Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]#[CH:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>C1COCC1.CCCCCC>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]#[C:14][CH:27]([C:26]2[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=2)[OH:28])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C#C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1[C@@H](C#CC(O)c2ccc(Cl)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (S)-4-ethynyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.16 g; CAS 173065-16-2) in dry THF (20 ml) under an argon atmosphere at −78° C. was added dropwise a solution of n-butyllithium in hexane (10.5 ml, 1.6 M solution) and stirring continued for 30 min. A solution of 4-chlorobenzaldehyde (2.17 g) in THF (10 ml) was added dropwise and the mixture was stirred for a further 2 h at −78° C. The reaction mixture was then quenched by careful addition of water (12 ml) and allowed to warm to room temperature. The mixture was diluted with ethyl acetate and washed with saturated brine. The combined organic phase was dried over sodium sulphate, filtered and concentrated in vacuo. The reside was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-[3-(4-chloro-phenyl)-3-hydroxy-prop-1-ynyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (mixture of epimers) as a yellow oil. MS (ISP): 426.1 ([{37Cl}M+OAc]−), 424.1 ([{35Cl}M+OAc]−).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[C:22]([OH:24])=O)=O)(C)(C)C.[ClH:25].[C:26]([C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)#[N:27]>CN(C=O)C>[ClH:25].[ClH:25].[C:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C@H:11]2[CH2:12][NH:8][C@H:9]([C:22]([N:29]3[CH2:30][CH2:31][CH2:32][C@H:28]3[C:26]#[N:27])=[O:24])[CH2:10]2)=[N:15][CH:16]=1)#[N:21]
Reactant: N#C[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Nc2ccc(C#N)cn2)C[C@H]1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc(N[C@H]2CN[C@H](C(=O)N3CCC[C@H]3C#N)C2)nc1

Procedure:
(2S,4R)-1-tert-Butoxycarbonyl-4-(5-cyano-2-pyridyl)aminopyrrolidine-2-carboxylic acid (title compound of Reference Example 4, 0.73 g) and (S)-2-cyanopyrrolidine hydrochloride (0.29 g) were dissolved in DMF (10 mL), and triethylamine (0.62 mL), HOBT (0.34 g) and EDC hydrochloride (0.42 g) were successively added thereto. The mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give (S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(5-cyano-2-pyridyl)amino-2-pyrrolidinylcarbonyl]-2-cyanopyrrolidine (0.58 g) as amorphous.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[C:22]([O-:25])(=[O:24])[CH3:23].[Na+]>C(#N)C.C(OCC)(=O)C>[C:22]([O:25][CH2:2][C:3](=[O:4])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)(=[O:24])[CH3:23]
Reactant: O=C(CBr)Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 74.6 %

Procedure:
A solution of 2-bromo-N-(3-(quinoxalin-2-yl)phenyl)acetamide (100 mg, 0.292 mmol) and sodium acetate (159 mg, 1.168 mmol) in acetonitrile (5 mL) was heated in microwave at 140° C. for 7.5 min. The dark-yellow solution was diluted with ethyl acetate (25 mL), washed with water (20 mL), dried over sodium sulphate and the solvent evaporated to afford 2-oxo-2-(3-(quinoxalin-2-yl)phenylamino)ethyl acetate (70 mg, 74% yield). LCMS calculated for C18H15N3O3 (M+H): 322.33. found 322. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.3 (1H, br.), 9.51 (1H, s), 8.52 (1H, m), 8.15-8.20 (2H, m), 8.08-8.10 (1H, m), 7.82-8.00 (3H, m), 7.55-7.60 (1H, m), 4.70 (2H, s), 2.15 (3H, s).
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[NH:26])[CH:18]=[CH:19][CH:20]=1>>[F:11][C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:10])[NH:27][C:25]([CH2:24][O:23][CH2:22][CH2:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:28])[F:29])[CH:16]=3)=[N:26][C:2]=2[N:3]=1
Reactant: N=C(N)COCCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(F)nc1F
Agent: Cl
Product: O=c1[nH]c(COCCc2cccc(C(F)(F)F)c2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(3-trifluoromethyl-phenyl)-ethoxy]-acetamidine hydrochloride. Brown solid. MS: m/e=368.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])/[CH:5]=[CH:6]/[C:7]#[N:8].[CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][CH:14]=1>>[C:7]([CH:6]1[CH:5]([C:4]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[CH:15]2[CH2:16][CH2:17][CH:18]1[CH:13]=[CH:14]2)#[N:8]
Reactant: C1=CCCC=C1
Reactant: N#C/C=C/c1ccc(Cl)c(Cl)c1
Product: N#CC1C2C=CC(CC2)C1c1ccc(Cl)c(Cl)c1

