Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:20][C:19]3[CH2:18][NH:17][CH2:16][C:15]=3[CH2:14]2)=[N:10][CH:9]=1)=[O:7].FC(F)(F)C([O-])=O.C(N(CC)CC)C.Cl[C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=[CH:39][N:38]=1>CN(C=O)C>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:14][C:15]3[CH2:16][N:17]([C:37]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[N:40]=[CH:39][N:38]=4)[CH2:18][C:19]=3[CH2:20]2)=[N:10][CH:9]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1cnc(N2CC3=C(CNC3)C2)s1
Reactant: Clc1ncnc2ccccc12
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)c1cnc(N2CC3=C(C2)CN(c2ncnc4ccccc24)C3)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-Methylbutyl)-2-(3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)thiazole-5-carboxamide, trifluoroacetate (220 mg, 0.52 mmol) and triethylamine (0.22 ml, 1.57 mmol) were dissolved in 10 ml of DMF and admixed in an ice bath with 4-chloroquinazoline (172 mg, 1 mmol). The mixture was stirred further for 1 h and allowed to warm to room temperature, and concentrated, water and ethyl acetate were added and the organic phase was removed, concentrated by evaporation and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). M+H+: 435.05.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][CH:30]2[CH2:32][CH2:31]2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)C(C)C)C>ClCCl>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]([CH:30]2[CH2:31][CH2:32]2)[C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([C:6]3[O:5][CH:4]=[N:3][C:2]=3[CH3:1])=[CH:8][CH:9]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: Cc1ncoc1-c1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncoc1-c1ccc(C(=O)N(C2CC2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Methyl-oxazol-5-yl)-benzoyl chloride (340 mg) is added portionwise to a mixture of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (369 mg) and ethyldiisopropylamine (274 μL) in dichloromethane (10 mL). The mixture is stirred for 1 h at room temperature, washed with water, aqueous citric acid solution and 0.5 M NaOH, dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 50:1) to afford the title compound. Mass spectrum (ESI+): m/z=426 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](OC)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][OH:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc(OCc2ccccc2)cc1
Yield: 80.2 %

Procedure:
A solution of 14.0 g of methyl 4-benzyloxyphenylacetate (7) in THF was slowly added with stirring to a solution of 2.0 g LAH in 500 mL of THF. The mixture was heated at reflux 1 h, cooled with ice, then treated sequentially with 2 mL water, 2 mL 15% NaOH, and 4 mL of water. The mixture was filtered and the filtrate evaporated to yield 10 g of crystalline 1-benzyloxy-4-(2-hydroxyethyl)benzene (8), m.p. 84°-85° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15](=O)[CH3:16])[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S(=O)(=O)(O)[O-].[Na+]>C1COCC1.O>[CH2:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:16]
Reactant: CC(=O)N1CCC[C@H]1CCc1cccc(F)c1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCN1CCC[C@H]1CCc1cccc(F)c1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A solution of 1-{(R)-2-[2-(3-fluorophenyl)ethyl]pyrrolidin-1-yl}ethanone (Intermediate 232, 0.48 g) in THF (20 mL) was cooled to 0° C. and treated with a solution of lithium aluminum hydride (2M in THF, 3.6 mL) under an atmosphere of nitrogen. The resultant mixture was allowed to warm to room temperature before heating to 60° C. overnight. The mixture was cooled to 0° C. and treated with water (0.35 ml), 4N sodium hydroxide solution (0.35 ml) and further water (0.9 ml). Sodium bisulphate powder was added to the suspension and the slurry was filtered through Celite and the filtrate was evaporated to dryness to give (R)-1-ethyl-2-[2-(3-fluoro-phenyl)ethyl]pyrrolidine (0.41 g) as an oil.
Reaction SMILES: [C:1]12([CH2:16][CH2:15][CH2:14][CH2:13]1)[C:9]1[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:3]([CH:10]([OH:12])[CH3:11])=[CH:2]2>[O-2].[O-2].[Mn+4]>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:2]=1)(=[O:12])[CH3:11]
Reactant: CC(O)C1=CC2(CCCC2)c2ccccc21
Agent: [Mn+4]
Agent: [O-2]
Product: CC(=O)C1=CC2(CCCC2)c2ccccc21

