Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([F:30])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:26]2[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: O=C(NCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
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: [I-]
Solvent: COCCOC
Solvent: O
Product: O=C(NCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cc(F)cc(F)c2)cc1
Yield: 15.2 %

Procedure:
N-((5-Chloro-1H-indol-3-yl)methyl)-4-(3,5-difluorobenzyl)benzamide was prepared following method B starting from N-((5-Chloro-1H-indol-3-yl)methyl)-4-(chloromethyl)benzamide (0.080 g, 0.240 mmol), 3,5-difluorophenylboronic acid (0.041 g; 0.252 mmol); Tetrakis(triphenylphosphine)palladium(0) (0.014 g; 0.012 mmol), sodium carbonate (0.051 g; 0.480 mmol) and sodium iodide (0.109 g; 0.720 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.015 g (15%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)=[CH:5][CH:4]=[N:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[NH2:49][C@@H:50]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[C:70]([F:73])([F:72])[F:71])[CH2:51][N:52]1[C:60](=[O:61])[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53]1=[O:62]>C(Cl)Cl>[O:61]=[C:60]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:62])[N:52]1[CH2:51][C@@H:50]([NH:49][C:12]([C:9]1[CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[S:11][CH:10]=1)=[O:14])[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[C:70]([F:72])([F:71])[F:73]
Reactant: Cn1nccc1-c1cc(C(=O)O)cs1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cs1
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxylic acid (100 mg, 0.48 mmol), PyBrOP (270 mg, 0.58 mmol) and diisopropylethyl amine (420 μL, 2.4 mmol) in DCM (5 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (168 mg, 0.48 mmol)[from Preparation 5]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (74 mg, 28%) as a white solid: LC-MS (ES) m/z=539 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[C:8]([C:13]([O:15]CC2C=CC=CC=2)=[O:14])[N:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:6]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[C:8]([C:13]([OH:15])=[O:14])[N:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nn(-c2ccc(F)cc2)c(C(=O)OCc2ccccc2)c1C(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nn(-c2ccc(F)cc2)c(C(=O)O)c1C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid 5-benzyl ester 3-methyl ester (18.95 g, 47.8 mmol) in MeOH (300 mL) at 25° C. under N2 was added 10% Pd—C (700 mg; commercially available from Sigma Aldrich). The reaction vessel was evacuated and filled with H2 and then stirred at 25° C. for 3 hrs. Subsequently, the reaction vessel was flushed with N2 and filtered through a pad of celite. The filtrate was concentrated to afford 1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid 3-methyl ester (14.6g, 99%) in sufficient purity for use in the next step: H-NMR (CDCl3) δ 7.36-7.31 (m, 2 H), 7.11-7.06 (m, 2 H), 3.90 (s, 3 H), 3.86-3.82 (m, 1 H), 1.43 (d, 6 H).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].Cl.[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)=[CH:4][C:3]=2[N+:20]([O-:22])=[O:21])=[CH:27][CH:26]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 113.1 %

Procedure:
To a 250 mL round-bottomed flask were added a stir bar, 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (15.0 g, 40 mmol) and 4-bromobenzyl amine hydrochloride (11 g, 50 mmol), DMA (130 mL), and DIPEA (22 mL, 125 mmol). The resulting mixture was heated to 100° C. After 24 h, the mixture was cooled and concentrated to dryness. The residue was triturated with IPA (200 mL) and the orange solid was collected by vacuum filtration. The collected solid was washed with IPA (2×50 mL) and hexanes (2×50 mL) to afford the title compound (21 g, 84%). MS (ESI): mass calcd. for C23H18BrN3O3, 463.05; m/z found 464.1 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.34-8.27 (m, 1H), 8.21 (d, J=8.4, 1H), 8.12-8.06 (m, 1H), 7.87-7.81 (m, 2H), 7.75 (ddd, J=8.4, 6.9, 1.4, 1H), 7.63 (d, J=8.5, 1H), 7.58-7.53 (m, 1H), 7.49-7.46 (m, 2H), 7.25-7.18 (m, 3H), 6.71 (d, J=9.4, 1H), 5.34 (s, 2H), 4.49 (d, J=5.8, 2H).
Reaction SMILES: [C:1]([NH:11][C:12]1([CH2:15][OH:16])[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN(C(C)C)C(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[C:1]([NH:11][C:12]1([CH2:15][O:16][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:13][CH2:14]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1(CO)CC1)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
N—CBZ-amino-1-(hydroxymethyl)cyclopropane (similarly prepared according to JMC 31, 2004, 1998) (250 mg) was dissolved into DCM (25 ml) with DIPEA (250 l) and stirred at 0° C. for 15 minutes. To the reaction was added MsCl (1.1 eq) and stirred for 30 minutes. The reaction was washed with NaHCO3 solution, water, brine and dried with Na2SO4. The solution was evaporated to give N—CBZ-amino-1-(methylsulfonyloxymethyl)cyclopropane as an off white solid. This solid was mixed with above 6-(7-hydroxy-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide and Cs2CO3 (250 mg) in DMA (4 ml). The reaction was heated at 100° C. for 10 hours and mixed with EtOAc and water, then filtered, further extracted with EtOAc. The combined organic layer was evaporated and purified with silica gel column to give the titled product. Mass: (M+1), 578
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CO.Cl>C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(N1CCc2ccc(Cl)c(N3CCCC3c3ccccc3)c2CC1)C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Clc1ccc2c(c1N1CCCC1c1ccccc1)CCNCC2
Yield: 82 %

