Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)[N:4]=[C:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C1C(=O)N([I:30])C(=O)C1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:30][C:6]1[N:2]([CH3:1])[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:4][C:5]=1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(-c2cn(C)c(-c3ccccn3)n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(-c3ccccn3)n(C)c2I)cc1
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
Methyl 4-(1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzoate (12.5 g, 42.6 mmol) was dissolved in methylene chloride (120 mL), to which was added NIS (10.6 g, 47 mmol) and 0.5 mL of TFA. After stirring for 5 min, the reaction was diluted with 120 mL of methylene chloride and quenched with aq NaHCO3. The organic layer was separated, washed with aq Na2S2O3, water, brine, dried over MgSO4, filtered, and concentrated to give 16.3 g of methyl 4-(5-iodo-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzoate. 1H NMR (500 MHz, (CDCl3): 8.63 (m, 1H), 8.24 (d, 1H), 8.18 (s, 4H), 7.83 (m, 1H), 7.31 (m, 1H), 4.22 (s, 3H), 3.96 (s, 3H). LCMS: [M+1]=420.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:20]([C:21]([O:23]C)=O)=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][N:17]=2)[N:12]=1)(=[O:4])=[O:3].[CH3:25]C(C[AlH]CC(C)C)C>C(Cl)Cl>[CH3:25][CH:21]([C:20]1[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])=[N:12][C:13]2[C:18]([CH:19]=1)=[N:17][CH:16]=[CH:15][CH:14]=2)[OH:23]
Reactant: CC(C)C[AlH]CC(C)C
Reactant: COC(=O)c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O
Solvent: ClCCl
Product: CC(O)c1cc2ncccc2nc1-c1ccccc1S(C)(=O)=O
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridine-3-carboxylate (1.2 g, 3.5 mmol) in DCM (30 mL) was added DIBAL-H (35 mL, 35 mmol) at −78° C. The reaction mixture was stirred for 4 h at same temperature. The reaction mixture was quenched with satd solution of ammonium chloride and extracted with EtOAc. The organic layer was concentrated in vacuo to give methyl (2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)methanol: LC-MS (ESI) m/z 315.0 [M+H]+. It was carried on crude for next step.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH3:11][C:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH2:13]>[Cl-].[Zn+2].[Cl-]>[C:12]([C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1)([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:11]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: C=C(C)CC(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)(C)CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
In a 2-liter reaction flask fitted with a condenser, nitrogen inlet, stirrer, thermometer and addition funnel is placed 272 grams (2.0 moles) of anhydrous zinc chloride. The flask is placed under a nitrogen atmosphere and 166 ml (2.0 moles) of concentrated (12 N) hydrochloric acid is added over a 10-minute period with the temperature rising from 22° to 40° C. To this is then added 276 grams (2.0 moles) of o-nitroaniline over a 15-minute period to avoid the formation of lumps. The resulting thick red slurry is heated to 60° C. and then 474 grams (3.0 moles) of diisobutylene is added gradually over a 110-minute period with the temperature rising during this period from 60° to 90° C. The deep red fluid reaction mixture is heated for another 18 hours at reflux till only a trace of o-nitroaniline is observed by thin layer chromatography.
