Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH:7]12[NH:12][CH:11]1[CH2:10][N:9]([C:13]1[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])=[CH:15][C:14]=1[F:30])[CH2:8]2.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][CH2:3][C:4]([N:12]1[CH:11]2[CH:7]1[CH2:8][N:9]([C:13]1[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])=[CH:15][C:14]=1[F:30])[CH2:10]2)=[O:5]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CC4NC4C3)c(F)c2)C(=O)O1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)N1C2CN(c3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)CC21
Reaction time: 1 h

Procedure:
Methoxyacetyl chloride (6 mL, 0.067 mmol) was added to a cooled (0° C.) solution of N-({(5S)-3-[4-(3,6-diazabicyclo[3.1.0]hex-3-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (15 mg, 0.05 mmol) in triethylamine (14 μL, 0.10 mmol) and dichloromethane (1.0 mL). After 1 hour, the solution was diluted with dichloromethane, and washed with dilute NaHCO3, brine, and dried (MgSO4), filtered and concentrated. Purification by pTLC (5% MeOH—CH2Cl2) provided the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH2:27]>>[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH:27][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)CCCN
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Product: COc1ccc(N(C)c2nc(NCCCN(C)C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and N′,N′-dimethyl-propane-1,3-diamine (16 μl, 0.070 mmol) by a procedure similar to Example 10 and was isolated as white powder (11 mg, 73%). 1H NMR (CDCl3): 7.43 (dd, J=8.4 and 1.2 Hz, 1H), 7.34 (ddd, J=7.8, 6.6 and 1.2 Hz, 1H), 7.11-7.07 (m, 2H), 6.89-6.86 (m, 3H), 6.65 (ddd, J=8.1, 6.6 and 1.2 Hz, 1H), 3.82 (s, 3H), 3.61 (t, J=6.9 Hz, 2H), 3.49 (s, 3H), 2.41 (t, J=6.9 Hz, 2H), 2.28 (s, 6H), 1.89 (m, 2H).
Reaction SMILES: Cl[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:32]=[N:33][OH:34])[CH:17]=3)[C:12]2=[O:35])=[CH:7][CH:6]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][C:44]#[CH:45])=[CH:39][CH:38]=1>ClCCl>[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][C:44]2[O:34][N:33]=[C:32]([C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[C:12](=[O:35])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=3)[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[CH:19]4)[CH:45]=2)=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(C=NO)ccc2c(=O)n1-c1ccc(F)cc1
Reactant: C#CCc1ccc(F)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(-c3cc(Cc4ccc(F)cc4)on3)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Sodium hypochlorite (1.408 mL, 0.912 mmol) was added to a stirred, room temperature mixture of tert-butyl 5-(2-(4-fluorophenyl)-6-((hydroxyimino)methyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (100 mg, 0.228 mmol) and 1-fluoro-4-(prop-2-ynyl)benzene (61.2 mg, 0.456 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for overnight. The reaction was checked with LCMS and starting material was all consumed. The mixture was diluted with dichloromethane (10 mL), washed with aqueous sodium hydrogen carbonate (saturated, 1×8 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane=50% to give tert-butyl 5-(6-(5-(4-fluorobenzyl)isoxazol-3-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (102 mg, 0.179 mmol) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([CH2:33][C:34]2[O:35][CH:36]=[CH:37][CH:38]=2)[CH3:32])[N:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([CH2:33][C:34]2[O:35][CH:36]=[CH:37][CH:38]=2)[CH3:32])[N:3]=1
Reactant: CN(Cc1ccco1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c1F
Solvent: CC(=O)O
Solvent: O
Product: CN(Cc1ccco1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c1F
Reaction time: 8 h
Yield: 59.3 %

Procedure:
[(2R)-3-(2-{2-Chloro-5-fluoro-6-[(2-furanylmethyl)(methyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.6318 g, 1.145 mmol) was dissolved in acetic acid (8 mL) and water (2 mL). This reaction mixture was left to stir overnight. The volatiles were evaporated, and the resulting residue was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(2-furanylmethyl)(methyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a beige solid (0.3182 g, 59%). LCMS: (M+H)+=469.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH2:13][Br:14])[CH:10]=[C:9]([CH2:15]Br)[CH:8]=1)[CH3:4].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>>[CH2:3]([O:5][C:6](=[O:17])[C:7]1[CH:8]=[C:9]([CH2:15][O:22][CH2:21][CH2:20][O:19][CH3:18])[CH:10]=[C:11]([CH2:13][Br:14])[CH:12]=1)[CH3:4]
Reactant: COCCO
Reactant: CCOC(=O)c1cc(CBr)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc(CBr)cc(COCCOC)c1