Procedure:
The alcohol from step (a) (14.3 g) is stirred for 2 days at about 20° C. with manganese dioxide (150 g) in light petroleum ether (b.p. 40°-60° C.; 450 ml). Solid material is filtered off and the filtrate concentrated. Distillation of the residual oil gives the title ketone, b.p. 148°-150° C./0.5 torr.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[CH2:9][N:8](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7]1)(=[O:3])[CH3:2].[ClH:23]>[OH-].[OH-].[Pd+2].C(O)C>[ClH:23].[C:1]([NH:4][CH2:5][CH:6]1[CH2:9][NH:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CC(=O)NCC1CNC1
Reaction time: 3 h

Procedure:
19.5 g (0.0662 mol) of the compound obtained in stage c), 200 ml of 95% ethanol, 3.91 g of 20% Pd(OH)2 on carbon and 5.4 ml of concentrated hydrochloric acid are charged into a hydrogenation apparatus. They are placed under a hydrogen atmosphere and hydrogenated at ambient pressure, at 40° C., for 3 hours. After filtering, the filtrate is concentrated by evaporation at reduced pressure and the oily residue is taken up with benzene (2×50 ml) and then with acetone. The organic solvent is evaporated at reduced pressure to obtain 10 g of 3-acetylaminomethylazetidine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]([Cl:13])=[C:8]([CH3:14])[C:3]=1/[C:4](=[N:6]/[OH:7])/[NH2:5].[OH:15][C:16]1[C:24]([O:25][CH3:26])=[CH:23][C:19]([C:20](Cl)=O)=[CH:18][C:17]=1[N+:27]([O-:29])=[O:28].N1C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:4]2[N:5]=[C:20]([C:19]3[CH:23]=[C:24]([O:25][CH3:26])[C:16]([OH:15])=[C:17]([N+:27]([O-:29])=[O:28])[CH:18]=3)[O:7][N:6]=2)=[C:8]([CH3:14])[C:9]([Cl:13])=[C:10]([CH3:12])[N:11]=1
Reactant: Cc1nc(Cl)c(/C(N)=N/O)c(C)c1Cl
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1cc(-c2nc(-c3c(Cl)nc(C)c(Cl)c3C)no2)cc([N+](=O)[O-])c1O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
In a second vessel, (Z)-2,5-dichloro-N′-hydroxy-4,6-dimethylnicotinimidamide (201.2 g, 1.24 eq) is suspended in 1,4-dioxane (720 mL, 4.5 vol) and the suspension is cooled to 10° C. The residue of example 3e in 1,4-dioxane is added slowly maintaining the temperature below 20° C. A clear orange solution is formed. After complete addition, the reaction mixture is stirred at 20° C. for 1 hour. Pyridine (483.7 mL, 8 eq) is then charged and the reaction mixture is heated slowly to 115° C. The mixture is stirred at 115° C. for 6 hours. The solution is then cooled to 20° C. Dioxane/pyridine is distilled off.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[F:33])[CH2:9][C:10](=[O:23])[N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[NH:14][C:13](=[O:22])[CH2:12]1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].CCCCCC>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:7][C@H:8]([CH2:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[F:33])[CH2:9][C:10]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[NH:14][C:13](=[O:22])[CH2:12]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CC(=O)Nc2ccccc2C1)Cc1cc(F)c(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Product: N[C@@H](CC(=O)N1CC(=O)Nc2ccccc2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of [(R)-3-oxo-3-(2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester (40 mg, 0.08 mmol) in DCM (5 mL), was added trifluoroacetic acid (0.24 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for 1 h. After completion of the reaction, as confirmed by TLC, excess of trifluoroacetic acid and DCM were evaporated in vacuo to afford a gummy solid which was solidified from hexane to afford trifluoroacetic acid salt of 4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (30 Mg, 73%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[H][H]>C(O)C.O.[Pt]=O>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)C=Cc1ccc(F)cc1Cl
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1ccc(F)cc1Cl
Yield: 101.4 %