Procedure:
Treat (+/−)-7-chloro-3-(2,2,2-trifluoroacetyl)-6-(2-phenyl-pyrrolidin-1-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (prepared essentially as described in Preparation 38) (80 mg, 0.19 mmol) with basic methanol in a similar fashion to the isolated enantiomers of (+/−)-7-chloro-3-(2,2,2-trifluoroacetyl)-6-(2-phenyl-pyrrolidin-1-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. Treat the resultant residue with excess 2 N HCl in diethyl ether to give the product as a white solid (57 mg, 82%).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:17]>Cl>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][CH2:16][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:14]
Reactant: C=Cc1ccccn1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: [Na]
Product: CCOC(=O)C(CCc1ccccn1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.5 %

Procedure:
A sample of 120 g (0.62 mole) of ethyl benzoylacetate was added to 1.44 g (0.062 mole) of sodium and 32.8 g (0.31 mole) of 2-vinylpyridine added under an atmosphere of nitrogen. The mixture was heated with mechanical stirring on the steam bath for 17 h. After cooling the reaction mixture to room temperature, 100 mL of 3N hydrochloric acid was added, and the aqueous mixture washed with ether. The hydrochloric acid layer was made basic with 10% potassium carbonate solution, and extracted with ether. The ether layer was washed with brine, dried (MgSO4), and the ether evaporated in vacuo to give 83.4 g (90% yield) of the crude title compound as a red oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[N:11]([CH2:12][CH2:13][N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=3[N:8]=2)[CH2:2]1.[C:29]([O:33][C:34]([NH:36][C@H:37]([CH2:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=1)[CH2:38][C:39](O)=[O:40])=[O:35])([CH3:32])([CH3:31])[CH3:30].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:24]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[N:14]1[CH2:13][CH2:12][N:11]1[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=2[N:8]=[C:7]1[C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:39](=[O:40])[CH2:38][C@H:37]([NH:36][C:34](=[O:35])[O:33][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:42][C:43]2[CH:52]=[CH:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Reactant: O=C1c2ccccc2C(=O)N1CCn1c(C2CCCNC2)nc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCC[C@@H](c2nc3ccccc3n2CCN2C(=O)c3ccccc3C2=O)C1)Cc1ccc2ccccc2c1
Yield: 4 %

Procedure:
(R)-2-(2-(2-(piperidin-3-yl)-1H-benzo[d]imidazol-1-yflethypisoindoline-1,3-dione (129B) (500 mg of mixture) from previous step, was weighed into a 25 mL round-bottomed flask equipped for stirring under nitrogen. DMF (3 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (2.48 mmoles, 0.817 g) and N-methylmorpholine (7.44 mmoles, 0.818 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (2.73 mmoles, 1.04 g) was added and the resultant solution was stirred at room temperature for 3 hrs. The reaction solution was then directly purified by preparative LC/MS (35-95% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-4-((R)-3-(1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (129C) as a clear oil. (0.105 mmoles, 0.072 g, 4% yield over 2-steps). ESI-MS: m/z 686.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-:12].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:12][C:2]1[CH:10]=[CH:9][C:8]([C:4]([C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[Cl:1])=[O:5])=[CH:7][CH:3]=1
Reactant: Cc1ccc(Cl)c(C(=O)Cl)c1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1ccc(Cl)c(C(=O)c2ccc(Cl)cc2)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 157.5 %

