2:16][CH2:17][CH3:18])(=[O:14])[O-:13])=O)(C)(C)C.[Na+].C(O)CC.C.C1OC1C>Cl.C(O)C>[NH2:8][CH2:9][C:10]([OH:20])([CH3:19])[CH2:11][P:12]([CH2:15][CH2:16][CH2:17][CH3:18])(=[O:13])[OH:14]
Reactant: CCCCP(=O)([O-])CC(C)(O)CNC(=O)OC(C)(C)C
Agent: CC1CO1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCCO
Product: CCCCP(=O)(O)CC(C)(O)CN
Reaction time: 18 h

Procedure:
A solution of 0.73 g of sodium 3-(N-tert.-butoxycarbonylamino)-2-hydroxy-2-methyl-propyl(n-butyl)phosphinate is dissolved in 10 ml of 1.0 aqueous hydrochloric acid and the solution stirred at 20° for 16-20 hours. After this time the solution is washed with dichloromethane followed by ether and the water removed under reduced pressure at 40° to afford an oily solid. This solid is treated with n-propanol and a few grams of charcoal. Subsequent heating to reflux and filtration gives a colourless solution. Removal of the solvent in vacuo and drying of the solid in vacuo at 80° gives a pale yellow solid. Dissolution of this solid in absolute ethanol followed by treatment with propylene oxide affords a white solid. Recrystallisation from an ethanol/acetone mixture gives 3-amino-2-hydroxy-2-methyl-propyl(n-butyl)phosphinic acid of m.p. 187°-189°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([C:18](O)=[O:19])=[C:12]([Cl:21])[N:11]3[CH:22]=2)[CH:5]=[CH:6][CH:7]=1.BrC1C=C(C2N=C3C=C(C)C(C(=O)[C:40]([O:42][CH3:43])=[O:41])=C(Cl)N3C=2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([C:18](=[O:19])[C:40]([O:42][CH3:43])=[O:41])=[C:12]([Cl:21])[N:11]3[CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)c(Cl)n2cc(-c3cccc(Br)c3)nc2c1C
Reactant: COC(=O)C(=O)c1c(C)cc2nc(-c3cccc(Br)c3)cn2c1Cl
Product: COC(=O)C(=O)c1c(C)c(C)c2nc(-c3cccc(Br)c3)cn2c1Cl

Procedure:
Prepared from 2-(3-bromophenyl)-5-chloro-7,8-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid following the same procedure as methyl 2-(2-(3-bromophenyl)-5-chloro-7-methylimidazo[1,2-a]pyridin-6-yl)-2-oxoacetate. LCMS (ESI, M+1): 420.85.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9](=[N:16][OH:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)c1ccc(Br)cc1
Temperature: 1 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
Crude ethyl 3-(4-bromophenyl)-3-oxopropanoate (24.5 g, 0.0884 mol) is dissolved in acetic acid (250 mL) at 23° C. under nitrogen, and water (60 mL) is added. The mixture is cooled to 1° C., and a solution of sodium nitrite (7.63 g, 0.111 mol) in water (60 mL) is added dropwise while maintaining the reaction temperature between 1 to 3° C. The mixture is allowed to stir at 1° C. for 3 hours. Water (100 mL) is added dropwise to the cooled reaction mixture to precipitate the product. The cold (about 5° C.) mixture is suction filtered and the collected solids are rinsed with cold 1:1 (v/v) HOAc/water (50 mL), followed by water (2×50 mL). The solids are suction dried overnight to give 18.3 g of crude title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:6][C@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@H]1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a mixture of (S)-tetrahydrofuran-3-ol (1 g, 11.4 mmol) and triethylamine (TEA) (2.3 g, 22.8 mmole) in dichloromethane (DCM) (20 mL) at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (2.2 g, 11.4 mmole). The resulting mixture was stirred at room temperature for 8 h. The mixture was washed with water, dried over MgSO4, filtered, and concentrated. The crude product was purified by ISCO (silica gel, 15% ethyl acetate in hexane) to give the title compound (2.5 g). MS (ESI) m/z: Found: 243.3 (M++1). Calc. 242.3 (M+).