Azzindani/Open_Reaction_Data huggingface dataset:
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.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-fluorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 30% overall yield. FDMS m/e=369 (M+ of free base). α[D]589=−2.49 (c=0.24, methanol).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:8][C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)=[N:6]1.OO.NC(N)=O.F[C:33](F)(F)[C:34]([O:36]C(=O)C(F)(F)F)=[O:35]>C(Cl)Cl.C(OC(=O)C)(=O)C>[C:34]([O:36][C:17]1[C:18]([F:21])=[CH:19][CH:20]=[C:15]([C:7]2[CH:8]=[C:9]([C:10]3[CH:14]=[CH:13][O:12][N:11]=3)[N:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])[N:6]=2)[N:16]=1)(=[O:35])[CH3:33]
Reactant: Fc1ccc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)nc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: NC(N)=O
Agent: OO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Oc1nc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)ccc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a cold mixture of 3-(1-(2-fluorobenzyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-5-yl)isoxazole (1 equiv.) and urea compound with hydrogen peroxide (1:1) (3 equiv.) in DCM (1.7 ml) at 0° C., was added trifluoroacetic anhydride (3 equiv.). The mixture was allowed to warm to 25° C. and stirred for 3 days. The mixture was quenched with saturated solution of sodium bisulfate and extracted with dichloromethane (50 ml×3). The organic layers were combined, filtered and evaporated to give solid. The solid was dissolved in acetic anhydride (1.4 ml) and heated to 145° C. for 4 h. The mixture was cooled to 25° C., diluted with dichloromethane (100 ml) and washed with saturated solution of sodium bicarbonate (50 ml). The organic layer was dried (MgSO4), filtered and evaporated to give an oil. Purification of the oil by column chromatography (0 to 30% ethyl acetate in hexanes) gave 3-fluoro-6-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl acetate as an yellow oil. The yellow oil was combined with methanol (1.7 ml) and potassium carbonate (1 equiv.). The mixture was heated to 65° C. for 30 min. The mixture was concentrated under vacuum. The resulting residue was diluted with dichloromethane (100 ml) and washed with 1N HCl (30 ml). The organic layer was dried (MgSO4), filtered and evaporated to give a solid. Purification of the solid by column chromatography (0 to 5% methanol in dichloromethane) gave 3-fluoro-6-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyridin-2(1H)-one as a yellow solid (7% overall yield).
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][CH2:29]3)[C:12]=2[C:16]2[CH:21]=[CH:20][C:19](OC(F)(F)F)=[CH:18][CH:17]=2)[CH:7]=1)([CH3:5])[CH2:3][OH:4].C([C@H]1CC[C@H](OC2C(C3C=CC=CC=3)=C3C(=CC=2)C=C([C@]2(C)COC(=O)N2)C=C3)CC1)(C)(C)C>>[NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:27][C@H:28]3[CH2:29][CH2:30][C@H:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:32][CH2:33]3)[C:12]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1)([CH3:5])[CH2:3][OH:4]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccccc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccccc2)CC1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-phenylnaphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 88% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-phenylnaphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z=415.44 [M-NH2]+. 1H NMR (MeOD) δ: 7.93 (s, 1H), 7.88 (d, J=9.0 Hz, 1H), 7.44-7.52 (m, 4H), 7.38-7.44 (m, 2H), 7.29-7.34 (m, 2H), 4.00-4.09 (m, 1H), 3.66-3.75 (m, 2H), 1.97-2.04 (m, 2H), 1.75-1.82 (m, 2H), 1.52 (s, 3H), 0.92-1.23 (m, 5H), 0.86 (s, 9H)
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[NH:14][C:12](=[O:13])[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)(Cl)Cl>[NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[NH:14][C:12](=[O:13])[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2cc3c(cc2Nc2ccccc2)C(=O)NC3=O)cc1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)c2cc(Nc3ccc(O)cc3)c(Nc3ccccc3)cc21
Temperature: -30 °C
Reaction time: 5 h