Procedure:
A stirred solution of 2-chloro-5-methylbenzoyl chloride (9.41 g, 49.8 mmol) in chlorobenzene (14 ml) at 80° C. was treated with aluminum chloride (7.32 g, 54.9 mmol) in portions over 15 minutes. The mixture was stirred 15 hours at 80° C., cooled, quenched by addition of ice and concentrated hydrochloric acid (5.0 ml) and extracted with diethyl ether (2×50 ml). The combined extracts were washed with water, dried over anhydrous magnesium sulfate, and evaporated under vacuum. The residue was crystallized from n-hexane to provide 10.4 g (79%) of 3-(4-chlorobenzoyl)-4-chlorotoluene, m.p. 85°-90° C. Recrystallization raised the melting point to 90°-92° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1>>[OH:29][CH:26]1[CH2:27][CH2:28][N:23]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:24][CH2:25]1
Reactant: OC1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC(O)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with piperidin-4-ol (1.2 equiv) to give 166 (16.4 mg, M+1 397.1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[N:30]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[N:30]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1nccc(Br)n1
Product: Cc1nccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2-methylpyrimidine in Step 4. LC-MS Method 2 tR=1.159, m/z=450; 1H NMR (CDCl3) 1.33 (m, 3H), 1.52 (m, 3H), 1.63 (m, 3H), 1.80-1.95 (m, 2H), 2.15-2.30 (m, 3H), 2.75 (s, 3H), 2.90 (m, 1H), 3.51 (m, 2H), 5.68 (m, 1H), 6.99 (m, 4H), 7.20 (m, 2H), 7.41 (m, 1H), 7.79 (d, 2H), 8.60 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1)#[N:2].[CH3:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:19]([C:20](O)=[O:21])[C:18]=1[SH:26]>N1C=CC=CC=1>[CH3:16][C:17]1[C:18]2[S:26][C:1]([C:3]3[N:8]=[C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=3)=[N:2][C:20](=[O:21])[C:19]=2[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(C(=O)O)c1S
Reactant: CC(C)(C)OC(=O)c1cccc(C#N)n1
Solvent: c1ccncc1
Product: Cc1cccc2c(=O)nc(-c3cccc(C(=O)OC(C)(C)C)n3)sc12
Yield: 58.3 %

Procedure:
tert-Butyl 6-cyano-2-pyridinecarboxylate (3.2 g, 15 mmol) and 3-methylthiosalicylic acid (4.7 g, 28 mmol) were dissolved in pyridine (40 ml), and the mixture was refluxed for 16 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-tetrahydrofuran (2:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (3.1 g, 56%) as pale yellow crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.[NH2:20][C:21]1[C:26]([C:27]([C:29]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([F:37])[C:30]=2[F:38])=[O:28])=[CH:25][N:24]=[C:23](S(CC)(=O)=O)[N:22]=1.O>CN(C)C=O>[NH2:20][C:21]1[C:26]([C:27](=[O:28])[C:29]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([F:37])[C:30]=2[F:38])=[CH:25][N:24]=[C:23]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH2:4][CH2:3]2)[N:22]=1
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NS(C)(=O)=O)CC2)nc1N
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(4-amino-cyclohexyl)-methanesulfonamide, Example 122, (211 mg, 0.69 mmol) in dimethylformamide, triethylamine (40 μL, 2.87 mmol) and the compound of Example 103 (200mg, 0.57 mmol) were added and the mixture was stirred at 90° C. for 1 hour. Then the mixture was poured into water and extracted with ethyl acetate, dried (sodium sulfate) and concentrated. The residue was chromatographed to give the product. 185 mg, 71%. MS(ES) (M+H)+=456.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6](I)[CH:7]=1.[C:11]([O:14][CH2:15][C:16]1[C:17]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:18][CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1)(=[O:13])[CH3:12].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].O.C(#N)C>[C:11]([O:14][CH2:15][C:16]1[C:17]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:18][CH:19]=[CH:20][C:21]=1[C:6]1[CH:7]=[C:2]([Br:1])[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(I)cc(Br)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 30 °C
Reaction time: 3 h
Yield: 21.5 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 3-bromo-5-iodo-1-methylpyridin-2(1H)-one 214b (1.57 g, 5.0 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (1.98 g, 5.0 mmol), PdCl2(dppf) (205 mg, 0.25 mmol), K3PO4 (2.12 g, 10.0 mmol), sodium acetate (820 mg, 10.0 mmol), acetonitrile (45 mL), and water (1 mL). The system was evacuated and refilled with N2. The reaction mixture was stirred at 30° C. for 3 h. It was then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 273a (580 mg, 22%) as a white solid. MS-ESI: [M+H]+ 539.2. 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J=5.0 Hz, 1H), 7.84 (d, J=2.5 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.09 (d, J=5.0 Hz, 1H), 6.79 (s, 1H), 5.15 (s, 2H), 4.55-4.51 (m, 1H), 4.27-4.25 (m, 1H), 4.15-4.13 (m, 1H), 4.06-4.04 (m, 1H), 3.68 (s, 3H), 2.58-2.56 (m, 2H), 2.51 (s, 2H), 1.86 (s, 3H), 1.28 (s, 6H).
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:29])[C:10]([C:26]([OH:28])=[O:27])=[CH:11][N:12]3CC3C=CC(OC)=CC=3OC)=[C:7]([CH3:30])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.O>FC(F)(F)C(O)=O>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:29])[C:10]([C:26]([OH:28])=[O:27])=[CH:11][NH:12]3)=[C:7]([CH3:30])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2cc(C(=O)O)c(=O)c3c(C)cc(N4CCC4)nc32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(N2CCC2)nc2[nH]cc(C(=O)O)c(=O)c12

