Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18](I)[CH3:19].O>CN(C)C=O>[CH3:1][CH:2]([CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:3][C:4]([O:6][CH2:18][CH3:19])=[O:5]
Reactant: CC(=O)CCC(C)CC(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)CCC(C)=O
Reaction time: 2 h

Procedure:
3-Methyl-6-oxoheptanoic acid (2.45 g) was stirred in dry dimethylformamide (60 ml) at 20° C. and anhydrous sodium carbonate (1.64 g) was added. Ethyl iodide (5.4 ml) was added dropwise and the mixture was refluxed with stirring for 2 hours. The mixture was cooled, poured into water and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with saturated aqueous sodium thiosulphate solution, water, and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was purified by chromatography on silica, eluting with 1:4 diethyl ether: hexane. Ethyl 3-methyl-6-oxoheptanoate was obtained as an orange oil (2.0 g) Mass spectrum (Chemical Ionisation) M+1 187
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:22](I)[CH3:23].O>CS(C)=O>[CH2:22]([N:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=1)[CH3:23]
Reactant: COc1ccc(NC(=O)c2ccc(OC)cc2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCN(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
A mixture composed of 600 mg of 4-methoxy-N-(4-methoxy-phenyl)benzamide and 150 mg of 60% sodium hydride was stirred in 7.5 ml of dimethyl sulfoxide at 50° C. for 10 minutes. Then, 1.05 ml of ethyl iodide was added, and the reaction mixture was stirred for 30 minutes. After water was added to the reaction mixture, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the resulting crude product was purified by TLC (using a 80:1 mixture of chloroform and acetone as the developing solvent) to obtain 591 mg of N-ethyl-4-methoxy-N-(4-methoxyphenyl)benzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:31][C:32]1[CH:37]=[C:36]([C:38](Cl)=[O:39])[CH:35]=[CH:34][N:33]=1.C1C2C(=CC=C(NC3N=C(C4C(C5C=C(NC(=O)C6C=CC=CC=6)C=CC=5)=NN5C=CC=CC=45)C=CN=3)C=2)CCN1>>[Cl:31][C:32]1[CH:37]=[C:36]([C:38]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=5)[N:18]=4)=[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][N:10]4[N:9]=3)[CH:3]=2)=[O:39])[CH:35]=[CH:34][N:33]=1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Agent: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)c1ccnc(Cl)c1

Procedure:
In a manner analogous to Example 66, 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine and 2-chloro-4-pyridinecarbonyl chloride are used to prepare the title compound. HRMS calcd for C29H19ClFN7O: 535.1324, found: 536.1392 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)[C:3]=1[F:21].[OH-].[Na+].[ClH:24]>O1CCOCC1>[Cl:24][C:7]1[CH:2]=[C:3]([F:21])[C:4]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)=[N:5][CH:6]=1
Reactant: CC(Oc1ccc(Oc2nccc(Cl)c2F)cc1)C(=O)O
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 13.0 g (0.04 mol) of (R) (+)-2-[4-(5-chloro-3-fluoropyridin-2-yloxy)]-methyl ester in 65 ml of dioxane are added 42 ml of 1N sodium hydroxide and the mixture is stirred for 21/2 hours at a temperature of 35°. Then it is poured onto an ice/water mixture and acidified with 22 ml of 2N hydrochloric acid. The organic material is extracted therefrom twice with ethyl acetate. The organic layers are washed with a saturated salt solution and dried over magnesium sulfate, filtered and concentrated. The residue is cristallized from ethyl acetate/hexane and yields 10.2 g (81.8% of the theory) of the above (2R) (+)-[4-(5-chloro-3-fluoropyridin-2-yloxy)-phenoxy]-propionic acid as white cristals, which melt at 95°-96° ([α]D20 =+37.5°±0.5°2% in acetone).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]([C:12]1[CH:22]=[CH:21][C:15]([CH:16]=[CH:17][C:18]([OH:20])=O)=[CH:14][CH:13]=1)=[O:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:47][CH2:48][C@@H:49]1[O:53][C:52](=[O:54])[N:51]([C:55]2[CH:60]=[CH:59][C:58]([C:61]3[S:62][CH2:63][C:64](=[O:67])[NH:65][N:66]=3)=[C:57]([F:68])[CH:56]=2)[CH2:50]1>CN(C=O)C>[F:68][C:57]1[CH:56]=[C:55]([N:51]2[CH2:50][C@H:49]([CH2:48][NH:47][C:18](=[O:20])[CH:17]=[CH:16][C:15]3[CH:14]=[CH:13][C:12]([CH:10]=[O:11])=[CH:22][CH:21]=3)[O:53][C:52]2=[O:54])[CH:60]=[CH:59][C:58]=1[C:61]1[S:62][CH2:63][C:64](=[O:67])[NH:65][N:66]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc(C=CC(=O)NC[C@H]2CN(c3ccc(C4=NNC(=O)CS4)c(F)c3)C(=O)O2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N,N-Diisopropylethylamine (0.169 ml, 0.972 mmol) is added to 4-formylcinnamic acid (0.057 g, 0.324 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.129 g, 0.340 mmol) in DMF (2 ml) and is stirred for 20 minutes at room temperature. 