Procedure:
trans-3,4-Dichlorocinnamonitrile (20 g.) and cyclohexadiene (16 g.) were heated at 150°C. for 3 weeks. The solution was evaporated, the resultant oil purified by column chromatography and crystallised from methanol to yield white crystals of 5-cyano-6-(3',4'-dichlorophenyl)bicyclo[2,2,2]oct-2-ene. The latter (14 g.) was hydrogenated as described in Example 1 to yield trans-3-cyano-2-(3',4'-dichlorophenyl)bicyclo[2,2,2]octane as white crystals (14 g.). Similarly the following compounds were prepared:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:44]=[C:43]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][C:52]5[CH2:57][CH2:56][C:55]([CH3:59])([CH3:58])[CH2:54][C:53]=5[C:60]5[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][CH:61]=5)[CH2:47][CH2:46]4)[CH:42]=[CH:41][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]4)=[C:21]([N+:38]([O-:40])=[O:39])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.FC(F)(F)C(O)=O>ClCCl>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:44]=[C:43]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][C:52]5[CH2:57][CH2:56][C:55]([CH3:59])([CH3:58])[CH2:54][C:53]=5[C:60]5[CH:61]=[CH:62][C:63]([Cl:66])=[CH:64][CH:65]=5)[CH2:47][CH2:46]4)[CH:42]=[CH:41][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:30][NH:29][CH2:28]4)=[C:21]([N+:38]([O-:40])=[O:39])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CN(C(=O)OC(C)(C)C)C5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CNC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 161A (0.257 g) in dichloromethane (5 mL) was added trifluoroacetic acid (0.211 mL), After 30 minutes an additional 0.2 ml of trifluoroacetic acid was added. After 3 hours, the reaction was concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[OH:15].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:15][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]
Reactant: Oc1cc(Nc2ccccn2)ccc1Cl
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2ccccn2)ccc1Cl
Yield: 74 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-chloro-5-(pyridin-2-ylamino)phenol (34 mg, 0.15 mmol) and Cs2CO3 (51 mg, 0.16 mmol) in acetone (1.5 mL) was treated with 4-bromo-2-methyl-2-butene (0.017 mL, 0.15 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 8/2) in 74% yield (32 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([NH:11][C:12]1[N:13]=[C:14]2[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:15]2=[N:16][CH:17]=1)=[O:10].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>CN(C)C=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([NH:11][C:12]1[N:13]=[C:14]2[CH:20]=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1)=[O:10]
Reactant: C[C@H]1CCCC[C@H]1NC(=O)Nc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: NCCN
Product: C[C@H]1CCCC[C@H]1NC(=O)Nc1cnc2[nH]ccc2n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 31.4 %

Procedure:
A mixture of 1-(cis-2-methyl-cyclohexyl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.3 g, 0.7 mmol), tetrabutyl ammonium fluoride (1 M in THF, 4.6 mL, 4.6 mmol) and ethylene diamine (0.46 mL, 4.2 mmol) in 5 mL of N,N-dimethylformamide was stirred at 80° C. for 20 h, then concentrated. The resulting residue was triturated in methanol, and solid was isolated by filtration, washing with ether, and dried to afford 0.060 g (30%) of 1-(cis-2-methyl-cyclohexyl)-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-urea as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1.[CH2:24](N)[CH2:25][NH2:26].C(=S)=S>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:26][CH2:25][CH2:24][N:22]=2)=[CH:17][CH:16]=1
Reactant: NCCN
Reactant: N#Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Solvent: CN(C)C=O
Solvent: S=C=S
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C2=NCCN2)cc1
Yield: 45 %