Procedure:
A mixture of 2-chloro-4-fluorocinnamic acid (22.9 g, 0.11 mol) and platinum oxide hydrate (0.5 g, EM Scientific) in 95% ethanol (140 ml) was placed on a Parr hydrogenation apparatus. After the appropriate amount of hydrogen was taken up, the catalyst was filtered and the mixture was concentrated in vacuo to give 22.6 g (98%) of 3-(2-chloro-4-fluorophenyl)propanoic acid as a purple solid. This material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11].CO>O1CCCC1>[CH3:9][C:6]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:4][C:10]([CH3:11])=[O:12])[CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C)c(N)c1
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(C)ccc1C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
2,5-Dimethylaniline 16 (5.0 gm, 0.041 moles) was dissolved in 30 ml tetrahydrofuran (THF) at room temperature under argon. Acetic anhydride (5.9 ml, 0.062 moles) was added. Within 15 minutes, solids formed and the mixture became a solid white mass after 1 hour. Methanol was added which dissolved the mass. The mixture was evaporated under reduced pressure, dissolved in hot DCM and purified by flash chromatography on silica gel, eluting with a mixture of methanol and DCM. 2,5-Dimethylacetanilide 17 (6.67 gm, 99% yield) was isolated after removing the solvent. NMR (CDCl3) δ 7.53, 1H, br s; 6.89-7.06, 3H, m; 2.30, 3H, s; 2.19, 3H, s; 2.17, 3H, s.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)#[N:13]>CCl>[C:12]([C:14]1[CH:15]=[C:16]([CH:17]=[CH:2][C:1]([C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])=[O:3])[CH:19]=[CH:20][CH:21]=1)#[N:13]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC(=O)c1cccc(C#N)c1
Agent: CCl
Product: N#Cc1cccc(C=CC(=O)c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 16.2 %

Procedure:
Part A. 3-acetylbenzonitrile (1 gm, 6.8 mmol) and 3-cyanobenzaldehyde (2.76 gm, 17 mmol) are dissolved in a minimal amount of methyl chloride and 20 g of basic alumina was added. The resulting slurry was vigorously stirred at room temperature for 72 hrs. The slurry was filtered and the filter cake thoroughly washed with methylene chloride. The solvent was removed under vacuum and the residue chromatographed on silica gel eluting methylene chloride to give 3-[3-(3-cyanophenyl)-1-oxo-2-propenyl]benzonitrile as a solid 0.285 gm (15%). MS: (M+H)+ 259; 1H NMR (CDCl3): 7.6 (t, 2H), 7.7 (m, 2H), 7.85 (m, 3H), 7.95 (s, 1H), 8.25 (d, 1H), 8.35 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:20])[CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:10][C:5]=2[O:4][C:3]1=[O:21].[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([OH:20])[CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:10][C:5]=2[O:4][C:3]1=[O:21]
Reactant: Cn1c(=O)oc2cc(C(=O)CCN3CCOCC3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)oc2cc(C(O)CCN3CCOCC3)ccc21
Reaction time: 4 h

Procedure:
0.01 mole of 3-methyl-6-(3-morpholinopropionyl)benzoxazolinone, prepared in stage A, is dissolved in 200 cm3 of methanol in a 250-cm3 flask equipped with a magnetic stirrer 0.02 mole of sodium borohydride is added very slowly and with stirring. Stirring is continued for 4 hours at room temperature. The reaction medium is evaporated on a water bath under vacuum. The residue is taken up with water and the mixture is extracted several times with chloroform. The extracts are filtered and evaporated to dryness on a water bath under vacuum and the product is recrystallized in cyclohexane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[CH3:26][NH:27][CH3:28]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:27]([CH3:28])[CH3:26])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(Cl)n3)cc(C)c21
Reactant: CNC
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(N(C)C)n3)cc(C)c21
Yield: 21.8 %

Procedure:
A solution of [6-(2-chloro-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (impure, 0.42 g, 1.16 mmol) in dimethylamine (2M solution in THF, 5 mL, 10 mmol) was stirred in a sealed tube at room temperature for 3 hours. The mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography using EtOAc and hexane (1:1) as eluant, followed by MeOH and CH2Cl2 (2:98 gradient) and preparative HPLC (CH3CN/0.1% AcOH in water). The required fraction was lyophilized to give [6-(2-dimethylamino-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester as a light yellow solid (0.094 g, 22%). 1H NMR (400 MHz, CD3OD) δ8.12 (d, J=5.85 Hz, 1H), 7.19 (s, 1H), 7.05 (s, 1H), 6.07 (d, J=5.85 Hz, 1H), 5.68-5.60 (m, 1H), 4.15-4.03 (m, 2H), 3.17 (dd, J=14.38, 2.34 Hz, 1H), 3.00 (s, 6H), 2.47 (dd, J=14.83, 8.20 Hz, 1H), 2.36 (s, 3H), 1.20 (t, J=7.03 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])(OCC)=O>>[C:30]1(=[O:39])[N:1]([C@H:2]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]12
Reactant: COC(=O)C[C@H](N)c1ccc(OC)c(OC)c1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)C[C@@H](c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O