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4]thiadiazin-5-one (0.100 g, 0.308 mmol) is added and stirring is continued at room temperature overnight. The reaction mixture is partially evaporated under vacuum and the residue is diluted with water (5 ml). The resulting precipitate is filtered and dried under vacuum to give crude product used directly in the next step (0.076 g, 51%). MS (m/z): [M+H]+=483.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=3[CH:11]=2)=[N:6][CH:7]=1.Br[C:23]1C=C(N)C(NCC2C=CC3N=C(SC)SC=3C=2)=CC=1OC>>[Cl:1][C:2]1[CH:3]=[C:4]2[N:21]=[CH:23][N:8]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Reactant: CSc1nc2ccc(CNc3ncc(Cl)cc3N)cc2s1
Product: CSc1nc2ccc(Cn3cnc4cc(Cl)cnc43)cc2s1

Procedure:
6-((6-Chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole was synthesized as a white foam (62 mg, 80%) using a procedure analogous to that described in Step 3 of Example 41, substituting 5-chloro-N2-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine from Step 2 of this Example for 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. LCMS (ESI) m/z 347 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH3:20]O>>[N:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([O:12][CH3:20])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CO
Reactant: O=C(O)c1ccnc(N2CCCCC2)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc(N2CCCCC2)c1
Temperature: 0 °C

Procedure:
A mixture of 2-Piperidin-1-yl-isonicotinic acid (30 g, 0.145 mol) in methanol (500 mL) was cooled to 0° C. and then thionylchloride (42 mL) was added. The reaction mixture was refluxed for 20 h. The solvent was removed under vacuum and the residue was taken up in EtOAc (500 mL). The organic layer was washed with 10% aqueous NaHCO3 solution, water, brine and dried. The solvent was removed under vacuum to methyl 2-piperidin-1-ylisonicotinate (18 g, 56%) as yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[O:10][CH:11]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:12]2[CH:16]([OH:17])[CH2:15][N:14]([C:18](=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:34])[CH2:13]2)=[CH:5][CH:4]=1.[C:50]1(=[O:56])[O:55][C:53](=[O:54])[CH2:52][CH2:51]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:49][O:48][C:45]1[CH:46]=[CH:47][C:42]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:10][CH:11]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:12]2[CH2:13][N:14]([C:18](=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:34])[CH2:15][CH:16]2[O:17][C:50](=[O:56])[CH2:51][CH2:52][C:53]([OH:55])=[O:54])=[CH:43][CH:44]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCN3C(=O)c4ccccc4C3=O)CC2O)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(OC(c2ccccc2)C2CN(C(=O)CCCCCN3C(=O)c4ccccc4C3=O)CC2OC(=O)CCC(=O)O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
Referring to scheme 19, Compound 77 (2 g, 3 mmol) was mixed with succinic anhydride (0.600 g, 6 mmol) and DMAP (0.366 g, 3 mmol) and dried in a vacuum at 40° C. overnight. The mixture was dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.913 g, 1.25 mL, 9 mmol) was added and the solution was stirred at room temperature under argon atmosphere for 4 h. It was then diluted with dichloromethane (50 mL) and washed with ice cold aqueous citric acid (5% wt., 50 mL) and water (2×50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography using 6% MeOH/DCM to afford compound 79 as white solid (2.05 g, 89% yield; Rf=0.4 in 10% MeOH/CHCl3).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:7]2O.[Br:19][C:20]1[CH:28]=[C:27]2[C:23]([CH:24](O)[N:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:26]2=[O:29])=[CH:22][CH:21]=1.O.C[O:37][CH2:38][CH2:39]OC>>[Br:3][C:4]1[CH:5]=[C:6]2[C:10]([C:9](=[O:13])[N:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:7]2[CH2:39][C:38]([O:29][CH2:26][CH3:27])=[O:37])=[CH:11][CH:12]=1.[Br:19][C:20]1[CH:28]=[C:27]2[C:23](=[CH:22][CH:21]=1)[CH:24]([CH2:39][C:38]([O:13][CH2:9][CH3:10])=[O:37])[N:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:26]2=[O:29]