Procedure:
N-(2-Amino-5-(thiophen-2-yl)phenyl)-4-cyanobenzamide 173 (30 mg, 0.1 mmol), ethylenediamine (0.126 mL, 1.9 mmol.) and carbon disulfide (catalyst) were stirred at 50° C. in DMF overnight. The reaction mixture was then evaporated to dryness, taken up in methanol and filtered to give the title compound 174 as a yellow solid (16.3 mg, 48%). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.78 (s, 1H), 8.02 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H), 7.45 (s, 1H), 7.33 (d, J=5.1 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 7.22 (d, J=3.3 Hz, 1H), 7.03 (t, J=3.9 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 5.18 (s, 2H), 3.63 (s, 4H). MS: 362.12 (calc), 363.1 (obs).
Reaction SMILES: [NH2:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:5]2[N:4]([CH2:11][CH2:12][CH3:13])[C:3]1=[O:14].[C:15]([O:18][CH:19]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:20]=O)(=[O:17])[CH3:16].C([O-])(=O)C.[Na+]>CO>[OH:10][CH:8]1[CH2:7][CH:6]2[N:2]([N:1]=[CH:20][CH:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[O:18][C:15](=[O:17])[CH3:16])[C:3](=[O:14])[N:4]([CH2:11][CH2:12][CH3:13])[CH:5]2[CH2:9]1
Reactant: CCCN1C(=O)N(N)C2CC(O)CC21
Reactant: CC(=O)OC(C=O)C1CCCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCCN1C(=O)N(N=CC(OC(C)=O)C2CCCCC2)C2CC(O)CC21
Temperature: 15 °C
Reaction time: 16 h
Yield: 117.8 %

Procedure:
A solution of the compound of step (g) (5.0 g) and 2-acetoxy-2-cyclohexylacetaldehyde (Ross et al, J. Med. Chem., 22, 412 (1979), 6.0 g) in methanol (175 ml) containing sodium acetate (3.64 g) was stirred at 15° C. under a nitrogen atmosphere for 16 hours. The alcohol was removed in vacuo and water (100 ml) and chloroform (100 ml) added. The organic phase was separated and washed with brine (100 ml), then dried over anhy. sodium sulphate. Filtration and concentration of the filtrate in vacuo gave a yellow oil (10.8 g).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:36](=[O:37])[N:6]2[C:7]([C:23]([O:25]CC3C=CC([N+]([O-])=O)=CC=3)=[O:24])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH2:20][CH2:21][OH:22])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].P([O-])([O-])([O-])=O.[Na+:43].[Na+].[Na+].[H][H]>C1COCC1.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:36](=[O:37])[N:6]2[C:7]([C:23]([O-:25])=[O:24])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH2:20][CH2:21][OH:22])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+:43]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCO)c4s3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(SCCO)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-hydroxyethyl)thioimidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate (48.4 mg) was dissolved in 2.5 ml of THF and 2.5 ml of a 1/15 M sodium phosphate buffer (pH 6.6). 10% Pd-C (50 mg) was added to the solution. The air in the reaction vessel was replaced by hydrogen, and the contents of the reaction vessel were stirred at room temperature for 2 hr. The catalyst was removed by filtration on Celite, and was washed with water. The filtrate was washed with ethyl acetate, and was then concentrated under the reduced pressure to bring the volume of the solution to about 1 ml. The residue was purified by column chromatography on Cosmosil 40C18-PREP (20% aqueous methanol solution) to prepare 15.8 mg of the title compound.
Reaction SMILES: [CH:1]1([C:4](=[O:20])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[C:9]=2[S:16]([CH3:19])(=[O:18])=[O:17])=[O:7])[CH2:3][CH2:2]1.[CH:21](OCC)(OCC)[O:22][CH2:23][CH3:24]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:20])[C:5](=[CH:21][O:22][CH2:23][CH3:24])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[C:9]=2[S:16]([CH3:19])(=[O:18])=[O:17])=[O:7])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1c(C(=O)CC(=O)C2CC2)ccc(F)c1F
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(F)c(F)c1S(C)(=O)=O)C(=O)C1CC1
Yield: 112.1 %