Procedure:
Sodium hydride (0.357 g, 60% dispersion in oil) was added to 2methoxyethanol (10 ml) with stirring. After 10 minutes 3,5-bis[bromomethyl]benzoic acid ethyl ester (J. Chem. Soc. Chem. Commun. 1992, 22, 1647) (3 g) was added and the mixture stirred for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 20% ethyl acetate in isohexane. Yield 0.45 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[N:15]3)[O:10][C:9]2=[O:20])=[N:6][CH:7]=1.C[Sn](C)(C)[C:23]1[S:27][C:26]([C:28]2[CH2:32][CH:31]([CH2:33][OH:34])[O:30][N:29]=2)=[CH:25][CH:24]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[OH:34][CH2:33][CH:31]1[O:30][N:29]=[C:28]([C:26]2[S:27][C:23]([C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:12][C@H:11]([CH2:13][N:14]5[CH:18]=[C:17]([CH3:19])[N:16]=[N:15]5)[O:10][C:9]4=[O:20])=[N:6][CH:7]=3)=[CH:24][CH:25]=2)[CH2:32]1
Reactant: C[Sn](C)(C)c1ccc(C2=NOC(CO)C2)s1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(Br)cn3)C(=O)O2)nn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(C5=NOC(CO)C5)s4)cn3)C(=O)O2)nn1
Temperature: 90 °C
Yield: 28.3 %

Procedure:
(5R)-3-(5-Bromopyrid-2-yl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (195 mg, 0.58 mM), {3-[5-(trimethylstannyl)thien-2-yl]-4,5-dihydroisoxazol-5-yl}methanol (200 mg, 0.58 mM), tris(dibenzylideneacetone)-dipalladium (0)-chloroform adduct (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 5 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (72 mg).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][N:7]([S:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[Cl-].[NH4+]>O1CCCC1.C1([Mg]Br)C=CC=CC=1>[O:1]1[C:5]2[CH2:6][N:7]([S:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]([C:13]4[CH:20]=[CH:19][CH:16]=[CH:15][CH:14]=4)[OH:18])=[CH:15][CH:14]=3)(=[O:12])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1ccc(S(=O)(=O)N2CCc3ccoc3C2)cc1
Agent: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(O)c2ccccc2)cc1)N1CCc2ccoc2C1