Reaction SMILES: [OH-].[Mg+2:2].[OH-].[NH2:4][CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8]>O.CO>[CH2:5]([NH2:4])[CH2:6][S:7]([O-:10])(=[O:9])=[O:8].[CH2:5]([NH2:4])[CH2:6][S:7]([O-:10])(=[O:9])=[O:8].[Mg+2:2]
Reactant: NCCS(=O)(=O)O
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NCCS(=O)(=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of magnesium hydroxide (433 mg, 7.46 mmol; Aldrich) and taurine (1.87 g, 14.9 mmol) in 20 ml water was heated under reflux for seven hours. The resulting milky mixture was allowed to cool, diluted with 40 ml methanol and allowed to stand overnight at room temperature. A white powder, consisting mostly of magnesium taurate complex, was removed by filtration. The clear filtrate was concentrated under vacuum to a pasty slurry, then diluted slowly with 10 ml methanol. After 2 hours, crystalline magnesium taurate salt was obtained by filtration. The yield was 940 mg (41%). The melting point (decomposition) was about 300° C. This salt was identical to that obtained in Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:25][CH2:26][O:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32]([CH:37]=O)=[CH:31]3)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:37][C:32]4[NH:33][C:34]5[C:30]([CH:31]=4)=[CH:29][C:28]([O:27][CH2:26][CH2:25][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:36][CH:35]=5)[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2cc3cc(OCCN4CCOCC4)ccc3[nH]2)c1

Procedure:
6-(3-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4].CC(C)([O-])C.[K+].Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>O1CCCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:1][CH2:2][C@@H:3]([OH:5])[CH3:4]
Reactant: C[C@H](O)CN
Reactant: Clc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H](O)CNc1ccccn1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
(S)-1-amino-2-propanol (43 g, 0.57M) was added to a stirred solution of potassium tertiary butoxide (64.2 g, 0.66M) in tetrahydrofuran (500 ml). 2-Chloropyridine (65.1 g 0.66M) was then added dropwise. After the exothermic reaction had subsided, the reaction was heated under reflux overnight, filtered to remove the potassium chloride and evaporated to an oil. The crude oil was dissolved in xylene (500 ml) and toluene-p-sulphonic acid (2 g) added and heated overnight under reflux under argon. After cooling to room temperature, the mixture was extracted with 2M hydrochloric acid. The acid extracts were basified with 2M sodium hydroxide and extracted into ethyl acetate. The ethyl acetate extracts were dried (MgSO4) and after removal of the acetic acid the product was distilled affording 73.5 g of the title compound, bp 100-110° C. at 0.2 mbar.
Reaction SMILES: [CH:1]12[NH:18][CH:14]([CH2:15][CH2:16][CH2:17]1)[CH2:13][NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3][CH2:2]2.CO.[Cl-:21].[Mn+2:22].[Cl-:23]>CCO>[Cl:21][CH:13]1[NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3][CH2:2][CH:1]2[NH:18][C:14]1([Cl:23])[CH2:15][CH2:16][CH2:17]2.[Mn+2:22]
Reactant: C1CC2CNCCNCCNCCNCC(C1)N2
Reactant: [Cl-]
Agent: [Mn+2]
Solvent: CCO
Solvent: CO
Product: ClC1NCCNCCNCCNCC2CCCC1(Cl)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
3,6,9,12,18-Pentaazabicyclo[12.3.1]octadecane prepared as in Example 38C (0.405 g, 1.59 mmol) was added to a refluxing solution of anhydrous MeOH (50 ml) containing anhydrous manganese(II) chloride (0.200 g, 1.59 mmo) under a dry nitrogen atmosphere. After refluxing for 2 h, the solution was stirred overnight at room temperature. The solution was taken to dryness. The solid was dissolved in EtOH (10 ml) and the solution was filtered through celite. Ethyl ether was added to the filtrate which induced crystallization of a white solid. The solid was collected by filtration, washed with ethyl ether and dried in vacuo to give 0.43 g (72% yield) of a white solid as product: FAB mass spectrum (NBA) m/z (relative intensity) 380 (M+, 3), 345/347 [(M-Cl)+, 100/2]; Anal. calcd for C14H31N5MnCl2 : C, 40.96; H, 7.67; N, 18.37. Found: C,40.85; H, 7.72; N, 18.32.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23].Cl>ClCCl>[Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH:5][C:22](=[O:23])[CH2:21][O:20][CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1cccc(Cl)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
