Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.O[C:39]1[CH:49]=[CH:48][C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:41][CH:40]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][C:39]3[CH:49]=[CH:48][C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:41][CH:40]=3)=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)CCSc2ccc(C(=O)O)cc21
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCS3)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 280 mg (1.26 mmol) of 4,4-dimethyl-6-carboxythiochroman and 252 mg (2.52 mmol) of triethylamine in 15 ml of chloroform was stirred at room temperature for 0.5 hours and then treated with 481 mg (1.26 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride. The reaction mixture was stirred for 0.5h, treated with 209 mg (1.26 mmol) of ethyl 4-hydroxybenzoate and then stirred at room temperature for a further 12 hours. The reaction mixture was washed successively with dilute HCl and saturated sodium bicarbonate solutions The organic layer was concentrated in-vacuo and the resultant crude product purified by flash chromatography (silica; 10% ethyl acetate in hexane) followed by reversed-phase high pressure liquid chromatography (Whatman Partisil M20 10/50 ODS-2; 10% water in acetonitrile) to give the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.C[O-].[Na+].O.[C:18](OCC)(=[O:20])C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:20][CH3:18]
Reactant: CCOC(C)=O
Reactant: CCS(=O)(=O)c1ccc(F)c(Br)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.4 %

Procedure:
A mixture of 2-bromo-4-ethylsulfonyl-1-fluorobenzene (0.6 g, 2.25 mmol) and sodium methoxide (1.2 g, 22.2 mmol) in THF (20 mL) was stirred at room temperature for 18 h. Water (30 mL) was added and extractive work up with ethyl acetate followed by silica gel chromatography (PE:EA=10:1 to 1:1) gave the title compound (0.5 g, 79.4%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.08 (d, J=2.4 Hz, 1H), 7.87-7.84 (dd, J1=8.6 Hz, J2=2.4 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.99 (s, 3H), 3.11 (q, J=7.4 Hz, 2H), 1.30 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 472 [M+1]+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[C:22]([C:29]3[NH:37][C:36]4[CH:35]([CH3:38])[CH2:34][NH:33][C:32](=[O:39])[C:31]=4[CH:30]=3)[CH:23]=[CH:24][CH:25]=2)[N:20]=1.C(O)(C(F)(F)F)=O>CS(C)=O>[CH3:38][CH:35]1[CH2:34][NH:33][C:32](=[O:39])[C:31]2[CH:30]=[C:29]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:21]=3[N:20]=[C:19]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:28]=[CH:27]4)[NH:37][C:36]1=2
Reactant: CC1CNC(=O)c2cc(-c3cccc4ccc(Cl)nc34)[nH]c21
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC1CNC(=O)c2cc(-c3cccc4ccc(Nc5ccccc5)nc34)[nH]c21
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A solution of LHMDS (1.0 M in THF; 2.197 ml, 2.197 mmol), aniline (0.200 ml, 2.197 mmol), and 2-(2-chloroquinolin-8-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 27; 0.137 g, 0.439 mmol) was stirred at RT for 1.5 h. An additional 2 equiv LHMDS (1.0 M in THF) was added, and the reaction was stirred overnight. The reaction was concentrated under N2, treated with DMSO and TFA (0.474 ml, 6.15 mmol), filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-80% ACN/H2O with 0.1% TFA); product-containing fractions were treated with saturated aq. NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give rac-7-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.065 g, 0.176 mmol, 40% yield, Example 238) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.11 (1H, br. s), 9.53 (1H, s), 8.12 (1H, d, J=9.0 Hz), 7.93 (1H, dt, J=7.4, 0.8 Hz), 7.56-7.71 (3H, m), 7.34-7.45 (2H, m), 7.29 (1H, t, J=7.6 Hz), 6.99-7.14 (2H, m), 6.85-6.98 (2H, m), 3.38-3.52 (1H, m), 2.86-3.08 (2H, m), 0.84 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 369.1 (M+H)+. A portion of this material was resolved by chiral SFC (ChiralPak AS-H (21×250, 5 μm); additive in supercritical fluid CO2 was 40% MeOH with 20 mM NH3; 60 mL/min; column temperature 40° C.; outlet pressure 100 bar) to give separated enantiomers 7-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 29, first eluting enantiomer) and 7-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 30, second eluting anantiomer).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O:12][C:13]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:20][C:14]=1[C:15]([O:17]CC)=[O:16])(=O)C>N1C=CC=CC=1>[OH:12][C:13]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH:8][C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:20][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: Cc1cccnc1N
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Cl)cc2)ccc1OC(C)=O
Solvent: c1ccncc1
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C#Cc2ccc(O)c(C(=O)O)c2)cc1
Reaction time: 18 h