Procedure:
A mixture of 3-cyclopropyl-1-(3,4-difluoro-2-methylsulphonylphenyl)propane-1,3-dione (0.85 g) and triethyl orthoformate (1.04 g) in acetic anhydride was stirred and heated at reflux for 4 hours. It was evaporated to dryness and the residue was treated with toluene and re-evaporated to give 3-cyclopropyl-1-(3,4-difluoro-2-methylsulphonylphenyl)-2-ethoxymethylenepropane-1,3-dione (1.13 g) as a brown oil which was not purified further.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][CH2:10][O:11][C:12]([CH3:14])=[O:13].[CH:15]1([C:20](=[O:33])[CH2:21][CH2:22][NH:23][C:24](=[O:32])[CH2:25][CH2:26][C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH2:10]([O:11][C:12](=[O:13])[CH2:14][C:20]([CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)([OH:33])[CH2:21][CH2:22][NH:23][C:24](=[O:32])[CH2:25][CH2:26][C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)[CH3:9]
Reactant: CCOC(C)=O
Reactant: O=C(CCc1ccco1)NCCC(=O)C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(CCNC(=O)CCc1ccco1)C1CCCC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of LDA (1.0 M, 1.1 mL, 1.1 mmol) cooled to −78° C. was added EtOAc (0.1 mL, 1.1 mmol). After stirring for 30 minutes, a solution of N-(3-cyclopentyl-3-oxo-propyl)-3-furan-2-yl-propionamide (100 mg, 0.38 mmol; described in Step 2 of example H(4)) dissolved in 3 mL THF was added. The reaction was stirred for 2 hours and then allowed to warm to −40° C. The reaction was quenched with 10 mL saturated NH4Cl, and the layers were separated. The aqueous layer was extracted with 3×10 mL CH2Cl2, and the organic layers were combined. After concentrating the organic layers by rotary evaporation, the product was purified by flash chromatography (86 mg, 64% yield). MS (ESI): 350 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][C@@H:6]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[O:7][C@H:8]2[CH2:14][NH:15][CH:16]=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[CH:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45]>ClC(Cl)C>[C:44]([O:43][C:42](=[O:48])[NH:41][CH2:40][CH2:39][N:21]1[CH2:20][CH2:19][CH:18]([C@@H:6]2[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:12]([CH3:13])[C:3]=3[O:2][CH3:1])[C@H:8]([CH2:14][NH:15][CH:16]=[O:17])[O:7]2)[CH2:23][CH2:22]1)([CH3:47])([CH3:46])[CH3:45]
Reactant: COc1c(C)ccc2c1C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1c(C)ccc2c1C[C@@H](C1CCN(CCNC(=O)OC(C)(C)C)CC1)O[C@H]2CNC=O
Reaction time: 42 h

Procedure:
Stir a solution of N-((1R,3S)-5-methoxy-6-methyl-3-(4-piperidinyl)-1-isochromanyl-methyl)formamide (4.0 g, 12.5 mmole) in dichloroethane (110 mL) and add sodium triacetoxyborohydride (4.0 g, 18.8 mmole). Dissolve t-butyl N-(2-oxoethyl)-carbamate (1.0 g, 6.3 mmole) in dichloroethane (20 mL) and add it to the reaction mixture. After 6 hours add another 6.3 mmole of t-butyl N-(2-oxoethyl)-carbamate in dichloroethane. After another 42 hours adjust the pH of the reaction mixture to about 14 with 50% NaOH and extract with dichloromethane. Wash the combined extracts with water and dry over Mg2SO4. Purify the crude product on a 33 g silica gel column (eluting with ammonium hydroxide:methanol:ethyl acetate 1:1:98). Collect the appropriate fractions and concentrate to obtain the title compound. CIMS 462, tR (min)=0.46.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Na].[O:11]1[CH2:26][CH:12]1[CH2:13][N:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:15][CH:16]1[O:18][CH2:17]1.O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:17][CH:16]2[CH2:15][N:14]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:13][CH:12]([CH2:26][OH:11])[O:18]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: c1ccc(CN(CC2CO2)CC2CO2)cc1
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(OCC2CN(Cc3ccccc3)CC(CO)O2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
A solution of 6.21 g of p-methoxyphenol (0.05 mole) in 150 ml of dry dioxane is stirred under dry nitrogen and 0.4 g of finely cut sodium added. The mixture is stirred at room temperature for 1 hour and then 10.96 g of N,N-bis(2,3-epoxypropyl)benzylamine (0.05 mole) is added to the reaction mixture. The mixture is then heated at reflux for 18 hours, cooled to room temperature and poured into 300 ml of water. The aqueous mixture is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined, washed with 200 ml of water and 200 ml of saturated NaCl solution. The CHCl3 layer is then dried over anhydrous NaSO4, evaporated in vacuo to yield 15.4 g (90%) of crude product as a pale yellow oil. The oil is chromatographed on 300 g of neutral Alumina III to give 11.8 g (69%) of wet product (eluted with 650 ml of chloroform and 200 ml of 2% methanolic chloroform). 11.8 g of wet product is dried in vacuo to give the desired product as a clear colorless oil.
Reaction SMILES: O[C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:15])[CH:3]=1.P(Cl)(Cl)([Cl:18])=O.CN(C)C1C=CC=CC=1>>[Cl:18][C:2]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:15])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c(O)cc(=O)n2c1CCC2
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1c(Cl)cc(=O)n2c1CCC2
Reaction time: 16 h
Yield: 69 %