[step 1] 3-Chloro-2-nitroaniline (2.0 g, 11.6 mmol) was dissolved in dichloromethane, triethylamine (2.6 mL, 18.5 mmol) and 2-methoxyacetyl chloride (1.4 mL, 15.1 mmol) were added, and the mixture was stirred at 70° C. for 18 hr. To the mixture was added 1 mol/L hydrochloric acid, and the mixture was extracted 3 times with chloroform. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 v/v-50/50 v/v) to give N-(3-chloro-2-nitrophenyl)-2-methoxyacetamide (1.7 g, 62%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:10])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.N1CC(=O)NC1=O.C(O)(C(F)(F)F)=O>>[CH3:10][C:3]1([CH2:2][NH:1][C:31](=[O:32])[CH2:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([CH3:11])[CH:21]=3)=[CH:25][CH:26]=2)[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7]1
Reactant: CC1(CN)NC(=O)NC1=O
Reactant: Cc1cc(COc2ccc(CC(=O)O)cc2)c2ccccc2n1
Agent: O=C1CNC(=O)N1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(CC(=O)NCC3(C)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 30.8 %

Procedure:
5-(aminomethyl)-5-methylhydantoin (109a) (30 mg, 0.17 mmol) was coupled with {4-[(2-methyl-4-quinolinyl)-methoxy]phenyl}acetic acid (46 mg, 0.15 mmol) using general coupling method B to give 20 mg (24%) of the product hydantoin as a TFA salt. MS found: (M+H)+=433.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][CH:9]=[N:10][C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.O>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:9]=[N:10][C:4]=2[CH:3]=1
Reactant: Clc1cc2nc[nH]c2cn1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc3cc(Cl)ncc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of 6-chloro-3H-imidazo[4,5-c]pyridine (3.50 g, 22.79 mmol) in THF (50 mL) at 0° C. was slowly added sodium hydride (60% dispersion in mineral oil, 1.82 g, 45.58 mmol) in several portions. After stirring at RT for 30 min, 1-(chloromethyl)-4-methoxybenzene (4.30 g, 27.48 mmol) was added and the mixture was stirred at RT for 2 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL×2). The combined extracts were washed with water (100 mL) and brine (50 mL), dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by SiO2 chromatography eluting with hexane/EtOAc (1:1) to afford 5.0 g (80%) of 6-chloro-3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridine as a white solid. MS (ESI): m/z=274.2 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[Cl-].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:25])=[C:19]([CH:24]=1)[CH:20]=[N+:21]([CH3:23])[CH3:22].BrC1C=CC(F)=C(C=1)C=O.CNC>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:25])=[C:19]([CH:20]([N:21]([CH3:22])[CH3:23])[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])[NH:8][CH:7]=2)[CH:24]=1
Reactant: C[N+](C)=Cc1cc(Br)ccc1F
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: CNC
Agent: O=Cc1cc(Br)ccc1F
Agent: [Cl-]
Product: CN(C)C(c1cc(Br)ccc1F)c1c[nH]c2cccc([N+](=O)[O-])c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-nitroindole and (5-bromo-2-fluoro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 5-bromo-2-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: C(S[CH:4]1[N:7]([CH:8]([C:22]([O:24][CH:25]2[CH2:30][O:29][CH2:28][O:27][CH2:26]2)=[S:23])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:31])[CH:5]1[CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36])C.[Cl:48]Cl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:48][CH:4]1[N:7]([CH:8]([C:22]([O:24][CH:25]2[CH2:30][O:29][CH2:28][O:27][CH2:26]2)=[S:23])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:31])[CH:5]1[CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36]
Reactant: CCSC1C(CCOC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=S)OC1COCOC1
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(OCCC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=S)OC2COCOC2)C1Cl)OCc1ccc([N+](=O)[O-])cc1
Temperature: -20 °C
Reaction time: 1.25 h

Procedure:
A solution of 6.90 g of p-nitrobenzyl 2-(4-ethylthio-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxo-1-azetidinyl)-2-(1,3-dioxan-5-yl-oxythiocarbonyl)-acetate in 110 ml methylene chloride was cooled to -20° C. under a nitrogen atmosphere. A solution of chlorine in carbon tetrachloride (98 ml of 0.1M solution) was then added. The reaction mixture was stirred at -20° C. for 75 min., then allowed to warm to 0° C. and was washed successively with 75 ml saturated aqueous sodium bicarbonate solution (5° C.), 75 ml H2O (5° C.) and 75 ml saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo yielding 5.97 g of crude title compound. The NMR spectraum in deuterochloroform shows absorptions at 1.5 (d, 3H); 3.4 (m, 1H); 3.8-4.14 (c, 5H); 4.75 (s, 2H); 4.98-5.5 (c, 6 H); 5.8-6.2 (c, 1H); 7.5 (m, 4H); 8.2 (m, 4H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][C:5]2[S:6][C:7]([C:9]#[N:10])=[CH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH:27]([F:29])[F:28]>O>[F:28][CH:27]([F:29])[O:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][C:5]2[S:6][C:7]([C:9]#[N:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: COc1cc2sc(C#N)cc2cc1O