Procedure:
Methyl (S)-3-amino-3-(3,4-dimethoxyphenyl)propionate (0.45 g, 1.63 mmol), sodium carbonate (0.17 g, 1.63 mmol) and N-carboethoxyphthalimide (0.36 g, 1.63 mmol) were allowed to react according to the procedure of Example 85. Methyl (S)-3-phthalimido-3-(3,4-dimethoxyphenyl)propionate was obtained as a white powder, 0.51 g (85%); 1H NMR (DMSO-d6, 250 MHz) δ 7.87 (br s, 4 H, Ar), 6.80-7.10 (m, 3 H, Ar), 5.65 (dd, 1 H, J1 =7 Hz, J2 =9 Hz), 3.73 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 3.55 (s, 3 H, OCH3), 3.30-3.67 (m, 2 H); 13C NMR (DMSO-d6) δ 170.8, 167.7, 148.6, 148.4, 134.7, 131.1, 131.0, 123.2, 119.3, 111.7, 111.0, 55.5, 51.6, 49.9, 35.6. Anal.Calcd for C20H19NO6. Theoretical C, 65.03; H, 5.18; N, 3.79. Found C, 64.94; H, 5.29; N, 3.86. HPLC 97%.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:12][N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1[C:39]2[NH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[C:30]([O:40][CH:41]2[O:43][C@H:42]2[CH3:44])=[CH:29][CH:28]=1>CO>[CH2:1]([N:8]([CH:9]1[CH2:12][N:11]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:10]1)[CH2:44][CH:42]([OH:43])[CH2:41][O:40][C:30]1[C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:38][C:39]=2[CH:27]=[CH:28][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1OC1Oc1cccc2[nH]c3ccccc3c12
Reactant: CCCCOc1ccc(S(=O)(=O)N2CC(NCc3ccccc3)C2)cc1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)CC(O)COc3cccc4[nH]c5ccccc5c34)C2)cc1
Yield: 105.7 %

Procedure:
To a solution of benzyl-[1-(4-butoxy-benzenesulfonyl)-azetidin-3-yl]-amine (0.14 g, 0.37 mmol) in methanol (2 ml) was added (2S)-3-(9H-carbazol-4-yloxy)-methyl oxirane (0.11 g, 0.45 mmol) and the mixture was stirred at reflux for 3 days. The methanol was then evaporated, and the residue was washed with a mixture of ether and hexanes to give 0.24 g of an off-white solid; m.p. 65-67° C.; MS (ES) m/z 614.2 (MH+); HRMS (ES) Calcd. for C35H40N3O5S (MH+): 614.2689, Found: 614.2706.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[CH3:17][O:18][C:19](=[O:43])/[CH:20]=[CH:21]/[C:22]1[CH:23]=[C:24]2[C:39](=[CH:40][CH:41]=1)[O:38][C:27]1([CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]1)[CH2:26][C:25]2=[O:42]>C(#N)C>[CH3:17][O:18][C:19](=[O:43])/[CH:20]=[CH:21]/[C:22]1[CH:23]=[C:24]2[C:39](=[CH:40][CH:41]=1)[O:38][C:27]1([CH2:30][N:29]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:28]1)[CH2:26][C:25]2=[O:42]
Reactant: Fc1ccc(CCBr)cc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccc(F)cc3)C1)O2
Temperature: 70 °C
Reaction time: 54 h
Yield: 29.2 %

Procedure:
K2CO3 (285 mg, 2.06 mmol) and 1-(2-bromoethyl)-4-fluorobenzene (0.43 ml, 3.1 mmol) were added to a suspension of Intermediate 4 (320 mg, 1.04 mmol) in acetonitrile (30 ml) and the mixture was stirred at 70° C. for 54 h. The solvent was evaporated and the residue was partitioned between water and DCM. The organic phase was dried over Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography on silica gel (eluent:petroleum ether:EtOAc 6:4) to give (E)-3-{1′-[2-(4-fluoro-phenyl)-ethyl]-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl}-acrylic acid methyl ester (120 mg) as a brown oil.
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@@H:8]1[CH2:10][O:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:13][C:14]1[CH:15]=[CH:16][C:17]2[S:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=2[CH:24]=1>CC#N>[C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@@H:8]([OH:9])[CH2:10][NH:13][C:14]1[CH:15]=[CH:16][C:17]2[S:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC[C@@H](O)CNc1ccc2c(c1)NC(=O)CS2
Temperature: 50 °C
Reaction time: 6 h
Yield: 47.3 %