Procedure:
To a solution of 359.4 mg (1 mmol) of 4-anilino-5-(4-methoxy-anilino)-phthalimide in 5 ml of chloroform, a solution of 186 μl (2 mmol) boron tribromide is added dropwise at -40° C. to -30° C. The reaction mixture is stirred for 5 hours at -30° C., and is then quenched with 5 ml of water. The reaction mixture is warmed up to room temperature, and the phases are separated. The organic phase is washed twice with water, dried over magnesium sulfate and concentrated by evaporation. Excluding light, the evaporation residue is chromatographed with ethylacetate/hexane 1:1 on a silica gel column that is cooled with ice-water (double jacket), the product fractions are combined and concentrated by evaporation. The title compound is obtained in the form of yellow crystals, FAB-MS: 346 [M+ +H].
Reaction SMILES: [CH3:1][P:2]1(=[O:14])[CH2:7][CH2:6][C:5](C(O)=O)([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C(=O)=O>O>[CH3:1][P:2]1(=[O:14])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CP1(=O)CCC(C(=O)O)(C(=O)O)CC1
Agent: O=C=O
Solvent: O
Product: CP1(=O)CCC(C(=O)O)CC1
Temperature: 215 °C

Procedure:
To a 50 mL microwave pressure flask equipped with a stir-bar was added 1-methyl-1-oxo-1λ5-phosphinane-4,4-dicarboxylic acid (0.25 g, 5.7 mmol) and water (20 mL) to give a suspension. The flask was sealed and heated to 215° C. over 60 seconds, at which point a pressure spike was observed. The flask was allowed to cool to room temperature then vented to release pressure from dissolved CO2. The resulting clear and colorless solution was concentrated by lyophilization to provide 1-methyl-1-oxo-1λ5-phosphinane-4-carboxylic acid in quantitative yield as a mixture of cis/trans isomers (˜2:1; identity of the favored isomer not determined). 1H NMR (400 MHz, D2O) δ ppm 2.6-2.4 (m, 1H), 2.2-1.6 (m, 8H), 1.48 (d, J=12.9 Hz, minor isomer, 1H), 1.44 (d, J=13.7 Hz, major isomer, 2H); ESMS m/z: found, 177 (M+1)+, 353 (2M+1)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[N:10]=1)(C)(C)C.[ClH:19]>C(OCC)(=O)C.O1CCOCC1>[ClH:19].[F:17][C:14]([F:15])([F:16])[C:11]1[N:10]=[C:9]([CH2:8][NH2:7])[O:13][N:12]=1
Reactant: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NCc1nc(C(F)(F)F)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.29 g (3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-carbamic acid tert-butyl ester in 3 ml ethyl acetate was added 1.5 ml of a 4M solution of hydrochloric acid in dioxane and the mixture was stirred at ambient temperature for 18 h. The resulting clear solution was evaporated and the residue was triturated under ethyl acetate. The solid was collected by filtration and dried to constant weight under high vacuum to yield 0.145 g of the title compound as white crystals, 169.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([N:28]1[CH2:33][CH2:32][O:31][CH:30]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:29]1)(=[O:27])=[O:26].ClC1C=C2C(=CC=1)NC(C(N)=O)=C2S(N1CCO[C@H](COC2C=CC=CC=2)C1)(=O)=O.O(C[C@H]1OCCNC1)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:13])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:25]([N:28]1[CH2:33][CH2:32][O:31][C@H:30]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:29]1)(=[O:27])=[O:26]
Reactant: CCOC(=O)c1c(S(=O)(=O)N2CCOC(COc3ccccc3)C2)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: NC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)N1CCO[C@H](COc2ccccc2)C1
Agent: c1ccc(OC[C@@H]2CNCCO2)cc1
Product: CCOC(=O)c1c(S(=O)(=O)N2CCO[C@H](COc3ccccc3)C2)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1

Procedure:
The product from Step A of Example 22 was resolved by preparative chiral HPLC (ChiralPak AD) to produce a first-eluting enantiomer and a second-eluting enantiomer. To assign the (S)-configuration to the first-eluting enantiomer, (S)-2-(phenoxymethyl)morpholine (from resolution of the racemate by preparative ChiralPak AD HPLC) was converted to the titled product using the procedure described in Step A of Example 22. The configuration of (S)-2-(phenoxymethyl)morpholine was assigned by 1H NMR analysis of the derived Mosher's amide (cf. J. Org. Chem. 1996, 61, 2056-2064).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[OH:12].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12]
Reactant: OC1CCOc2ccc(I)cc21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCOc2ccc(I)cc21
Yield: 100.1 %