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2sc(C#N)cc2cc1OC(F)F
Temperature: 40 °C

Procedure:
A mixture of 5-hydroxy-6-methoxy-benzo[b]thiophene-2-carbonitrile (10.30 g) and anhydrous potassium carbonate (7.63 g) was treated with a solution of dry dimethylformamide (110 ml) which has been previously saturated with chlorodifluoromethane gas. The mixture was then sealed in an autoclave, stirred, and heated to 40° C. After 3 days the reaction mixture was cooled and poured into water (700 ml). The resultant precipitate was iiltered off, dried, and extracted with hot dichloromethane (300 ml). The organic extract was concentrated then poured through a column of fine silica (200 g). The appropiate fractions were combined and evaporated to dryness to give 5-difluoromethyloxy-6-methoxy-benzo[b]thiophene-2-carbonitrile as an off-white solid (5.49 g), m.p. 99°-101° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH3:12][NH:13][CH3:14]>CO.C(OCC)(=O)C>[CH3:12][N:13]([CH3:14])[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)c1nccc(C(F)(F)F)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
2-Chloro-4-trifluoromethylpyrimidine (600 μL, 5.0 mmol) was dissolved with 2.0M dimethylamine in methanol (10 mL), and stirred for 2 hours in a sealed tube at 60° C. The reaction mixture was diluted with ethyl acetate (50 mL), and the whole was washed with water (50 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 640 mg of the title Reference Compound as a colorless oil (Yield: 67%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:18]=[C:19]2[C@:30]3([CH2:34][O:33][C:32]([NH2:35])=[N:31]3)[C:29]3[C:24](=[CH:25][CH:26]=[C:27](I)[CH:28]=3)[O:23][C:20]2=[N:21][CH:22]=1.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:16][C:17]1[CH:18]=[C:19]2[C@:30]3([CH2:34][O:33][C:32]([NH2:35])=[N:31]3)[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:28]=3)[O:23][C:20]2=[N:21][CH:22]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ncc(Br)cc12
Temperature: 80 °C

Procedure:
A vial charged with pyridin-3-ylboronic acid (0.295 g, 2.401 mmol), palladiumtetrakis (0.126 g, 0.109 mmol), potassium carbonate (1.509 g, 10.92 mmol), and (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (1.000 g, 2.183 mmol) was treated with 11 mL dioxane followed by 4.5 mL water. The vial was flushed with argon and was heated to 80° C. for 4 hours. The reaction mixture was diluted with EtOAc and dried over MgSO4. The organics were then concentrated, and the crude residue was purified by column chromatography yielding (S)-3-bromo-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.I[CH2:14][CH3:15]>CN(C=O)C>[CH2:14]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[Br:3])[CH:9]=[CH:10]1)[CH3:15]
Reactant: Brc1cccc2cc[nH]c12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2cccc(Br)c21
Reaction time: 0.33 h

Procedure:
To a 60% dispersion of sodium hydride in mineral oil (0.80 g, 21 mmol), suspended in DMF (50 mL), was added 7-bromoindole (2.0 g, 10 mmol) in DMF (15 mL) followed by a solution of iodoethane (1.64 mL, 26.3 mmol). After 20 minutes, the mixture was quenched with saturated NaHCO3, and poured into EtOAc. The organic layer which was separated, washed with saturated NaHCO3, dried (MgSO4) and concentrated to afford 1-ethyl-7-bromoindole as a brown oil which was used without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:35])[O:30][CH2:31][CH2:32][O:33][CH3:34]>C(Cl)Cl>[CH3:34][O:33][CH2:32][CH2:31][O:30][C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])=[O:35]
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: COCCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.8 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (150 mg, 0.45 mmol) in DCM (5 ml), was added triethylamine (188 μl, 1.35 mmol) and 2-methoxyethyl carbonochloridate (63 μl, 0.54 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc, and the organic phase was washed with water and brine, dried over Na2SO4 and evaporated to dryness, obtaining (R)-quinuclidin-3-yl 2-((2-methoxyethoxy)-carbonylamino)-2-phenylacetate (73.0 mg; 45% yield).