Reactant: CC(C)CN1C(=O)c2ccc(Br)cc2C1O
Reactant: COCCOC
Reactant: CC(C)CN1C(=O)c2cc(Br)ccc2C1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC1c2cc(Br)ccc2C(=O)N1CC(C)C
Product: CCOC(=O)CC1c2ccc(Br)cc2C(=O)N1CC(C)C
Temperature: 20 °C

Procedure:
Ethyl (5-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate and ethyl (6-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are prepared as described in Example 2, starting with 5.0 g of 60% sodium hydride in 250 cm3 of 1,2-dimethoxyethane, 24.8 cm3 of triethyl phosphonoacetate and 23.7 g of 5-bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one. The mixture is refluxed for 4 hours and then cooled to a temperature in the region of 20° C. The reaction mixture is treated with 300 cm3 of water and the mixture is then extracted with 3 times 250 cm3 of diethyl ether. The organic extracts are combined, washed with 300 cm3 of saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography under argon pressure (80 kPa), on a column of silica gel (particle size 32-63 μm), eluting with successive mixtures of cyclohexane/ethyl acetate (95/5 by volume), cyclohexane/methanol (90/10) and cyclohexane/ethyl acetate (80/20). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 3.72 g of ethyl (5-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate and ethyl (6-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a colorless oil. (Rf=0.70, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[CH2:10][OH:11]>ClCCl.[O-2].[Mn+2]>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: Nc1c(F)cc(Br)cc1CO
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: Nc1c(F)cc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A mixture of (2-amino-5-bromo-3-fluorophenyl)methanol (13 g, 59.4 mmol) and manganese oxide (31 g, 356.4 mmol) in dichloromethane (400 mL) was stirred at room temperature overnight. The solid was filtered off, and the filtrate was concentrated to give the title compound (11 g, 85%) as a light yellow solid, which was directly used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[S:13][CH:14]=[CH:15][C:8]=2[C:7]1=[O:16].[Br:17]Br.O>C(O)(=O)C>[Br:17][C:14]1[S:13][C:9]2[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:7](=[O:16])[C:8]=2[CH:15]=1
Reactant: O=C1c2ccsc2CCCN1CCCCCl
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cc(Br)sc2CCCN1CCCCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
To a solution of 3.0 g of 5-(4-chlorobutyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one in 20 ml of acetic acid was added dropwise a solution of 2.1 g of bromine in 5 ml of acetic acid for 10 minutes. After the mixture was stirred at room temperature for 3 hours, the mixture was poured into chilled water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to give 4.0 g of 2-bromo-5-(4-chlorobutyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one as a pale brown oil. The obtained compound was employed in the subsequent reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.C(O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OCCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(COc1ccc(C(=O)Nc2ccc(F)cc2)cn1)OCCc1ccccc1
Yield: 4.2 %

Procedure:
A solution of [5-(4-fluoro-phenylcarbamoyl)-pyridin-2-yloxy]-acetic acid methyl ester (0.020 g, 0.66 mmole), phenethyl alcohol (0.078 mL, 0.66 mmol) and sulfuric acid (1 drop) in toluene (3 mL) was heated at reflux. After 4 h the reaction mixture was poured into ethyl acetate and washed with saturated sodium bicarbonate and dried over sodium sulfate. Removal of the solvents provided a solid. Purification by trituration using ethyl acetate/hexanes gave 0.011 g (42%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.29 (s. H); 8.65 (m, 1H); 8.23 (m, 1H); 7.74 (m, 2H); 7.01–7.27 (m, 8H); 4.94 (s, 2H); 4.27 (m, 2H); 2.85 (m, 2H); MS (EI) m/z 393.03 (M−H)−.