Procedure:
3-methyl-2-pyridinamine (1.3 g, 12 mmol) was dissolved in dry pyridine (20 ml) and ethyl 2-acetyloxy-5-[(4-chlorosulfonylphenyl)ethynyl]-benzoate (4.1 g, 10 mmol) was added. The solution was kept at ambient temperature for 18 h. The solvent was evaporated and the residue dissolved in a small amount of tetrahydrofuran. The solution was added to a refluxing solution of potassium hydroxide (6 g) in water (100 ml) and ethanol (50 ml). After 15 min the solution was acidified with formic acid to produce a precipitate. The solid was collected by filtration, washed with water and dried. Yield 1.2 g, 29%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][C@H:13]([F:15])[CH2:12][N:11]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([N:27](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[O:26])=[C:18]3[CH:17]=2)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][C@H:13]([F:15])[CH2:12][N:11]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([NH2:27])=[O:26])=[C:18]3[CH:17]=2)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](F)C[C@@H]4c4cc(F)cc(C#N)c4)cc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(F)cc([C@H]2C[C@H](F)CN2c2ccn3ncc(C(N)=O)c3c2)c1
Temperature: 50 °C

Procedure:
A solution of 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-53) (10 mg, 0.02 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) and heated to 50° C. for 12 hours. The reaction was reduced to dryness and purified by column chromatography on silica gel with DCM/MeOH gradient as eluant to yield 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (X-10). 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J=8.0 Hz, 1 H), 8.23 (s, 1 H), 7.61 (m, 1 H), 7.48-7.42 (m, 1 H), 7.03 (d, J=2.4 Hz, 1 H), 6.52 (dd, J=2.8, 7.6 Hz, 1 H), 5.42 (d, J=52.4 Hz, 1 H), 5.14 (dd, J=7.2, 9.6 Hz, 1 H), 4.21 (ddd, J=3.2, 12.0, 36.8 Hz, 1 H), 3.94 (ddd, J=2.0, 12.4, 23.6 Hz, 1 H), 2.98-2.85 (m, 1 H), 2.16 (dddd, J=3.6, 9.6, 14.0, 40.4 Hz, 1 H). MS m/z 368.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[O:13][C:5]2=[C:6]([NH:11][CH3:12])[N:7]=[CH:8][C:9](I)=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]3)[CH:26]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Cl:1][C:2]1[O:13][C:5]2=[C:6]([NH:11][CH3:12])[N:7]=[CH:8][C:9]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:28][CH2:29][N:30]([C:33](=[O:35])[CH3:34])[CH2:31][CH2:32]4)[CH:26]=3)=[C:4]2[CH:3]=1
Reactant: CNc1ncc(I)c2cc(Cl)oc12
Reactant: CC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNc1ncc(-c2cnn(C3CCN(C(C)=O)CC3)c2)c2cc(Cl)oc12
Temperature: 95 °C
Yield: 99.1 %