Procedure:
To a CH2Cl2 (300 ml) suspension of 6-iodo-4-chromanol (15 g, 54.3 mmol) and 30 g of silica gel, at r.t., was added PCC (15.2 g, 70.6 mmol) as a solid. The mixture was stirred at r.t. for 3 h at which time TLC (20% EtOAc/hexanes) indicated complete reaction. The reaction mixture was filtered through a silica gel plug and the filtrate concentrated in vacuo to yield 14.9 g (95%) of 6-iodo-2,3-dihydro-4H-chromen-4-one as a white solid consistent with the literature report (Synthesis 1997, 23–25). HRMS (ESI+) calcd for C9H7IO2 m/z 273.9492; found 273.9500.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:49])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28]([C:39]3[C:44]([F:45])=[CH:43][C:42]([O:46][CH3:47])=[CH:41][C:40]=3[F:48])[S:29][C:30]=2[NH:31]C(OC(C)(C)C)=O)=[O:25])[CH2:13][CH2:12]1)C1C=CC=CC=1.Cl>>[NH2:31][C:30]1[S:29][C:28]([C:39]2[C:40]([F:48])=[CH:41][C:42]([O:46][CH3:47])=[CH:43][C:44]=2[F:45])=[N:27][C:26]=1[C:24]([NH:23][C:22]1[CH:21]=[N:20][N:19]([CH3:49])[C:18]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@@H:11]([NH2:10])[CH2:12][CH2:13]1)=[O:25]
Reactant: COc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](NC(=O)OCc4ccccc4)CC3)c(NC(=O)OC(C)(C)C)s2)c(F)c1
Agent: Cl
Product: COc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](N)CC3)c(N)s2)c(F)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
A heterogeneous mixture of [(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2,6-difluoro-4-methoxyphenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamic acid benzyl ester (14.5 mg, 0.02 mmol) and 2M aq. HCl (5 mL) was stirred at 100° C. under N2 for 4 h. The resultant homogeneous reaction was cooled to RT and the water solvent was removed using toluene azeotrope. The crude was redissolved in 9:1 v/v DMF:MeOH (1 mL) and purified via reverse phase HPLC to afford 202 (9.2 mg, 94.3%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.75 (broad s, 1H), 8.46 (s, 1H), 7.53 (s, 1H), 7.42 (s, 2H), 6.95 (s, 1H), 6.92 (s, 1H), 3.85 (s, 3H), 3.64 (s, 3H), 3.20-3.04 (m, 6H), 1.95-1.77 (m, 3H), 1.68-1.52 (m, 3H); MS (ESI) m/z: 479.1 [M+H]+
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=2)=[CH:11][C:10]=1[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:32]C(=O)OC(C)(C)C)[CH:29]=[CH:30][CH:31]=1)=O)(C)(C)C.CO.[ClH:42]>O1CCOCC1>[ClH:23].[ClH:42].[ClH:23].[NH2:32][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][C:10]2[CH:11]=[C:12]([NH:15][C:16]3[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=3)[CH:13]=[CH:14][C:9]=2[NH2:8])[CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cnc(Cl)nc1Nc1ccc(NC(=O)OC(C)(C)C)c(CCc2cccc(NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cnc(Cl)nc1Nc1ccc(N)c(CCc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
Into the reaction flask was added tert-butyl [3-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5-methylpyrimidin-4-yl)amino]phenyl}ethyl)phenyl]carbamate (0.25 g, 0.45 mmol), methanol (3 mL), and 4.0 M of hydrogen chloride in 1,4-dioxane (5 mL). The reaction mixture was stirred at rt for 16 h and concentrated to give the desired product (0.21 g, 90%). LCMS for C19H21ClN5 (M+H)+: m/z=354.1.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:18][O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Br)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:18][O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:15][CH:12]2[CH2:11][CH2:10][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:17]=[CH:16][C:5]=4[N:6]=3)[CH2:14][CH2:13]2)[CH:23]=1
Reactant: NC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Reactant: COC(=O)Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(CNC2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A mixture of 1-(6-chlorobenzothiazole-2-yl)piperidine-4-ylamine (500 mg), (3-bromomethylphenyl)acetic acid methyl ester (454 mg), potassium carbonate (284 mg) and dimethylformamide (6 mL) was stirred at room temperature for 1 hour. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (434 mg). Yield: 55%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](B(O)O)[CH:6]=[CH:5]2.Br[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1)[CH:6]=[CH:5]2
Reactant: COC(=O)c1ccc(Br)nc1
Reactant: OB(O)c1ccc2cc(O)ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc3cc(O)ccc3c2)nc1
Temperature: 120 °C