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]([O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:15]([Si:12]([CH3:14])([CH3:13])[O:11][C@H:9]1[CH2:10][C@H:5]([OH:4])[CH2:6][C@@H:7]([O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:8]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)O[C@@H]1C[C@@H](OC(=O)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(=O)O[C@@H]1C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
A solution of 7.45 g of (1R,3R,5S)-2,2-dimethyl-propionic acid 3-acetoxy-5-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl ester and 2.76 g of potassium carbonate in 52 ml of methanol and 24 ml of water was stirred at 22° for 6 h after which time t.l.c. showed completion of the reaction. The mixture was evaporated and the residue partitioned between dichloromethane and water. The organic layer was dried over MgSO4 and evaporated to give 6.49 g of the pure (t.l.c.) title compound as a white solid, m.p. 39-42°. IR (nujol): 3240m (OH), 1731s (C═O); MS (EI): 273/10 (M-tert-butyl).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH:15]1[C:25]2[CH2:24][CH2:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[CH:20]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].CO>C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:33]3[CH2:32][CH2:31][CH:30]([CH:20]4[C:19]5[CH:18]=[CH:17][CH:16]=[CH:15][C:25]=5[CH2:24][CH2:23][C:22]5[CH:26]=[CH:27][CH:28]=[CH:29][C:21]4=5)[CH2:35][CH2:34]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc2c(c1)CCc1ccccc1C2C1CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(C2c3ccccc3CCc3ccccc32)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 89% overall yield. FDMS m/e=466 (M+ of free base). α[D]589 =-10.02 (c=0.72, methanol).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([NH:16][CH:17]([CH3:19])[CH3:18])[C:10]=1[N+:20]([O-])=O)[CH2:2]2.[OH2:23].NN.[CH3:26][OH:27]>[Ni]>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([NH:16][CH:17]([CH3:18])[CH3:19])[C:10]=1[NH2:20])[CH2:2]2.[CH3:4][N:3]([CH3:9])[CH2:2][CH2:1][C:26]([O-:27])=[O:23]
Reactant: CC(C)Nc1nc(Cl)nc(N2CC3CCC(C2)O3)c1[N+](=O)[O-]
Reactant: CO
Reactant: O
Agent: [Ni]
Agent: NN
Product: CC(C)Nc1nc(Cl)nc(N2CC3CCC(C2)O3)c1N
Product: CN(C)CCC(=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-N-isopropyl-5-nitropyrimidin-4-amine (47, 1.45 g, 4.42 mmoles) was dissolved in methanol and Raney™ nickel (approx. 2:1 by weight with respect to starting material) was added under a nitrogen atmosphere. Hydrazine hydrate (0.833 mL, 26.54 mmoles) was added and the reaction mixture was stirred at room temperature for 18 hours, filtered over Celite™, and the filtrate was concentrated to provide 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-N4-isopropylpyrimidine-4,5-diamine 3-(dimethylamino)propanoate (48) as a tan solid. Yield: 1.25 g (95%). LCMS (HP walk-on); 3.45 min., 298.5, M+H.