Procedure:
A mixture of 2-chloro-4-iodo-N-methylfuro[2,3-c]pyridin-7-amine (125 mg, 0.405 mmol), 1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone (142 mg, 0.446 mmol), (1,1′-bis-(diphenylphosphine)-ferrocene)palladium dichloride (29.6 mg, 0.0405 mmol) and potassium carbonate (140 mg, 1.01 mmol) in 1,4-dioxane (1.35 mL) and water (0.58 mL) was heated to 95° C. for 20 h. The mixture was adsorbed directly onto a dry 5 g silica gel cartridge and purified by ISCO chromatography (0 to 10% methanol:ethyl acetate) to afford 150 mg (99%) of the title compound as a tan solid. 1H NMR (400 MHz, CD3OD): δ 8.06 (s, 1 H), 7.92 (s, 1 H), 7.82 (s, 1 H), 7.05 (s, 1 H), 4.74-4.60 (m, 1 H), 4.51 (tt, J=4.4, 11.5 Hz, 1 H), 4.14-4.00 (m, 1 H), 3.39-3.34 (m, 1 H), 3.05 (s, 3 H), 2.85 (td, J=3.0, 13.0 Hz, 1 H), 2.28-2.11 (m, 5 H), 2.11-1.89 (m, 2 H); MS (ESI): 374.11, 376.08 [M+H]+; HPLC tR=2.29 min (ZQ3, polar—4 min).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH3:7][O:8][CH2:9][CH2:10]OCC(O)=O>CN(C=O)C.C(Cl)Cl>[CH3:7][O:8][CH2:9][CH2:10][O:3][CH2:2][C:1]([Cl:6])=[O:5]
Reactant: COCCOCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCOCC(=O)Cl
Reaction time: 17 h

Procedure:
Under a nitrogen atmosphere, 2.56 ml (29.8 mmol) of oxalyl chloride and 2 drops of DMF are added to 1.69 ml (14.9 mmol) of 2-(2-methoxyethoxy)-acetic acid (Fluka; Buchs/Switzerland) in 75 ml of methylene chloride. After 17 h at RT, the reaction mixture is carefully concentrated by evaporation in a RE with the exclusion of moisture. A 1H-NMR spectrum of the residue exhibits the signals of the title compound in addition to signals of ≈40% solvent (especially methylene chloride): 1H-NMR (200 MHz, CDCl3): 3.37 (s, MeO), 3.58 and 3.77 (2d, J=5 Hz, CH2 --CH2), 4.48 (s, CH2). That mixture is used above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COc1ccc(N)cc1
Reactant: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(OC)cc3)nc21