Procedure:
A mixture of 6-hydroxynaphthalen-2-ylboronic acid (250 mg, 1.33 mmol), methyl 6-bromonicotinate (260 mg, 1.21 mmol), Pd(dppf)Cl2 (90 mg, 0.12 mmol) and sodium carbonate (205 mg, 2.41 mmol) in DME/water (3 mL/1 mL) was heated to 120° C. by microwave for 1 h. Then the mixture was partitioned with water (10 mL) and EA (20 mL). The precipitate was filtered off. The organic phase was separated, washed with brine (15 mL), dried over Na2SO4 and concentrated to afford product (crude, 380 mg) as a brown oil.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]3)[C:9]([N:11]3[CH2:16][CH2:15][O:14][C@@H:13]4[CH2:17][CH2:18][CH2:19][C@@H:12]34)=[N:10][C:6]=2[CH:5]=[C:4]([Cl:28])[N:3]=1.[Cl:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[C:33]([F:36])=[N:34][CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CCOC(C)=O>[Cl:28][C:4]1[N:3]=[C:2]([C:32]2[C:33]([F:36])=[N:34][CH:35]=[C:30]([Cl:29])[CH:31]=2)[C:7]2[N:8]([CH2:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([CH3:27])[CH2:25][CH2:26]3)[C:9]([N:11]3[CH2:16][CH2:15][O:14][C@@H:13]4[CH2:17][CH2:18][CH2:19][C@@H:12]34)=[N:10][C:6]=2[CH:5]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(Cl)c32)CC1
Reactant: CC1(C)OB(c2cc(Cl)cnc2F)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(-c4cc(Cl)cnc4F)c32)CC1
Temperature: 90 °C

Procedure:
4,6-dichloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic, 422 mg, 1 mmol), 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (340 mg, 2 mmol) and Cs2CO3 (980 mg, 3 mmol) were added to degassed dioxane:water (10 mL: 2 mL), followed by the addition of [1,1′-bis(di-tert-butylphosphino)ferrocene]PdCl2 (130 mg, 0.2 mmol). The reaction was heated at 90° C. for 24 hours. Water and EtOAc were added. The aqueous layer was extracted with EtOAc several times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified on a silica gel column (0 to 60% EtOAc/hexanes) to afford 6-chloro-4-(5-chloro-2-fluoropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic). MS ES calc'd. for C26H30Cl2FN5O [M+H]+ 518. found 518.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C(O)(C(F)(F)F)=[O:12].S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[O:12])=[C:4]([F:10])[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: NC(=O)c1ccc(Br)cc1F
Temperature: 0 °C
Yield: 87.4 %