Procedure:
To a solution of 0.142 g (0.487 mmol) of 4-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-ylsulfonyl)benzaldehyde in 30 ml of tetrahydrofuran, phenylmagnesium bromide in tetrahydrofuran (prepared from 2.0 g of bromobenzene and 0.31 g of magnesium in 30 ml of tetrahydrofuran) was added at room temperature until the starting material disappeared on thin-layer chromatography (TLC). To the reaction mixture, aqueous ammonium chloride was added, followed by stirring and 3 extractions with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) to yield the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])=[C:25]([CH:40]=O)[CH:24]=2)[N:20]=[N:19][C:18]=1[O:42][CH3:43])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN.C(O)(=O)C.[C:50]([BH3-])#[N:51].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:24]=[C:25]([CH2:40][NH:51][CH3:50])[C:26]([O:31][CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])=[C:27]([O:29][CH3:30])[CH:28]=2)[N:20]=[N:19][C:18]=1[O:42][CH3:43])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [BH3-]C#N
Reactant: COc1cc(-c2cc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c(OC)nn2)cc(C=O)c1OCOCC[Si](C)(C)C
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1cc(-c2cc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c(OC)nn2)cc(OC)c1OCOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
175 mg of 2-{6-[3-Formyl-5-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-3-methoxy-pyridazin-4-yl}-indole-1-carboxylic acid tert-butyl ester is dissolved in 5 ml of methanol and 0.16 ml of methylamine solution in THF is added. The solution is stirred for 10 min at RT then 19 mg of acetic acid and 20 mg of sodium cyanoborohydride is added. The reaction is stirred for 20 h at RT. The product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 118 mg. LC-MS (ES+) 621 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)[C@H:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Br[C:31]1[CH:32]=[C:33](I)[C:34](=[O:37])[NH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:33]3[C:34](=[O:37])[NH:35][CH:36]=[CH:31][CH:32]=3)=[CH:10][CH:9]=2)[C@H:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1[nH]cc(Br)cc1I
Reactant: CC1(C)OC(=O)N(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@H]1c1ccccc1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3ccc[nH]c3=O)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A resealable tube was charged with (S)-5,5-dimethyl-4-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-2-one (Intermediate J)(0.100 g, 0.254 mmol), 5-bromo-3-iodopyridin-2(1H)-one (commercially available from Adesis, Inc., New Castle, Del.)(0.153 g, 0.509 mmol), sodium carbonate (0.108 g, 1.017 mmol), dioxane (2.0 mL), and water (0.40 mL). Tetrakis(triphenylphosphine)palladium(0) (0.147 g, 0.127 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture was then stirred at 100° C. for 16 hours. The reaction mixture was filtered through Celite® brand filter aid. The filtrate was then concentrated to afford a black oil. The oil thus obtained was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-100% EtOAc-hexane) to afford (S)-5,5-dimethyl-3-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)-4-phenyloxazolidin-2-one (0.021 g, 0.058 mmol, 23% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (s, 3H), 1.64 (s, 3H), 5.46 (s, 1H), 6.24 (t, J=6.70 Hz, 1H), 7.20-7.43 (m, 6H), 7.48 (d, J=8.90 Hz, 2H), 7.58 (dd, J=6.94, 2.05 Hz, 1H), 7.65 (d, J=8.80 Hz, 2H), 11.72 (br. s., 1H). m/z (ESI) 361 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O(C(C)(C)C)[K]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[CH:11]=[C:10]([CH3:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1cc(Cl)nc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc12
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a degassed solution of 2-chloro-4-methyl-quinoline (1.00 g, 5.63 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.35 g, 6.76 mmol, 1.2 equiv; commercially available) in dimethoxyethane (15 mL) was added KOtert-Bu (0.88 g, 7.88 mmol, 1.4 equiv), (R)-(−)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine (3.12 mg, 0.0056 mmol, 0.1 mol %; Josiphos ligand [CAS RN 158923-11-6]; commercially available from Strem Chemicals, USA) and palladium(II) acetate (1.26 mg, 0.0056 mmol, 0.1 mol %). The reaction mixture was stirred at 90° C. for 18 h, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate providing 0.54 g (28%) of the title compound. 1H NMR (300 MHz, DMSO): δ1.31-1.40 (m, 2H), 1.41 (s, 9H), 1.91-1.96 (m, 2H), 2.46 (s, 3H), 2.93-3.01 (m, 2H), 3.86-3.91 (m, 2H), 4.11-4.17 (m, 1H), 6.59 (s, 1H), 6.80 (d, J=7.7 Hz, 1H), 7.13-7.17 (m, 1H), 7.44-7.47 (m, 2H), 7.73 (d, J=7.7 Hz, 1H). 13C NMR (75 MHz, DMSO): δ18.16, 28.07, 31.57, 42.39, 46.37, 78.51, 112.89, 120.88, 123.12, 123.64, 125.96, 128.69, 143.28, 147.91, 153.91, 155.93. MS (ISP): 342.5 [M+H]+.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:21]([OH:23])=[O:22])[C:15](=[CH:19][CH:20]=1)[C:16]([OH:18])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>>[O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:21](=[O:22])[O:23][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCCCOc2ccccc2)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(OCCCOc3ccccc3)ccc21

Procedure:
4-(3-phenoxypropoxy)phthalic acid (41 g; 0.134 mole) was refluxed for 30 minutes with excess acetic anhydride and the product evaporated to dryness in vacuo. Recrystallisation of the resulting white solid from ethyl acetate afforded material of m.p. 96°-98°. (Found; C, 68.48; H, 4.75; C17H14O5 requires; C, 68.45; H, 4.73%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([NH:5][C:6]1[C:7](=[O:21])[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:4]>[Pd].CO>[F:23][C:2]([F:1])([F:22])[C:3]([NH:5][C@H:6]1[CH2:10][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]1=[O:21])=[O:4]
Reactant: CC(C)CN1C(=O)C(NC(=O)C(F)(F)F)=CC1c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)CN1C(=O)[C@@H](NC(=O)C(F)(F)F)C[C@@H]1c1ccccc1