Procedure:
A solution of Example 18B (0.230 g) in trifluoroacetic acid (5.6 mL) was heated at 60° C. for 1.5 hours then cooled, poured into water, and filtered. NMR (300 MHz, DMSO-d6) δ 12.88 (m, 1H), 8.33 (m, 1H), 6.32 (m, 1H), 4.14 (m, 4H), 2.72 (s, 3H), 2.38 (m, 2H). (C(O)OH not observed).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C:11]([OH:27])([CH3:26])[CH2:12][N:13]([CH3:25])[C:14](=[O:24])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>O1CCOCC1>[CH3:25][N:13]([CH2:12][C:11]1([CH3:26])[O:27][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1)[C:14](=[O:24])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1
Reactant: CN(CC(C)(O)Cn1cc([N+](=O)[O-])nc1Cl)C(=O)OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(CC1(C)Cn2cc([N+](=O)[O-])nc2O1)C(=O)OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
4-Fluorobenzyl [3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-N-methylcarbamate prepared in Example 212 (1.683 g, 4.20 mmol) was dissolved in 1,4-dioxane (30 ml). To the solution, sodium hydride (0.185 g, 4.62 mmol) was added followed by stirring at room temperature for 1 hour and then stirred under reflux for 7 hours. The reaction mixture was concentrated under reduced pressure. To the residue, water was added, and the precipitates were filtered off and purified by silica gel column chromatography (n-hexane/acetone=2/1). The resulting solid was treated with a mixture of n-hexane and ethyl acetate to afford 4-fluorobenzyl N-methyl-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)carbamate (0.381 g, yield 25%) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1>[CH2:9]([C:2]1([CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[O:13][CH2:12][CH2:11][O:1]1)[CH3:10]
Reactant: OCCO
Reactant: CCC(=O)CCC(=O)OC
Solvent: Cc1ccccc1
Product: CCC1(CCC(=O)OC)OCCO1
Yield: 94.1 %

Procedure:
To a stirring solution of 4.05 g (28 mmol) of methyl 4-oxohexanoate (16), prepared as described above in Example 16, in 200 mL of toluene and 0.53 g (2.8 mmol) of tosyl acid was added 5.59 g (90 mmol) of ethylene glycol. After refluxing for 2 hours using a Dean-Stark trap, the solvent was removed under vacuum. The resulting orange oil was dissolved in 200 mL of EtOAc. The EtOAc was then washed with 2×200 mL of H2O. The organic layer was then dried over Na2SO4 anhydrous, filtered, and concentrated in vacuo to yield 4.96 g (94%) of methyl 2-ethyl-1,3-dioxolane-2-propanoate (17), which was employed immediately in Example 18 below.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:13]1[CH:14]=[C:15]([CH3:20])[C:16]([CH3:19])=[CH:17][CH:18]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)[CH:3]=1
Reactant: Cc1ccc(Br)cc1C
Reactant: Clc1ccnc2ccccc12
Product: Cc1ccc(-c2cc(Cl)c3ccccc3n2)cc1C

Procedure:
The title compound, MS: m/e=267 (M+), was prepared from 4-chloro-quinoline and 4-bromo-o-xylene.
Reaction SMILES: [F:1]/[C:2](=[C:8](/[C:10]1[CH:19]=[C:18]2[C:13]([C:14]([CH3:25])([CH3:24])[CH2:15][CH:16]=[C:17]2[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:12][C:11]=1[O:26][CH2:27][CH2:28][CH3:29])\[CH3:9])/[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[F:1]/[C:2](=[C:8](/[C:10]1[CH:19]=[C:18]2[C:13]([C:14]([CH3:25])([CH3:24])[CH2:15][CH:16]=[C:17]2[C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:12][C:11]=1[O:26][CH2:27][CH2:28][CH3:29])\[CH3:9])/[CH2:3][OH:4]
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)C(=O)OCC)C(C(C)(C)C)=CCC2(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)(C)C)=CCC2(C)C

Procedure:
As described in General Procedure G-1, ethyl (2E)-2-fluoro-3-(4,4 dimethyl-6-n-propoxy-1-tert-butyl-3,4-dihydronaphthalen-7-yl)-2-butenoate (Compound A-48, 0.044 g, 0.109 mmol) and diisobutylaluminum hydride (1.0 M in hexanes, 0.87 mL, 0.87 mmol) were reacted in THF (0.87 mL) to produce the title compound as an oil.