Procedure:
A solution of 0.100 g (0.25 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 68 and 0.061 g (0.50 mmol) of 4-methoxyaniline in 0.5 mL of dimethylformamide was heated at reflux for 10 minutes. Three drops of water were added. Crystals separated on inducement. An additional 3 drops of water were added to precipitate additional tacky solid. After decantation, the solid was triturated with 0.5 mL of ethyl acetate and 0.5 mL of petroleum ether. The solids were filtered and washed with 50% ethyl acetate/petroleum ether and dried; wt 0.080 g. Purification was effected by filtering an ethyl acetate solution through a layer of silica gel. Concentration of the filtrate to 1 mL volume yielded pure crystalline product; wt 0.033 g; mp 213°-215° C.
Reaction SMILES: C[Mg]I.[Br:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Br:19])[CH:13]=3)[C:8](=O)[C:7]=2[CH:6]=1.[CH3:21]C(O)=O>C1COCC1.CCOC(C)=O>[Br:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Br:19])[CH:13]=3)[C:8](=[CH2:21])[C:7]=2[CH:6]=1
Reactant: O=c1c2ccc(Br)cc2oc2ccc(Br)cc12
Reactant: CC(=O)O
Agent: C[Mg]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1c2ccc(Br)cc2Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Referring to Scheme 10, methylmagnesium iodide (14.12 mL, 3 M in Et2O, 42.4 mmol) was added to a stirred solution of 2,6-dibromo-9H-xanthen-9-one (7-2) (10 g, 28.2 mmol) in THF (30 mL) at 0° C. The reaction mixture was allowed to warm up to rt and stirred for 2 h. The reaction mixture was cooled to 0° C. and quenched with saturated NH4Cl solution (250 mL) and stirred for 30 min. The volatiles were removed in vacuo. The residue was taken up in CHCl3 (200 mL), and the organic layer was separated and the aqueous phase was extracted with CHCl3 (2×200 mL) and combined organics was dried over MgSO4, filtered and solvents removed in vacuo to crude product (9.46 g). The crude reaction was taken up in EtOAc (200 mL) and AcOH was added (20 mL) and the reaction mixture was stirred at room temperature for 3 h, the volatiles removed in vacuo and the residue was precipitated from isohexanes to give 2,6-dibromo-9-methylene-9H-xanthene (9-1) (6.43 g, 64.7% yield).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH:21]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH:21]1([NH:27][C:28]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH3:19])[C:3]2=[O:20])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=NC1CCCCC1
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)NC2CCCCC2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and cyclohexylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p 287°-288° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:5])[CH3:2].N1C=CN=C1.[CH3:25][C:26]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])[CH3:27].Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:14]=[CH:15][C:16]([O:19][Si:29]([CH3:31])([CH3:30])[C:26]([CH3:28])([CH3:27])[CH3:25])=[CH:17][CH:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H](c2ccc(O)cc2)CC(=O)N1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1[C@@H](c2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC(=O)N1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
To a solution of (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-hydroxyphenyl)pyrrolidin-2-one (Intermediate W, 0.400 g, 1.53 mmol) in anhyd. DMF (1.5 mL) was added imidazole (0.240 g, 3.05 mmol), followed by TBDMSCl (0.250 g, 1.68 mmol) and the mixture stirred at room temperature for 18 h. The resulting mixture was poured into a 0.5N HCl solution and extracted with EtOAc. The combined organic layers were dried (MgsO4) and concentrated under reduced pressure give a clear oil which was purified by flash chromatography (gradient from 67% to 100% EtOAc/hex) to yield (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-[4-(1,1,2,2-tetramethyl-1-silapropoxy)-phenyl)pyrrolidin-2-one (512 mg, 89%) as a light yellow oil: 1H NMR (DMSO-d6) δ 0.13 (s, 6H), 0.75 (t, J=7.0 Hz, 3H), 0.91 (s, 9H), 0.24-0.70 (m, 5H), 3.55-3.76 (m, 2H), 3.88 (q, J=9.1 Hz, 1H), 4.43 (d, J=9.1 Hz, 1H), 6.75-6.79 (m, 2H), 7.07-7.13 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][CH:10]2C#N)=O)=[CH:5][CH:4]=1.F[B-](F)(F)F.[H+].[C:28]([C:34]([O:36][CH3:37])=[O:35])#[C:29][C:30]([O:32][CH3:33])=[O:31]>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[N:9]3[C:10]([S:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=43)=[C:29]([C:30]([O:32][CH3:33])=[O:31])[C:28]=2[C:34]([O:36][CH3:37])=[O:35])=[CH:20][CH:21]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3SC2C#N)cc1
Reactant: COC(=O)C#CC(=O)OC
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(=O)OC)c2sc3ccccc3n2c1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
To a solution of 3-(4-methoxybenzoyl)-2,3-dihydrobenzo[d]thiazole-2-carbonitrile (5.3 g, 17.9 mmol) in dichloromethane (50 mL) was added dropwise 5 mL of tetrafluoroboric acid (HBF4). The solution was stirred for 3 h at room temperature. The brown precipitates appeared were collected by filtration and the filter cake was washed with ether. The solid salt was added to a solution of dimethyl acetylenedicarboxylate (7.6 g, 54.0 mmol) in DMF (40 mL) and then warmed at 35° C. for 14 h. The reaction mixture was concentrated in vacuo and the residue was crystallized from methanol to give dimethyl 1-(4-methoxyphenyl)benzo[d]pyrrolo[2,1-b]thiazole-2,3-dicarboxylate 1.7 g (24%); mp 167-168° C. 1H NMR (DMSO-d6) δ 3.63 (3H, s, COOMe), 3.82 (3H, s, COOMe), 3.86 (3H, s, Me), 6.84-6.86 (1H, m, ArH), 7.12 (2H, d, J=8.4 Hz, 2×ArH), 7.28-7.32 (1H, m, ArH), 7.37-7.40 (1H, m, ArH), 7.48 (2H, d, J=8.4 Hz, 2×ArH), 8.03-8.05 (1H, m, ArH). Anal. Calcd. for (C21H17NO5S): C, 63.79; H, 4.33; N, 3.54; S, 8.11.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[C:11](=[CH:17][C:18]([O:20][CH3:21])=[O:19])[CH2:10][CH2:9]2.Cl>C(OCC)C>[CH3:1][C:12]1[C:13]2[C:8](=[CH:7][C:6]([O:5][CH3:4])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C=C1CCc2cc(OC)ccc2C1=O
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: COC(=O)Cc1ccc2cc(OC)ccc2c1C
Temperature: 180 °C
Reaction time: 1 h