Procedure:
A solution of 2,2,2-trifluoro-N-(1-isobutyl-2-oxo-5-phenyl-2,5-dihydro-1H-pyrrol-3-yl)acetamide (300 mg, 0.919 mmol) and 10% palladium on carbon (50.0 mg) in methanol (6 mL) was stirred under a hydrogen balloon. After 2 hours the reaction was filtered through a Celite plug and concentrated. The crude product was purified by chromatography (silica gel, 0 to 50% ethyl acetate in hexane gradient elution) to give the title compound as a 1.4/1 mixture of cis/trans isomers (300 mg). Careful chromatography (silica gel, 0 to 20% ethyl acetate in hexane gradient elution, then 20 to 50% ethyl acetate in hexane gradient elution) allowed for the isolation of a portion of each the cis isomer (2nd eluting, 150 mg) and the trans isomer (1st eluting, 85 mg), along with several mixed fractions. Each isomer was carried forward individually. cis 1H NMR (500 MHz, CDCl3) □ 7.42-7.35 (m, 3H), 7.26-7.24 (m, 3H), 4.60 (dd, J=9.3, 6.2 Hz, 1H), 4.53-4.48 (m, 1H), 3.48 (dd, J=13.7, 9.8 Hz, 1H), 3.21-3.16 (m, 1H), 2.46 (dd, J=13.7, 5.6 Hz, 1H), 1.88-1.72 (m, 2H), 0.81 (d, J=6.6 Hz, 3H), 0.78 (d, J=6.8 Hz, 3H); trans 1H NMR (500 MHz, CDCl3) □ 7.55 (bs, 1H), 7.42-7.38 (m, 2H), 7.36-7.33 (m, 1H), 7.13 (d, J=7.8 Hz, 1H), 4.77 (d, J=8.8 Hz, 1H), 4.57-4.52 (m, 1H), 3.54 (dd, J=13.7, 9.3 Hz, 1H), 2.68-2.65 (m, 1H), 2.58 (dd, J=13.7, 5.9 Hz, 1H), 2.48-2.41 (m, 1H), 1.96-1.88 (m, 1H), 0.90 (d, J=2.2 Hz, 3H), 0.89 (d, J=2.4 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([O:28][CH3:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][C:17]=1[O:30][CH3:31]>>[CH3:13][N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([O:28][CH3:29])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:18][C:17]=3[O:30][CH3:31])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14]
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: COc1cc(C2(OC)CCOCC2)ccc1O
Product: COc1cc(C2(OC)CCOCC2)ccc1OCc1ccc2c(ccc(=O)n2C)c1
Yield: 49 %

Procedure:
Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one was reacted with 4-(4-hydroxy-3-methoxyphenyl)-4-methoxytetrahydropyran to give 4-[4-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)-3-methoxyphenyl]-4-methoxytetrahydropyran in 49% yield, m.p. 172°-173° C. (recrystallised from ethyl acetate).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([N:18]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23](F)[CH:24]=2)[C:19]1=[O:38])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O>[CH2:11]([N:18]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:24]=2)[C:19]1=[O:38])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil, 400 mg) was added to benzyl alcohol (6 ml) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 30 min. To the reaction mixture was added 2-benzyl-6-fluoro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (310 mg) and the mixture was stirred at 120° C. for 6 hrs. To the reaction mixture were added water and 10% hydrochloric acid to acidify the aqueous layer of the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diisopropyl ether-hexane and the crystals were collected by filtration. Recrystallization (ethyl acetate-hexane) gave the title compound (250 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[C:17](Cl)(=[O:28])[O:18][CH2:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=1.[OH-].[Na+]>C(Cl)Cl>[Cl:26][C:24]1[CH:25]=[C:20]([CH:21]=[C:22]([Cl:27])[CH:23]=1)[CH2:19][O:18][C:17]([NH:1][CH:2]1[CH2:3][CH:4]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]([CH2:6][CH2:5]2)[CH2:8]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(N)C2
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(NC(=O)OCc1cc(Cl)cc(Cl)c1)C2

Procedure:
A reaction mixture comprising of tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (210 mg, 0.928 mmol), 3,5-dichlorobenzyl carbonochloridate (222 mg, 0.928 mmol), and sodium hydroxide (4.64 ml, 93 mmol) in DCM (3.1 ml) was stirred at room temperature for 4 hours. The reaction mixture separated and the organic portion dried over MgSO4, filtered and concentrated under reduced pressure. No further purification was carried out and the material was taken on crude to the next step.
Reaction SMILES: [Na].COC([C:6]1[C:7]2[N:8]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:14]=2)[CH:9]=[CH:10][N:11]=1)=O.[CH3:22][OH:23]>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:14]=[C:7]3[C:6]([O:23][CH3:22])=[N:11][CH:10]=[CH:9][N:8]3[CH:12]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Reactant: CO
Agent: [Na]
Product: COc1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 50 °C

Procedure:
A mixture of MeOH (18 mL) and sodium (1.1 g, 48 mmol) was stirred at ambient temperature until the sodium was consumed then 8-chloro-2-(4-fluorophenyl)-imidazo[1,2-a]pyrazine (prepared from general procedure B using 3-chloropyrazin-2-ylamine and 2-bromo-1-(4-fluorophenyl)-ethanone; 1.0 g, 4 mmol) was added. The mixture was heated at about 50° C. for about 1 h. The mixture was cooled to ambient temperature and filtered. The beige solid isolated was carried on crude. (0.98 g, 100%): LC/MS (Table 1, Method b) Rt=1.8 min; MS m/z: 244.1 (M+H)+.