Procedure:
To a solution of tert-butyl-dimethyl-((S)-1-oxiranylmethoxy)-silane (commercial; 13.0 g, 69 mmol) in MeCN (220 mL) was added LiClO4 (22 g, 207 mmol). 6-amino-4H-benzo[1,4]thiazin-3-one (commercial; 11.45 g, 64 mmol) was added and the mixture was stirred at 50° C. for 6 h. The solvent was removed in vacuo and the residue was purified by CC (DCM/MeOH/NH4OH 1000:25:2 to 1000:100:2) to afford the title compound as a pale brown foam (11.16 g, 44% yield).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:15][CH2:14][CH2:13]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:67][CH:68]1[CH:73]2[CH2:74][CH2:75][N:70]([CH2:71][CH2:72]2)[CH2:69]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14][CH2:15]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:67][CH:68]5[CH:73]6[CH2:74][CH2:75][N:70]([CH2:71][CH2:72]6)[CH2:69]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)C(=O)N2C
Reactant: NC1CN2CCC1CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 7) (15 mg, 0.033 mmol), DIPEA (12 μl, 0.066 mmol, 2 eq) and TBTU (12 mg, 0.036 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 5 min before the addition of 3-aminoquinuclidine dihydrochloride (8 mg, 0.04 mmol, 1.2 eq) and DIPEA (13 μL). The RM was then stirred at rt for 3 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide (±)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[OH-].[K+].O.[ClH:21]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[ClH:21]
Reactant: COC(=O)c1cc(Cl)cnc1-c1cccnc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Cl)cnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-chloro-2,3′-bipyridine-3-carboxylate (1-2, 0.500 g, 2.01 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added potassium hydroxide (0.200 g, 3.61 mmol) and water (1.25 mL) and the system was stirred at room temperature overnight. The reaction mixture was then neutralized with 6N HCl to a pH of 2.0 and then concentrated in vacuo to afford 5-chloro-2,3′-bipyridine-3-carboxylic acid as a bone powder in the form of a bis HCl salt. ESI+ MS [MH]+C11H7ClN2O2=234.9. To a solution of the bis HCl salt form of 5-chloro-2,3′-bipyridine-3-carboxylic acid (0.613 g, 2.00 mmol) and 3,4-dimethoxybenzylamine (0.367 g, 2.2 mmol) in dimethylformamide (10 mL) was added EDC (0.764 g, 4.00 mmol), HOBt (0.612 g, 4.00 mmol) and triethylamine (0.6 mL, 10 mmol) and the system was stirred in an oil bath at 100° C. for 3 h. The system was cooled to room temperature, extracted with EtOAc, washed with water and dried over magnesium sulfate. The crude reaction mixture was then tritirated with ether to afford 5-chloro-N-(3,4-dimethoxybenzyl)-2,3′-bipyridine-3-carboxamide as a bone powder. ESI+ MS [MH]+ C20H18ClN3O3=234.9. To a solution of 5-chloro-N-(3,4-dimethoxybenzyl)-2,3′-bipyridine-3-carboxamide (0.600 g, 1.56 mmol) in dioxane (5.2 mL) was added 3,5-dichlorophenyl boronic acid (1.50 g, 7.82 mmol), N,N-dicylohexylmethylamine (0.368 mL, 1.72 mmol), and bis(tri-t-butylphosphine)palladium (0.023 g, 0.047 mmol) and the system was stirred at 110° C. for 20 minutes in the microwave. The reaction was then cooled to room temperature, and partitioned between ethyl acetate and water. The reaction mixture was filtered and purified via normal phase chromatography (0→6% MeOH in DCM) followed by reverse phase chromatography (10%→65% 0.1% TFA in water: 0.1% TFA in ACN) followed by free basing with saturated sodium carbonate afforded the title compound (2-1) as a white powder. 1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.95 (s, 1H), 8.66-8.68 (m, 1H), 8.15 (s, 1H), 7.98-8.00 (m, 1H), 7.53-7.54 (m, 2H), 7.46-7.47 (m, 1H), 7.28-7.30 (m, 1H), 6.77 (d, J=5 Hz, 1H), 6.39-6.66 (m, 2H), 5.69 (br s, 1H), 4.42 (d, J=5.5 Hz, 2H), 3.85 (s, 3H), 3.88 (s, 3H). HRMS [M+H] C26H21Cl2N3O3 calc'd 494.1033, found 494.1023.