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[C:6]([Cl:16])=[N:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][C:10]=1I.[CH:18]([Li])(CC)C.COC(=O)NC1C(Cl)=NC(C(F)(F)F)=CC=1.CN(C)CCN(C)C.II>C1COCC1>[Cl:16][C:6]1[N:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:10]2[CH:18]=[CH:3][NH:4][C:5]=12
Reactant: [Li]C(C)CC
Reactant: COC(=O)Nc1c(I)cc(C(F)(F)F)nc1Cl
Agent: CN(C)CCN(C)C
Agent: COC(=O)Nc1ccc(C(F)(F)F)nc1Cl
Agent: II
Solvent: C1CCOC1
Product: FC(F)(F)c1cc2cc[nH]c2c(Cl)n1
Temperature: -10 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
(2-Chloro-4-iodo-6-trifluoromethyl-pyridin-3-yl)-carbamic acid methyl ester: sec-Butyllithium solution (1.3 M in cyclohexane, 7.55 mL, 5.81 mmol) was added at −78° C. to a solution of (2-chloro-6-trifluoromethyl-pyridin-3-yl)-carbamic acid methyl ester (1.00 g, 3.93 mmol) and N,N,N′,N′-tetramethylethylenediamine (1.14 g, 9.82 mmol) in THF (50 mL). The solution was stirred for 1 h at −10° C., then cooled again to −78° C. and treated with a solution of iodine (1.66 g, 6.52 mmol) in THF (20 mL). After stirring for 1 h at −10° C., the reaction mixture was partitioned between ethyl acetate and 30% aq. sodium sulfite solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography of the residue (SiO2, dichloromethane) afforded the title compound (810 mg, 54%). White solid, MS (EI) 345.0 (100), 379.9 (2, M+).
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5][O:6][C:7]=1[C:8]([OH:10])=O.O/[N:19]=[C:20](/[C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[CH2:30][CH:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)=[CH:24][CH:23]=1)\[NH2:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:17][CH:2]([F:1])[C:3]1[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5][O:6][C:7]=1[C:8]1[O:10][N:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:27]3[CH2:28][CH:29]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:30]3)=[CH:38][CH:39]=2)[N:19]=1
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)F
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)F)n3)cc2)C1
Temperature: 55 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
A mixture of 4-(difluoromethyl)-3-phenylisoxazole-5-carboxylic acid (28 mg, 0.117 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.1, (35.7 mg, 0.117 mmol), HOBT (28.7 mg, 0.187 mmol), EDC (52.7 mg, 0.275 mmol) and diisopropylethylamine (82 μL, 0.468 mmol) in DMF was stirred at rt for 3 hr and at 55° C. for 18 hr. The reaction mixture was partitioned between EtOAc (30 ml) and saturated sodium bicarbonate solution (30 ml). The organic layer was washed with water (2×30 ml) and brine (30 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a yellow oil that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-50% EtOAc/Hex gradient. The essentially pure fractions containing the product were concentrated to afford tert-butyl 1-(4-(5-(4-(difluoromethyl)-3-phenylisoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (23 mg, 0.045 mmol, 38.6% yield) as a white solid. HPLC retention time=1.80 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS: (M+H)=509.14.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:13])=[O:12]>[OH-].[Na+]>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:12])[CH3:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C=Cc1ccc(O)cc1
Yield: 70.4 %

Procedure:
4-Hydroxybenzaldehyde (10 g, 82 mmol) was dissolved in 28 ml of 10% sodium hydroxide aqueous solution, then acetone (20 ml) and 10% sodium hydroxide aqueous solution (40 ml) was added under stirring, and the reaction mixture was stirred for 6 hr at room temperature. separated solid diluted with water until all separated solid dissolved. The reaction mixture was neutralized with hydrochloric acid to pH=7.0. The precipitated solid was collected by filtration and washed with water and ethanol successively. The crude product was recrystallized from ethanol to give 9.3 g of a pale yellow solid, mp: 104-105° C., yield: 70.4%.