Procedure:
Compound 1a (8.0 g, 38.3 mmol) was stirred in phosphorous oxychloride (20 mL, 218 mmol) at RT. Dimethylaniline (1 mL, 7.9 mmol) was added, and the reaction stirred for 16 h. The solution was concentrated in vacuo, quenched with ice, and made basic with sat. NaHCO3 solution. The aqueous solution was concentrated in vacuo. The residue was taken up in a 20% MeOH/CH2Cl2 and insoluble inorganic salts were removed by filtration. Organics were concentrated and purified by silica gel chromatography (75% EtOAc/CH2Cl2) to give 6.02 g (69%) of compound 1b as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.46 (s, 1H), 3.99 (t, 2H, J=7.6 Hz), 3.78 (s, 3H), 3.30 (t, 2H, J=7.6 Hz), 2.04-2.14 (m, 2H). MS (ES) [m⇄H] calc'd for C10H10ClNO3, 228, 230. found 228, 230.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@H:14]2[C@H:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:33]1[CH2:35][C@@H:34]1[CH2:36][O:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH:40]=[CH:41][CH:42]=[N:43]2>C(O)(C)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@H:14]2[C@H:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:21])[CH2:18][CH2:17][N:16]([CH2:35][C@@H:34]([OH:33])[CH2:36][O:37][C:38]3[CH:47]=[CH:46][CH:45]=[C:44]4[C:39]=3[CH:40]=[CH:41][CH:42]=[N:43]4)[CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCCCc1ccccc1)[C@@H]1CCNC[C@H]1C(=O)NCCCCc1ccccc1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CC(C)O
Product: O=C(NCCCCc1ccccc1)[C@@H]1CCN(C[C@@H](O)COc2cccc3ncccc23)C[C@H]1C(=O)NCCCCc1ccccc1
Temperature: 70 °C
Yield: 61.1 %

Procedure:
trans- Piperidine-3,4-dicarboxylic acid bis[(4-phenyl-butyl)-amide] (8) (78.1 mg; 0.179 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (36.1 mg; 0.179 mmol) is added then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (0%→50% methanol in methylene chloride) affording the desired product (69.6 mg) as a solid. ESMS:MH+ 637.4 (base).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[Cl:18][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCCNC2=O
Product: COc1ccc(-c2cc(Cl)cc3c(C)c4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, off-white solid (81 mg, 91%), MS (ISP) m/z=355.4 [(M+H)+], mp 240.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-chloro-11-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 13) (81.9 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]1([CH3:37])[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[N:20][C:21]([NH:24][C:25]3[O:26][C@:27]4([CH2:35][N:36]=3)[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]4)=[N:22][CH:23]=2)[CH:13]=1>C1COCC1>[C:12]1([CH3:37])[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[N:20][C:21]([NH:24][C:25]3[O:26][C@:27]4([CH2:35][N:36]=3)[CH:32]3[CH2:31][CH2:30][N+:29]([O-:9])([CH2:34][CH2:33]3)[CH2:28]4)=[N:22][CH:23]=2)[CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(-c2cnc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc2)c1
Solvent: C1CCOC1
Product: Cc1cccc(-c2cnc(NC3=NC[C@@]4(C[N+]5([O-])CCC4CC5)O3)nc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
mCPBA (0.074 g, 0.332 mmol) was added to a suspension of (R)—N-(5-m-tolylpyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.116 g, 0.332 mmol) in THF (10 ml). The mixture was stirred at room temperature for 18 h, concentrated and purified by silica gel chromatography (5-25% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford (S)-2-(5-m-tolylpyrimidin-2-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide as an off-white solid (0.067 g, 0.176 mmol, 53%). 1H NMR (400 MHz, MeOD) δ ppm 8.79 (2H, s), 7.27-7.49 (3H, m), 7.20 (1H, d, J=7.55 Hz), 4.03 (1H, d, J=10.32 Hz), 3.88 (1H, d, J=10.58 Hz), 3.59-3.77 (2H, m), 3.38-3.52 (3H, m), 3.21-3.28 (1H, m), 2.40-2.52 (1H, m), 2.28-2.35 (1H, m), 1.96-2.21 (3H, m). LC/MS RT=1.71; [M+H]+=366.34.