Reaction SMILES: Br[C:2]1C=C(NC2C=CC(N3CCN(C(C)C)CC3)=CN=2)C(=O)N(C)C=1.[Br:26][C:27]1[N:28]=[C:29]([NH:35][C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][NH:40][CH2:39]3)[C:30](=[O:34])[N:31]([CH3:33])[CH:32]=1>>[Br:26][C:27]1[N:28]=[C:29]([NH:35][C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][N:40]([CH3:2])[CH2:39]3)[C:30](=[O:34])[N:31]([CH3:33])[CH:32]=1
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CNC3)c1=O
Reactant: CC(C)N1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Product: CN1Cc2ccc(Nc3nc(Br)cn(C)c3=O)cc2C1

Procedure:
Following the procedures as described for 220a and starting with 336 mg of 5-bromo-3-(isoindolin-5-ylamino)-1-methylpyrazin-2(1H)-one, compound 231f was obtained as a yellow solid (237 mg, 75%). MS: [M+H]+ 337. 1H NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 7.67 (s, 1H), 7.52 (t, J=7.0, 1H), 7.18 (d, J=8.0, 1H), 6.74 (s, 1H), 3.94 (s, 2H), 3.89 (s, 2H), 3.52 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.[Br:40]C1C=CC(N2CCNCC2)=CC=1>O1CCCC1>[Br:40][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CN(C)CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccc(Br)cc2)CC1
Yield: 84 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 4.8 g (0.03 mole) of 1,1'-carbonyldiimidazole, 2.6 g (0.03 mole) of unsym-dimethylethylenediamine, and 6.2 g (0.03 mole) of 1-(4-bromophenyl)piperazine in a total of 200 ml of tetrahydrofuran gave a pale yellow semisolid. The material was triturated with ethyl ether to give 7.7 g (84%) of the title compound as a white solid, m.p. 133°-135° C.
Reaction SMILES: [OH:1][C:2]1([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19](O)=[O:20])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[N:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:36][NH2:37])[CH:29]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][C:2]1([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([NH:37][CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:28]2[CH:29]=[N:25][N:26]=[CH:27]2)=[O:20])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C(O)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Reactant: NCc1ccccc1-n1cnnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1ccccc1-n1cnnc1)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a stirred solution of 1-[(9-hydroxy-9H-fluoren-9-yl)carbonyl]-L-proline (Example 16, Step B, 0.06 g, 0.19 mmol) in DMF (1 mL) was added 1-[2-(4H-1,2,4triazol-4-yl) phenyl]methanamine (Example 5, Step A, 0.05 g, 0.31 mmol), BOP Reagent (0.11 g, 0.24 mmol) and N-methylmorpholine to pH=8. The mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour, filtered and purified on a Gilson Preparative HPLC to give the solid 1-[(9-hydroxy-9H-fluoren-9-yl)carbonyl]-N-[2-(4H-1,2,4-triazol-4-yl)benzyl]-L-prolinamide (0.065 g, HPLC RT=2.77 min, Method A; LCMS m/z=480). 1H NMR (400 MHz, CDCl3): δ 8.75 (s, 2H), 7.67–7.64 (m, 3H), 7.62–7.52 (m, 1H), 7.44–7.37 (m, 2H), 7.35–7.29 (m, 3H), 7.23–719 (m, 1H), 7.15 (s, 1H), 7.04 (d, 1H), 4.55–4.53 (m, 1H), 4.31–4.11 (m, 2H), 2.34–2.26 (m, 1H), 2.24–1.95 (m, 1H), 1.72–1.55 (m, 2H), 1.46–1.43 (m, 1H).