Procedure:
To a mixture of 12 g. of methyl magnesium bromide and 200 ml. of diethyl ether, 25 g. of 6-methoxy-2-(methoxycarbonylmethylene)-1-tetralone are added. The alkylating mixture is refluxed for one hour after it has been allowed to stand for one hour; the mixture is made acidic to litmus by the addition of 1 N methanolic HCl, filtered, and evaporated. The residue, containing methyl 1-methyl-6-methoxy-3,4-dihydro-2-naphthylacetate, is added to 1 g. of 10% palladium-on-charcoal and the resulting mixture is heated to 180° C. for six hours. The mixture is cooled, diluted with 200 ml. of chloroform, filtered, and evaporated to yield methyl 1-methyl-6-methoxy-2-naphthylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[O:22]=[C:23]1[N:27]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][N:24]1[C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:34]([N:24]3[CH2:25][CH2:26][N:27]([CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[C:23]3=[O:22])=[O:35])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 118.9 %

Procedure:
A 0° C. mixture of Example A5 (1 g, 4.51 mmol) and pyridine (1.1 mL, 13.6 mmol) in DCM (25 mL) was treated with a solution of Example B2 (1.680 g, 7.22 mmol) in DCM (8 mL), warmed to RT and stirred 45 min. The mixture was concentrated to dryness, the residue treated with DCM and Et2O, sonicated and the resulting solid collected via filtration. The solid was dissolved in DCM, washed with water, the aqueous layer back-extracted with DCM (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (2.24 g, 119%) which was used without further purification. MS (ESI) m/z: 418.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:16].[I-].[CH3:25][N:26]1[C:34]2[C:29](=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:36][N+](C)(C)C)=[CH:27]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:36][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[N:26]([CH3:25])[CH:27]=2)[C:6]1=[O:16]
Reactant: COC(=O)[C@@H](C1CCCCC1)n1c(=O)[nH]c2ccccc2c1=O
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C1CCCCC1)n1c(=O)c2ccccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
To a mixture of (R)-cyclohexyl-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid methyl ester (100 mg, 0.32 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (160 mg, 0.47 mmol) in DMF (2.5 mL) is added potassium carbonate (K2CO3) (100 mg, 0.72 mmol). The mixture is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, dilute with EtOAc (50 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and concentrated. The resulting residue is triturated with EtOAc and hexanes to afford (R)-cyclohexyl-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-acetic acid methyl ester (124 mg, 94%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([OH:14])[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:22][CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][C:25]1=[O:33].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>C(C(C)=O)C(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([OH:14])[CH:8]1[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]2=[O:33])[CH2:10][CH2:9]1
Reactant: O=c1[nH]c2ccccc2n1CCBr
Reactant: OC(c1ccccc1)(c1ccccn1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCN1CCC(C(O)(c2ccccc2)c2ccccn2)CC1

Procedure:
2.5 g (10-2 mole) of 4-[(2-pyridinyl)(phenyl)hydroxymethyl]piperidine, 2.5 g (10-2 mole) of 1-(1-bromo-2-ethyl)-1,3-dihydro-2(2H)-benzimidazolone, 1.2 g of Na2CO3, one crystal of NaI and 75 ml of methyl isobutyl ketone are introduced into a round flask.