Procedure:
A solution of 4-bromo-2-fluorobenzonitrile (10.0 g, 50.0 mmol) in a 70 mL mixture of TFA (56.0 mL, 727 mmol)-sulfuric acid (14.0 mL, 263 mmol) (4:1 V/V) was stirred at 40° C. for 16 h. The reaction was poured while still warm over ice water. The product precipitated and the solid was filtered and dried to give 4-bromo-2-fluorobenzamide (9.53 g, 43.7 mmol, 87% yield) as a white solid. MS (ESI) m/z 218.1 [M]+, 220.1 [M+2]+.
Reaction SMILES: N[C@H](C(O)=O)CC(O)=O.N[C@H](C([O-])=O)CC([O-])=O.[C:19]([NH:26][C@H:27]([C:32]([O-:34])=[O:33])[CH2:28][C:29]([O-:31])=O)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(OC(=O)C)(=O)C>>[C:22]([O:21][C:19]([NH:26][C@@H:27]1[C:32](=[O:33])[O:34][C:29](=[O:31])[CH2:28]1)=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)[O-])C(=O)[O-]
Agent: N[C@@H](CC(=O)O)C(=O)O
Agent: N[C@@H](CC(=O)[O-])C(=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC(=O)OC1=O

Procedure:
Due to its low cost, L aspartic acid appears to be the most attractive starting material for the preparation of (S)-3-amino-1-substituted-pyrrolidines. The literature method from L-aspartate (D. T. Witiak, loc. cit.) involves treatment of N-boc-L-aspartate with acetic anhydride to give (S)-3-(tert butoxycarbonylamino)succinic anhydride followed by addition of a primary amine and ring closure with heat to give the succinimide, (S)-3-(tert-butoxycarbonylamino)-1-substituted pyrrolidine-2,5-dione. The latter is then reduced and deblocked to give the 1-substituted-3-aminopyrrolidine in low overall yield. From our experience with this method some racemization takes place when the blocking group is p-toluenesulfonyl(tosyl) and the primary amine is benzylamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2O[CH:3]12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:27][CH:26]=[N:25][CH:24]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:27]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]=3)[CH:26]=[N:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: Clc1ccc(-c2cnc[nH]2)cc1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)C=C(n2cncc2-c2ccc(Cl)cc2)c2cc(C#N)ccc2O1

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-(4-chloro-phenyl)-1H-imidazole as starting materials, the title compounds were prepared as white solid.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:38]([C:40]1[CH:41]=[C:42]([N:46]([CH2:52][C:53]2[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=2)[S:47]([CH2:50][CH3:51])(=[O:49])=[O:48])[CH:43]=[CH:44][CH:45]=1)=O>C1COCC1>[C:3]1([CH:2]=[CH:38][C:40]2[CH:41]=[C:42]([N:46]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[S:47]([CH2:50][CH3:51])(=[O:49])=[O:48])[CH:43]=[CH:44][CH:45]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C=O)c1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C=Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyltriphenylphosphonium bromide (0.765 g, 1.77 mmol) was dispersed into THF (12 ml) and cooled at 0° C. To the cooled suspension was added dropwise a solution of potassium bis(trimethylsilyl)amide (0.5 M, 3.5 ml, 1.75 mmol). After stirring at 0° C. for 1 h, a solution of). N-(3-formyl-phenyl)-N-(ethylsulfonyl)pyrid-3-ylmethylamine (0.304 g, 1.0 mmol) in THF was added. The reaction mixture was stirred at ambient temperature for 2 h. Evaporation and chromatography on silica-gel eluting with toluene-EtOAc to give the title compound. 1H NMR: 8.48 (d,1H,J=3.4 Hz), 8.30 (d,1H,J=2.0 Hz), 7.65 (d,1H,J=7.8 Hz), 7.30-6.74 (m,8H), 6.60 (q,2H,J=12.2, 37.1 Hz), 4.68 (s,2H), 2.87 (q,2H,J=7.3 Hz), 1.28 (t,3H,J=7.4 Hz). MS calcd 378.1; MS (M+1) 379.1.
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12.N[C@H](C1C=CC(OC)=C(OC)C=1)CC(OC)=O.C(=O)([O-])[O-].[Na+].[Na+].C(N1C(=O)C2=CC=CC=C2C1=O)(OCC)=O>>[C:4]1(=[O:22])[N:5]([C@H:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:1](=[O:27])[C:2]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:3]12
Reactant: COC(=O)CC(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: COC(=O)C[C@H](N)c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Product: COC(=O)C[C@@H](c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O

Procedure:
Prepared as described earlier as methyl 3-phthalimido-3-(3',4'-dimethoxyphenyl)propionate from 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). 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%.